Category Archives: Chemotherapy

A2058, Akt, anti-carcinogenic, anti-inflammatory, Anti-metastatic, anti-mitogenic, anti-oxidant, anti-proliferative, apoptosis, Apoptotic, Breast cancer, Breast cancer cell lines, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemotherapy, Cytostatic, cytotoxic, EMT, ER, FAK, honeybee hives, Immune, Immunomodulatory, inflammation, inhibits NF-κB, JNK, Lung cancer, MAPK, MCF-7/Adr, MCF-7/wt, Mcl-1, Melanoma, Oral cancer, p38, p65, PANC-1, Pancreatic cancer, Prostate cancer, ROS, S, SCC-9, TIMP-2, TNF, Twist

Caffeic acid phenethyl ester (CAPE)

Cancer:
Breast, prostate, leukemia, cervical., oral., melanoma

Action: EMT, anti-mitogenic, anti-carcinogenic, anti-inflammatory, immunomodulatory

Anti-mitogenic, Anti-carcinogenic, Anti-inflammatory, Immunomodulatory Properties

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory properties. A variety of in vitro pharmacology for CAPE has been reported. A study using CAPE showed a positive effect on reducing carcinogenic incidence. It is known to have anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory properties in vitro (Orban et al., 2000) Another study also showed that CAPE suppresses acute immune and inflammatory responses and holds promise for therapeutic uses to reduce inflammation (Huang et al., 1996).

Caffeic acid phenethyl ester (CAPE) specifically inhibits NF-κB at µM concentrations and shows ability to stop 5-lipoxygenase-catalyzed oxygenation of linoleic acid and arachidonic acid. Previous studies have demonstrated that CAPE exhibits anti-oxidant, anti-inflammatory, anti-proliferative, cytostatic, anti-viral., anti-bacterial., anti-fungal., and, most importantly, anti-neoplastic properties (Akyol et al., 2013).

Multiple Immunomodulatory and Anti-inflammatory Activities

The results show that the activation of NF-kappa B by tumor necrosis factor (TNF) is completely blocked by CAPE in a dose- and time-dependent manner. Besides TNF, CAPE also inhibited NF-kappa B activation induced by other inflammatory agents including phorbol ester, ceramide, hydrogen peroxide, and okadaic acid. Since the reducing agents reversed the inhibitory effect of CAPE, it suggests the role of critical sulfhydryl groups in NF-kappa B activation. CAPE prevented the translocation of the p65 subunit of NF-kappa B to the nucleus and had no significant effect on TNF-induced I kappa B alpha degradation, but did delay I kappa B alpha resynthesis. When various synthetic structural analogues of CAPE were examined, it was found that a bicyclic, rotationally constrained, 5,6-dihydroxy form was superactive, whereas 6,7-dihydroxy variant was least active.

Thus, overall our results demonstrate that CAPE is a potent and a specific inhibitor of NF-kappa B activation and this may provide the molecular basis for its multiple immunomodulatory and anti-inflammatory activities (Natarajan et al., 1996).

Breast Cancer

Aqueous extracts from Thymus serpyllum (ExTs), Thymus vulgaris (ExTv), Majorana hortensis (ExMh), and Mentha piperita (ExMp), and the phenolic compounds caffeic acid (CA), rosmarinic acid (RA), lithospermic acid (LA), luteolin-7-O-glucuronide (Lgr), luteolin-7-O-rutinoside (Lr), eriodictiol-7-O-rutinoside (Er), and arbutin (Ab), were tested on two human breast cancer cell lines: Adriamycin-resistant MCF-7/Adr and wild-type MCF-7/wt.

ExMh showed the highest cytotoxicity, especially against MCF-7/Adr, whereas ExMp was the least toxic; particularly against MCF-7/wt cells. RA and LA exhibited the strongest cytotoxicity against both MCF-7 cell lines, over 2-fold greater than CA and Lgr, around 3-fold greater than Er, and around 4- to 7-fold in comparison with Lr and Ab. Except for Lr and Ab, all other phytochemicals were more toxic against MCF-7/wt, and all extracts exhibited higher toxicity against MCF-7/Adr. It might be concluded that the tested phenolics exhibited more beneficial properties when they were applied in the form of extracts comprising their mixtures (Berdowska et al., 2013).

Prostate Cancer

Evidence is growing for the beneficial role of selective estrogen receptor modulators (SERM) in prostate diseases. Caffeic acid phenethyl ester (CAPE) is a promising component of propolis that possesses SERM activity. CAPE-induced inhibition of AKT phosphorylation was more prominent (1.7-folds higher) in cells expressing ER-α such as PC-3 compared to LNCaP. In conclusion, CAPE enhances the anti-proliferative and cytotoxic effects of DOC and PTX in prostate cancer cells (Tolba et al., 2013).

EMT, Prostate Cancer

CAPE suppressed the expression of Twist 2 and growth of PANC-1 xenografts without significant toxicity. CAPE could inhibit the orthotopic growth and EMT of pancreatic cancer PANC-1 cells accompanied by down-regulation of vimentin and Twist 2 expression (Chen et al., 2013).

CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells (Lin et al., 2013). Combined treatments of CAPE with chemotherapeutic drugs exhibit synergistic suppression effects. Pharmacokinetic studies suggest that intraperitoneal injection of CAPE at concentration of 10mg/kg is not toxic. CAPE treatment sensitizes cancer cells to chemotherapy and radiation treatments. In addition, CAPE treatment protects therapy-associated toxicities (Liu et al., 2013).

Cervical Cancer

CAPE preferentially induced S- and G2 /M-phase cell-cycle arrests and initiated apoptosis in human cervical cancer lines. The effect was found to be associated with increased expression of E2F-1, as there is no CAPE-mediated induction of E2F-1 in the pre-cancerous cervical Z172 cells. CAPE also up-regulated the E2F-1 target genes cyclin A, cyclin E and apoptotic protease activating of factor 1 (Apaf-1) but down-regulated cyclin B and induced myeloid leukemia cell differentiation protein (Mcl-1) (Hsu et al., 2013).

Oral Cancer

CAPE attenuated SCC-9 oral cancer cells migration and invasion at noncytotoxic concentrations (0  µM to 40 µM). CAPE exerted its inhibitory effects on MMP-2 expression and activity by upregulating tissue inhibitor of metalloproteinase-2 (TIMP-2) and potently decreased migration by reducing focal adhesion kinase (FAK) phosphorylation and the activation of its downstream signaling molecules p38/MAPK and JNK (Peng et al., 2012).

Melanoma

CAPE is suggested to suppress reactive-oxygen species (ROS)-induced DNA strand breakage in human melanoma A2058 cells when compared to other potential protective agents. CAPE can be applied not only as a chemo-preventive agent but also as an anti-metastatic therapeutic agent in lung cancer and because CAPE is a nuclear factor-κB (NF-κB) inhibitor and 5α reductase inhibitor, it has potential for the treatment of prostate cancer (Ozturk et al., 2012).

References

Akyol S, Ozturk G, Ginis Z, et al. (2013). In vivo and in vitro antõneoplastic actions of caffeic acid phenethyl ester (CAPE): therapeutic perspectives. Nutr Cancer, 65(4):515-26. doi: 10.1080/01635581.2013.776693.


Berdowska I, Ziel iński B, Fecka I, et al. (2013). Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells. Food Chem, 15;141(2):1313-21. doi: 10.1016/j.foodchem.2013.03.090.


Chen MJ, Shih SC, Wang HY, et al. (2013). Caffeic Acid phenethyl ester inhibits epithelial-mesenchymal transition of human pancreatic cancer cells. Evid Based Complement Alternat Med, 2013:270906. doi: 10.1155/2013/270906.


Hsu TH, Chu CC, Hung MW, et al. (2013). Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells. FEBS J, 280(11):2581-93. doi: 10.1111/febs.12242.


Huang MT, Ma W, Yen P, et al. (1996). Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis, 17(4):761–5. doi:10.1093/carcin/17.4.761.


Lin HP, Lin CY, Liu CC, et al. (2013). Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling. Int J Mol Sci, 14(3):5264-83. doi: 10.3390/ijms14035264.


Liu CC, Hsu JM, Kuo LK, et al. (2013). Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer. Med Hypotheses, 80(5):617-9. doi: 10.1016/j.mehy.2013.02.003.


Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB. (1996). Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA, 93(17):9090-5.


Orban Z, Mitsiades N, Burke TR, Tsokos M, Chrousos GP. (2000). Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation, 7(2): 99–105. doi:10.1159/000026427.


Ozturk G, Ginis Z, Akyol S, et al. (2012). The anti-cancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers. Eur Rev Med Pharmacol Sci, 16(15):2064-8.


Peng CY, Yang HW, Chu YH, et al. (2012). Caffeic Acid phenethyl ester inhibits oral cancer cell metastasis by regulating matrix metalloproteinase-2 and the mitogen-activated protein kinase pathway. Evid Based Complement Alternat Med, 2012:732578. doi: 10.1155/2012/732578.


Tolba MF, Esmat A, Al-Abd AM, et al. (2013). Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells. IUBMB Life, 65(8):716-29. doi: 10.1002/iub.1188.

A549 cells, angiogenesis, Anti-angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BAX, Bcl-2, Bcl-xL, c-Jun, CAM, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemotherapy, cytotoxic, DUBs, G0/G1, G1, G1/S, Glioblastoma, growth-inhibitory, HT-29, IL-2, Immune, induces apoptosis, Ki-67, Leukemia, Lung cancer, MAPK, Mcl-1, Medulloblastoma, Melanoma, metastasis, Neuroblastoma, Nitric Oxide, Ovarian cancer, p21, p38, p53, Pancreatic cancer, Pro-apoptotic, Prostate cancer, radiotherapy, Rectal cancer, Rhabdomyosarcoma, ROS, Sarcoma, SK-N-AS, TNF, VEGF, VEGF

Betulin and Betulinic acid

Cancer:
Neuroblastoma, medulloblastoma, glioblastoma, colon, lung, oesophageal, leukemia, melanoma, pancreatic, prostate, breast, head & neck, myeloma, nasopharyngeal, cervical, ovarian, esophageal squamous carcinoma

Action: Anti-angiogenic effects, induces apoptosis, anti-oxidant, cytotoxic and immunomodifying activities

Betulin is a naturally occurring pentacyclic triterpene found in many plant species including, among others, in Betula platyphylla (white birch tree), Betula X caerulea [Blanch. (pro sp.)], Betula cordifolia (Regel), Betula papyrifera (Marsh.), Betula populifolia (Marsh.) and Dillenia indica L . It has anti-retroviral., anti-malarial., and anti-inflammatory properties, as well as a more recently discovered potential as an anti-cancer agent, by inhibition of topoisomerase (Chowdhury et al., 2002).

Betulin is found in the bark of several species of plants, principally the white birch (Betula pubescens ) (Tan et al., 2003) from which it gets its name, but also the ber tree (Ziziphus mauritiana ), selfheal (Prunella vulgaris ), the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus, Diospyros leucomelas , a member of the persimmon family, Tetracera boiviniana , the jambul (Syzygium formosanum ) (Zuco et al., 2002), flowering quince (Chaenomeles sinensis ) (Gao et al., 2003), rosemary (Abe et al., 2002) and Pulsatilla chinensis (Ji et al., 2002).

Anti-cancer, Induces Apoptosis

The in vitro characterization of the anti-cancer activity of betulin in a range of human tumor cell lines (neuroblastoma, rhabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukaemia and multiple myeloma), and in primary tumor cultures isolated from patients (ovarian carcinoma, cervical carcinoma and glioblastoma multiforme) was carried out to probe its anti-cancer effect. The remarkable anti-proliferative effect of betulin in all tested tumor cell cultures was demonstrated. Furthermore, betulin altered tumor cell morphology, decreased their motility and induced apoptotic cell death. These findings demonstrate the anti-cancer potential of betulin and suggest that it may be applied as an adjunctive measure in cancer treatment (Rzeski, 2009).

Lung Cancer

Betulin has also shown anti-cancer activity on human lung cancer A549 cells by inducing apoptosis and changes in protein expression profiles. Differentially expressed proteins explained the cytotoxicity of betulin against human lung cancer A549 cells, and the proteomic approach was thus shown to be a potential tool for understanding the pharmacological activities of pharmacophores (Pyo, 2009).

Esophageal Squamous Carcinoma

The anti-tumor activity of betulin was investigated in EC109 cells. With the increasing doses of betulin, the inhibition rate of EC109 cell growth was increased, and their morphological characteristics were changed significantly. The inhibition rate showed dose-dependent relation.

Leukemia

Betulin hence showed potent inhibiting effects on EC109 cells growth in vitro (Cai, 2006).

A major compound of the methanolic extract of Dillenia indica L. fruits, betulinic acid, showed significant anti-leukaemic activity in human leukaemic cell lines U937, HL60 and K562 (Kumar, 2009).

Betulinic acid effectively induces apoptosis in neuroectodermal and epithelial tumor cells and exerts little toxicity in animal trials. It has been shown that betulinic acid induced marked apoptosis in 65% of primary pediatric acute leukemia cells and all leukemia cell lines tested. When compared for in vitro efficiency with conventionally used cytotoxic drugs, betulinic acid was more potent than nine out of 10 standard therapeutics and especially efficient in tumor relapse. In isolated mitochondria, betulinic acid induced release of both cytochrome c and Smac. Taken together, these results indicated that betulinic acid potently induces apoptosis in leukemia cells and should be further evaluated as a future drug to treat leukemia (Ehrhardt, 2009).

Multiple Myeloma

The effect of betulinic acid on the induction apoptosis of human multiple myeloma RPMI-8226 cell line was investigated. The results showed that within a certain concentration range (0, 5, 10, 15, 20 microg/ml), IC50 of betulinic acid to RPMI-8226 at 24 hours was 10.156+/-0.659 microg/ml, while the IC50 at 48 hours was 5.434+/-0.212 microg/ml, and its inhibiting effect on proliferation of RPMI-8226 showed both a time-and dose-dependent manner.

It is therefore concluded that betulinic acid can induce apoptosis of RPMI-8226 within a certain range of concentration in a time- and dose-dependent manner. This phenomenon may be related to the transcriptional level increase of caspase 3 gene and decrease of bcl-xl. Betulinic acid also affects G1/S in cell-cycle which arrests cells at phase G0/G1 (Cheng, 2009).

Anti-angiogenic Effects, Colorectal Cancer

Betulinic acid isolated from Syzygium campanulatum Korth (Myrtaceae) was found to have anti-angiogenic effects on rat aortic rings, matrigel tube formation, cell proliferation and migration, and expression of vascular endothelial growth factor (VEGF). The anti-tumor effect was studied using a subcutaneous tumor model of HCT 116 colorectal carcinoma cells established in nude mice. Anti-angiogenesis studies showed potent inhibition of microvessels outgrowth in rat aortic rings, and studies on normal and cancer cells did not show any significant cytotoxic effect.

In vivo anti-angiogenic study showed inhibition of new blood vessels in chicken embryo chorioallantoic membrane (CAM), and in vivo anti-tumor study showed significant inhibition of tumor growth due to reduction of intratumor blood vessels and induction of cell death. Collectively, these results indicate betulinic acid as an anti-angiogenic and anti-tumor candidate (Aisha, 2013).

Nasopharyngeal Carcinoma Melanoma, Leukemia, Lung, Colon, Breast,Prostate, Ovarian Cancer

Betulinic acid is an effective and potential anti-cancer chemical derived from plants. Betulinic acid can kill a broad range of tumor cell lines, but has no effect on untransformed cells. The chemical also kills melanoma, leukemia, lung, colon, breast, prostate and ovarian cancer cells via induction of apoptosis, which depends on caspase activation. However, no reports are yet available about the effects of betulinic acid on nasopharyngeal carcinoma (NPC), a widely spread malignancy in the world, especially in East Asia.

In a study, Liu & Luo (2012) showed that betulinic acid can effectively kill CNE2 cells, a cell line derived from NPC. Betulinic acid-induced CNE2 apoptosis was characterized by typical apoptosis hallmarks: caspase activation, DNA fragmentation, and cytochrome c release.

These observations suggest that betulinic acid may serve as a potent and effective anti-cancer agent in NPC treatment. Further exploration of the mechanism of action of betulinic acid could yield novel breakthroughs in anti-cancer drug discovery.

Cervical Carcinoma

Betulinic acid has shown anti-tumor activity in some cell lines in previous studies. Its anti-tumor effect and possible mechanisms were investigated in cervical carcinoma U14 tumor-bearing mice. The results showed that betulinic acid (100 mg/kg and 200 mg/kg) effectively suppressed tumor growth in vivo. Compared with the control group, betulinic acid significantly improved the levels of IL-2 and TNF-alpha in tumor-bearing mice and increased the number of CD4+ lymphocytes subsets, as well as the ratio of CD4+/CD8+ at a dose of 200 mg/kg.

Furthermore, treatment with betulinic acid induced cell apoptosis in a dose-dependent manner in tumor-bearing mice, and inhibited the expression of Bcl-2 and Ki-67 protein while upregulating the expression of caspase-8 protein. The mechanisms by which BetA exerted anti-tumor effects might involve the induction of tumor cell apoptosis. This process is also related to improvement in the body's immune response (Wang, 2012).

Anti-oxidant, Cytotoxic and Immunomodifying Activities

Betulinic acid exerted cytotoxic activity through dose-dependent impairment of viability and mitochondrial activity of rat insulinoma m5F (RINm5F) cells. Decrease of RINm5F viability was mediated by nitric oxide (NO)-induced apoptosis. Betulinic acid also potentiated NO and TNF-α release from macrophages therefore enhancing their cytocidal action. The rosemary extract developed more pronounced anti-oxidant, cytotoxic and immunomodifying activities, probably due to the presence of betulinic acid (Kontogianni, 2013).

Pancreatic Cancer

Lamin B1 is a novel therapeutic target of Betulinic Acid in pancreatic cancer. The role and regulation of lamin B1 (LMNB1) expression in human pancreatic cancer pathogenesis and betulinic acid-based therapy was investigated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Elevation of circulating LMNB1 marker in plasma could detect early stages of HCC patients, with 76% sensitivity and 82% specificity. Lamin B1 is a clinically useful biomarker for early stages of HCC in tumor tissues and plasma (Sun, 2010).

It was found that lamin B1 was significantly down-regulated by BA treatment in pancreatic cancer in both in vitro culture and xenograft models. Overexpression of lamin B1 was pronounced in human pancreatic cancer and increased lamin B1 expression was directly associated with low grade differentiation, increased incidence of distant metastasis and poor prognosis of pancreatic cancer patients.

Furthermore, knockdown of lamin B1 significantly attenuated the proliferation, invasion and tumorigenicity of pancreatic cancer cells. Lamin B1 hence plays an important role in pancreatic cancer pathogenesis and is a novel therapeutic target of betulinic acid treatment (Li, 2013).

Multiple Myeloma, Prostate Cancer

The inhibition of the ubiquitin-proteasome system (UPS) of protein degradation is a valid anti-cancer strategy and has led to the approval of bortezomib for the treatment of multiple myeloma. However, the alternative approach of enhancing the degradation of oncoproteins that are frequently overexpressed in cancers is less developed. Betulinic acid (BA) is a plant-derived small molecule that can increase apoptosis specifically in cancer but not in normal cells, making it an attractive anti-cancer agent.

Results in prostate cancer suggest that BA inhibits multiple deubiquitinases (DUBs), which results in the accumulation of poly-ubiquitinated proteins, decreased levels of oncoproteins, and increased apoptotic cell death. In the TRAMP transgenic mouse model of prostate cancer, treatment with BA (10 mg/kg) inhibited primary tumors, increased apoptosis, decreased angiogenesis and proliferation, and lowered androgen receptor and cyclin D1 protein.

BA treatment also inhibited DUB activity and increased ubiquitinated proteins in TRAMP prostate cancer but had no effect on apoptosis or ubiquitination in normal mouse tissues. Overall, this data suggests that BA-mediated inhibition of DUBs and induction of apoptotic cell death specifically in prostate cancer but not in normal cells and tissues may provide an effective non-toxic and clinically selective agent for chemotherapy (Reiner, 2013).

Melanoma

Betulinic acid was recently described as a melanoma-specific inducer of apoptosis, and it was investigated for its comparable efficacy against metastatic tumors and those in which metastatic ability and 92-kD gelatinase activity had been decreased by introduction of a normal chromosome 6. Human metastatic C8161 melanoma cells showed greater DNA fragmentation and growth arrest and earlier loss of viability in response to betulinic acid than their non-metastatic C8161/neo 6.3 counterpart.

These effects involved induction of p53 without activation of p21WAF1 and were synergized by bromodeoxyuridine in metastatic Mel Juso, with no comparable responses in non-metastatic Mel Juso/neo 6 cells. These data suggest that betulinic acid exerts its inhibitory effect partly by increasing p53 without a comparable effect on p21WAF1 (Rieber, 1998).

As a result of bioassay–guided fractionation, betulinic acid has been identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumor growth was completely inhibited without toxicity. As judged by a variety of cellular responses, anti-tumor activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preclinical development for the treatment or prevention of malignant melanoma (Pisha, 1995).

Betulinic acid strongly and consistently suppressed the growth and colony-forming ability of all human melanoma cell lines investigated. In combination with ionizing radiation the effect of betulinic acid on growth inhibition was additive in colony-forming assays.

Betulinic acid also induced apoptosis in human melanoma cells as demonstrated by Annexin V binding and by the emergence of cells with apoptotic morphology. The growth-inhibitory action of betulinic acid was more pronounced in human melanoma cell lines than in normal human melanocytes.

The properties of betulinic acid make it an interesting candidate, not only as a single agent but also in combination with radiotherapy. It is therefore concluded that the strictly additive mode of growth inhibition in combination with irradiation suggests that the two treatment modalities may function by inducing different cell death pathways or by affecting different target cell populations (Selzer, 2000).

Betulinic acid has been demonstrated to induce programmed cell death with melanoma and certain neuroectodermal tumor cells. It has been demonstrated currently that the treatment of cultured UISO-Mel-1 (human melanoma cells) with betulinic acid leads to the activation of p38 and stress activated protein kinase/c-Jun NH2-terminal kinase (a widely accepted pro-apoptotic mitogen-activated protein kinases (MAPKs)) with no change in the phosphorylation of extracellular signal-regulated kinases (anti-apoptotic MAPK). Moreover, these results support a link between the MAPKs and reactive oxygen species (ROS).

These data provide additional insight in regard to the mechanism by which betulinic acid induces programmed cell death in cultured human melanoma cells, and it likely that similar responses contribute to the anti-tumor effect mediated with human melanoma carried in athymic mice (Tan, 2003).

Glioma

Betulinic acid triggers apoptosis in five human glioma cell lines. Betulinic acid-induced apoptosis requires new protein, but not RNA, synthesis, is independent of p53, and results in p21 protein accumulation in the absence of a cell-cycle arrest. Betulinic acid-induced apoptosis involves the activation of caspases that cleave poly(ADP ribose)polymerase.

Betulinic acid induces the formation of reactive oxygen species that are essential for BA-triggered cell death. The generation of reactive oxygen species is blocked by BCL-2 and requires new protein synthesis but is unaffected by caspase inhibitors, suggesting that betulinic acid toxicity sequentially involves new protein synthesis, formation of reactive oxygen species, and activation of crm-A-insensitive caspases (Wolfgang, 1999).

Head and Neck Carcinoma

In two head and neck squamous carcinoma (HNSCC) cell lines betulinic acid induced apoptosis, which was characterized by a dose-dependent reduction in cell numbers, emergence of apoptotic cells, and an increase in caspase activity. Western blot analysis of the expression of various Bcl-2 family members in betulinic acid–treated cells showed, surprisingly, a suppression of the expression of the pro-apoptotic protein Bax but no changes in Mcl-1 or Bcl-2 expression.

These data clearly demonstrate for the first time that betulinic acid has apoptotic activity against HNSCC cells (Thurnher et al., 2003).

References

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Aisha AF, Ismail Z, Abu-Salah KM, et al. (2013). Syzygium campanulatum korth methanolic extract inhibits angiogenesis and tumor growth in nude mice. BMC Complement Altern Med,13:168. doi: 10.1186/1472-6882-13-168.


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Ehrhardt H, Fulda S, FŸhrer M, Debatin KM & Jeremias I. (2004). Betulinic acid-induced apoptosis in leukemia cells. Leukemia, 18:1406–1412. doi:10.1038/sj.leu.2403406


Gao H, Wu L, Kuroyanagi M, et al. (2003). Anti-tumor-promoting constituents from Chaenomeles sinensis KOEHNE and their activities in JB6 mouse epidermal cells. Chemical & Pharmaceutical Bulletin, 51(11):1318–21. doi:10.1248/cpb.51.1318. PMID 14600382.


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A375 and Hs294, A431, angiogenesis, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, anti-oxidant, anti-oxidative, anti-proliferative, anti-proliferative effect, apoptosis, apoptosis induction, Apoptotic, Autophagy, BAX, Bcl-2, Bcl-xL, BCRP/ABCG2, Berberis amurensis, BIU-87 and T24, Breast cancer, Breast cancer cell lines, CDK, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-enhancing, chemo-preventive, Chemo-preventive agent, Chemoprevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, cytotoxic, Diarrhea or Constipation, ER, ER-negative, ER-positive, FAK, G0/G1, G1, growth-inhibitory, hepato-protective, HIF, HL-60, inflammation, Leukemia, Liver cancer, LNCaP, DU145, PC-3, Lymphoma, MCF-7, MCF-7, MDA-MB-231, Melanoma, metastasis, Nitric Oxide, OVCAR-3, SKOV-3, PARP, PC3, PGE2, Pro-apoptotic, Prostate cancer, Radio-sensitizer, radiotherapy, ROS, SiHa and CaSki, Skin cancer, T98G, type, u-PA, VEGF, VEGF

Berberine

Cancer:
Liver,leukemia, breast, prostate, epidermoid (squamous-cell carcinoma), cervical.,testicular, melanoma, lymphoma, hepatoma

Action: Radio-sensitizer, anti-inflammatory, cell-cycle arrest, angiogenesis, chemo-enhancing, anti-metastatic, anti-oxidative

Berberine is a major phytochemical component of the roots and bark of herbal plants such as Berberis, Hydrastis canadensis and Coptis chinensis. It has been implicated in the cytotoxic effects on multiple cancer cell lines.

Anti-inflammatory

Berberine is an isoquinoline alkaloid widely distributed in natural herbs, including Rhizoma Coptidis chinensis and Epimedium sagittatum (Sieb. et Zucc.), a widely prescribed Chinese herb (Chen et al., 2008). It has a broad range of bioactivities, such as anti-inflammatory, anti-bacterial., anti-diabetes, anti-ulcer, sedation, protection of myocardial ischemia-reperfusion injury, expansion of blood vessels, inhibition of platelet aggregation, hepato-protective, and neuroprotective effects (Lau et al., 2001; Yu et al., 2005; Kulkarni & Dhir, 2010; Han et al., 2011; Ji, 2011). Berberine has been used in the treatment of diarrhea, neurasthenia, arrhythmia, diabetes, and so forth (Ji, 2011).

Angiogenesis, Chemo-enhancing

Inhibition of tumor invasion and metastasis is an important aspect of berberine's anti-cancer activities (Tang et al., 2009; Ho et al., 2009). A few studies have reported berberine's inhibition of tumor angiogenesis (Jie et al., 2011; Hamsa & Kuttan, 2012). In addition, its combination with chemotherapeutic drugs or irradiation could enhance the therapeutic effects (Youn et al., 2008; Hur et al., 2009).

Cell-cycle Arrest

The potential molecular targets and mechanisms of berberine are rather complicated. Berberine interacts with DNA or RNA to form a berberine-DNA or a berberine-RNA complex, respectively (Islam & Kumar. 2009; Li et al., 2012). Berberine is also identified as an inhibitor of several enzymes, such as N-acetyltransferase (NAT), cyclooxygenase-2 (COX-2), and telomerase (Sun et al., 2009).

Other mechanisms of berberine are mainly related to its effect on cell-cycle arrest and apoptosis, including regulation of cyclin-dependent kinase (CDK) family of proteins (Sun et al., 2009; Mantena, Sharma, & Katiyar, 2006) and expression regulation of B-cell lymphoma 2 (Bcl-2) family of proteins (such as Bax, Bcl-2, and Bcl-xL) (Sun et al., 2009), and caspases (Eom et al., 2010; Mantena, Sharma, & Katiyar, 2006). Furthermore, berberine inhibits the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and induces the formation of intracellular reactive oxygen species (ROS) in cancer cells (Sun et al., 2009; Eom et al., 2010). Interestingly, these effects might be specific for cancer cells (Sun et al., 2009).

Several studies have shown that berberine has anti-cancer potential by interfering with the multiple aspects of tumorigenesis and tumor progression in both in vitro and in vivo experiments. These observations have been well summarized in recent reports (Sun et al., 2009; Tan et al., 2011). Berberine inhibits the proliferation of multiple cancer cell lines by inducing cell-cycle arrest at the G1 or G 2 / M phases and by apoptosis (Sun et al., 2009; Eom et al., 2010; Burgeiro et al., 2011). In addition, berberine induces endoplasmic reticulum stress (Chang et al., 1990; Eom et al., 2010) and autophagy (Wang et al., 2010) in cancer cells.

However, compared with clinically prescribed anti-cancer drugs, the cytotoxic potency of berberine is much lower, with an IC50 generally at 10 µM to 100 µM depending on the cell type and treatment duration in vitro (Sun et al., 2009). Besides, berberine also induces morphologic differentiation in human teratocarcinoma (testes) cells (Chang et al., 1990).

Anti-metastatic

The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-κB, urokinase-type plasminogen-activator (u-PA), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP-9) (Ho et al., 2009; Hamsa & Kuttan. (2011); reduction of Rho kinase-mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-2, prostaglandin E, and prostaglandin E receptors (Singh et al., 2011); down-regulation of hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), pro-inflammatory mediators (Jie et al., 2011; Hamsa & Kuttan, 2012).

Hepatoma, Leukaemia

The cytotoxic effects of Coptis chinensis extracts and their major constituents on hepatoma and leukaemia cells in vitro have been investigated. Four human liver cancer cell lines, namely HepG2, Hep3B, SK-Hep1 and PLC/PRF/5, and four leukaemia cell lines, namely K562, U937, P3H1 and Raji, were investigated. C. chinensis exhibited strong activity against SK-Hep1 (IC50 = 7 microg/mL) and Raji (IC50 = 4 microg/mL) cell lines. Interestingly, the two major compounds of C. chinensis, berberine and coptisine, showed a strong inhibition on the proliferation of both hepatoma and leukaemia cell lines. These results suggest that the C. chinensis extract and its major constituents berberine and coptisine possess active anti-hepatoma and anti-leukaemia activities (Lin, 2004).

Leukemia

The steady-state level of nucleophosmin/B23 mRNA decreased during berberine-induced (25 g/ml, 24 to 96 hours) apoptosis of human leukemia HL-60 cells. A decline in telomerase activity was also observed in HL-60 cells treated with berberine. A stable clone of nucleophosmin/B23 over-expressed in HL-60 cells was selected and found to be less responsive to berberine-induced apoptosis. About 35% to 63% of control vector–transfected cells (pCR3) exhibited morphological characteristics of apoptosis, while about 8% to 45% of nucleophosmin/B23-over-expressed cells (pCR3-B23) became apoptotic after incubation with 15 g/ml berberine for 48 to 96 hours.

These results indicate that berberine-induced apoptosis is associated with the down-regulation of nucleophosmin/B23 and telomerase activity. Nucleophosmin/B23 may play an important role in the control of the cellular response to apoptosis induction (Hsing, 1999).

Prostate Cancer

In vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24–72 hours) manner. Berberine significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential., and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase.

The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy (Mantena, 2006).

In another study, the treatment of human prostate cancer cells (PC-3) with berberine-induced dose-dependent apoptosis; however, this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential., release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins.

Berberine-induced apoptosis was blocked in the presence of the anti-oxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. Taken together, these results suggest that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer (Meeran, 2008).

Breast Cancer

DNA microarray technology has been used to understand the molecular mechanism underlying the anti-cancer effect of berberine carcinogenesis in two human breast cancer cell lines, the ER-positive MCF-7 and ER-negative MDA-MB-231 cells; specifically, whether it affects the expression of cancer-related genes. Treatment of the cancer cells with berberine markedly inhibited their proliferation in a dose- and time-dependent manner. The growth-inhibitory effect was much more profound in MCF-7 cell line than that in MDA-MB-231 cells.

IFN-β is among the most important anti-cancer cytokines, and the up-regulation of this gene by berberine is, at least in part, responsible for its anti-proliferative effect. The results of this study implicate berberine as a promising extract for chemoprevention and chemotherapy of certain cancers (Kang, 2005).

Breast Cancer Metastasis

Berberine also inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Anoikis, or detachment-induced apoptosis, may prevent cancer progression and metastasis by blocking signals necessary for survival of localized cancer cells. Resistance to anoikis is regarded as a prerequisite for metastasis; however, little is known about the role of berberine in anoikis-resistance.

The anoikis-resistant cells have a reduced growth rate and are more invasive than their respective adherent cell lines. The effect of berberine on growth was compared to that of doxorubicine, which is a drug commonly used to treat breast cancer, in both the adherent and anoikis-resistant cell lines. Berberine promoted the growth inhibition of anoikis-resistant cells to a greater extent than doxorubicine treatment. Treatment with berberine-induced cell-cycle arrest at G0/G1 in the anoikis-resistant MCF-7 and MDA-MB-231 cells was compared to untreated control cells. These results reveal that berberine can efficiently inhibit growth by inducing cell-cycle arrest in anoikis-resistant MCF-7 and MDA-MB-231 cells. Further analysis of these phenotypes is essential for understanding the effect of berberine on anoikis-resistant breast cancer cells, which would be relevant for the therapeutic targeting of breast cancer metastasis (Kim, 2010).

Melanoma

Berberine inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. The effects and associated molecular mechanism of berberine on human melanoma cancer cell migration using melanoma cell lines A375 and Hs294 were probed in an in vitro cell migration assay, indicating that over- expression of cyclo-oxygenase (COX)-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells.

Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF-kB), an up- stream regulator of COX-2, in A375 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kB, inhibited cell migration. Together, these results indicate that berberine inhibits melanoma cell migration, an essential step in invasion and metastasis, by inhibition of COX-2, PGE2 and PGE2 receptors (Sing, 2011).

Cell-cycle Arrest, Squamous-cell Carcinoma

The in vitro treatment of human epidermoid carcinoma A431 cells with berberine decreases cell viability and induces cell death in a dose (5-75 microM)- and time (12–72 hours)-dependent manner, which was associated with an increase in G(1) arrest. G(0)/G(1) phase of the cell-cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin kinase inhibitors (Cdki) and cyclins.

Pre-treatment of A431 cells with the pan-caspase inhibitor (z-VAD-fmk) significantly blocked the berberine-induced apoptosis in A431 cells confirmed that berberine-induced apoptosis is mediated through activation of caspase 3-dependent pathway.

Together, these results indicate berberine as a chemotherapeutic agent against human epidermoid carcinoma A431 (squamous-cell) cells in vitro; further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of non-melanoma skin cancers (Mantena, 2006).

Cervical Cancer, Radio-sensitizer

Cervical cancer remains one of the major killers amongst women worldwide. In India, a cisplatin based chemo/radiotherapy regimen is used for the treatment of advanced cervical cancer. Evidence shows that most of the chemotherapeutic drugs used in current clinical practice are radio-sensitizers. Natural products open a new avenue for treatment of cancer, as they are generally tolerated at high doses. Animal studies have confirmed the anti-tumorigenic activity of natural products, such as curcumin and berberine.

Berberine is a natural chemo-preventive agent, extracted from Berberis aristata, which has been shown to suppress and retard carcinogenesis by inhibiting inflammation.

The combined therapy of cisplatin/berberine and radiotherapy produced up-regulation of pro-apoptotic proteins Bax and p73, while causing down regulation of the anti-apoptotic proteins Bcl-xL, COX-2, cyclin D1. This additionally was accompanied by increased activity of caspase-9 and caspase-3, and reduction in telomerase activity. Results demonstrated that the treatment combination of berberine/cisplatin had increased induction of apoptosis relative to cisplatin alone (Komal., Singh, & Deshwal., 2013).

Anti-oxidative; Breast, Liver and Colon Cancer

The effect of B. vulgaris extract and berberine chloride on cellular thiobarbituric acid reactive species (TBARS) formation (lipid peroxidation), diphenyle–alpha-picrylhydrazyl (DPPH) oxidation, cellular nitric oxide (NO) radical scavenging capability, superoxide dismutase (SOD), glutathione peroxidase (GPx), acetylcholinesterase (AChE) and alpha-gulcosidase activities were spectrophotometrically determined.

Barberry crude extract contains 0.6 mg berberine/mg crude extract. Barberry extract showed potent anti-oxidative capacity through decreasing TBARS, NO and the oxidation of DPPH that is associated with GPx and SOD hyperactivation. Both berberine chloride and barberry ethanolic extract were shown to have inhibitory effect on the growth of breast, liver and colon cancer cell lines (MCF7, HepG2 and CACO-2, respectively) at different incubation times starting from 24 hours up to 72 hours and the inhibitory effect increased with time in a dose-dependent manner.

This work demonstrates the potential of the barberry crude extract and its active alkaloid, berberine, for suppressing lipid peroxidation, suggesting a promising use in the treatment of hepatic oxidative stress, Alzheimer and idiopathic male factor infertility. As well, berberis vulgaris ethanolic extract is a safe non-toxic extract as it does not inhibit the growth of PBMC that can induce cancer cell death (Abeer et al., 2013).

Source:

Alkaloids Isolated from Natural Herbs as the Anti-cancer Agents. Evidence-Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/485042

References

Burgeiro A, Gajate C, Dakir EH, et al. (2011). Involvement of mitochondrial and B-RAF/ERK signaling pathways in berberine-induced apoptosis in human melanoma cells. Anti-Cancer Drugs, 22(6):507–518.


Chang KSS, Gao C, Wang LC. (1990). Berberine-induced morphologic differentiation and down-regulation of c-Ki-ras2 protooncogene expression in human teratocarcinoma cells. Cancer Letters, 55(2):103–108.


Chen J, ZHao H, Wang X, et al. (2008). Analysis of major alkaloids in Rhizoma coptidis by capillary electrophoresis-electrospray-time of flight mass spectrometry with different background electrolytes. Electrophoresis, 29(10):2135–2147.


Eom KS, Kim HJ, So HS, et al. (2010). Berberine-induced apoptosis in human glioblastoma T98G Cells Is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction. Biological and Pharmaceutical Bulletin, 33(10):1644–1649.


El-Wahab AEA, Ghareeb DA, et al. (2013). In vitro biological assessment of berberis vulgaris and its active constituent, berberine: anti-oxidants, anti-acetylcholinesterase, anti-diabetic and anti-cancer effects. BMC Complementary and Alternative Medicine, 13:218 doi:10.1186/1472-6882-13-218


Hamsa TP & Kuttan G. (2011). Berberine inhibits pulmonary metastasis through down-regulation of MMP in metastatic B16F-10 melanoma cells. Phytotherapy Research, 26(4):568–578.


Hamsa TP & Kuttan G. (2012). Anti-angiogenic activity of berberine is mediated through the down-regulation of hypoxia-inducible factor-1, VEGF, and pro-inflammatory mediators. Drug and Chemical Toxicology, 35(1):57–70.


Han J, Lin H, Huang W. (2011). Modulating gut microbiota as an anti-diabetic mechanism of berberine. Medical Science Monitor, 17(7):RA164–RA167.


Ho YT, Yang JS, Li TC, et al. (2009). Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-κB, u-PA and MMP-2 and -9. Cancer Letters, 279(2):155–162.


Hur JM, Hyun MS, Lim SY, Lee WY, Kim D. (2009). The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. Journal of Cellular Biochemistry, 107(5):955–964.


Islam MM & Kumar GS. (2009). RNA-binding potential of protoberberine alkaloids: spectroscopic and calorimetric studies on the binding of berberine, palmatine, and coralyne to protonated RNA structures. DNA and Cell Biology, 28(12):637–650.


Ji JB. (2011). Active Ingredients of Traditional Chinese Medicine: Pharmacology and Application, People's Medical Publishing House Cp., LTD.


Jie S, Li H, Tian Y, et al. (2011). Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down-regulation in vitro. Journal of Gastroenterology and Hepatology, 26(1):179–185.


Kang JX, Liu J, Wang J, He C, Li FP. (2005). The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by up-regulation of interferon-β and TNF-α in human breast cancer cells. Carcinogenesis, 26(11):1934-1939. doi:10.1093/carcin/bgi154


Kim JB, Yu JH, Ko E, et al. (2010). The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Phytomedicine, 17(6):436-40. doi: 10.1016/j.phymed.2009.08.012.


Komal Singh M, & Deshwal VK. (2013). Natural plant product berberine/cisplatin based radiotherapy for cervical cancer: The new and effective method to treat cervical cancer. Global Journal of Research on Medicinal Plants and Indigenous Medicine, 2(5), 278-291.


Kulkarni SK & Dhir A. (2010). Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytotherapy Research, 24(3):317–324.


Lau CW, X. Q. Yao XQ, et al. (2001). Cardiovascular actions of berberine. Cardiovascular Drug Reviews, 19(3):234–244.


Li, XL Hu XJ, Wang H, et al. (2012). Molecular spectroscopy evidence for berberine binding to DNA: comparative binding and thermodynamic profile of intercalation. Biomacromolecules, 13(3):873–880.


Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC. (2004). Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth. Clin Exp Pharmacol Physiol, 31(1-2):65-9.


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine, a natural product, induces G1-phase cell-cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther, 5(2):296-308. doi: 10.1158/1535-7163.MCT-05-0448


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki–Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Carcinogenesis, 27(10):2018-27. doi: 10.1093/carcin/bgl043


Meeran SM, Katiyar S & Katiyar SK. (2008). Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicology and Applied Pharmacology, 229(1):33-43. doi:10.1016/j.taap.2007.12.027


Singh T, Vaid M, Katiyar N, et al. (2011). Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E and prostaglandin E receptors. Carcinogenesis, 32(1):86–92.


Sun Y, Xun K, Wang Y, Chen X. (2009). A systematic review of the anti-cancer properties of berberine, a natural product from Chinese herbs. Anti-Cancer Drugs, 20(9):757–769.


Tan W, Lu J, Huang M, et al. (2011). Anti-cancer natural products isolated from chinese medicinal herbs. Chinese Medicine, 6(1):27.


Tang F, Wang D, Duan C, et al. (2009) Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting rho kinase-mediated ezrin phosphorylation at threonine 567. Journal of Biological Chemistry, 284(40):27456–27466.


Wang N, Feng Y, Zhu M et al. (2010). Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism. Journal of Cellular Biochemistry, 111(6):1426–1436.


Wu HL, Hsu CY, Liu WH, Yung BYM. (1999). Berberine‐induced apoptosis of human leukemia HL‐60 cells is associated with down‐regulation of nucleophosmin/B23 and telomerase activity. International Journal of Cancer, 81(6):923–929.


Youn MJ, So HS, Cho HJ, et al. (2008). Berberine, a natural product, combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cells. Biological and Pharmaceutical Bulletin, 31(5):789–795.


Yu HH, Kim KJ, Cha JD, et al. (2005). Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Journal of Medicinal Food, 8(4):454–461.

Akt, Anti-cancer, Anti-metastatic, anti-tumor, anti-tumor activity, apoptosis, BAX, Bcl-2, BCR, Breast cancer, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, Chemotherapy, G0/G1, G1, HL-60 and K562, induces apoptosis, inhibits proliferation, Leukemia, Liver cancer, MDR, NB4, p65, SMAD3, VEGF, VEGF

Berbamine

Cancer: Breast, leukemia, liver, neutropenia

Action: Anti-metastatic, chemo-sensitizer

Breast Cancer, Leukemia

Berbamine (BER), isolated from the Chinese herb Berberis amurensis and Berberis vulgaris (L.), selectively induces apoptosis in certain breast cancer and leukemia cell lines.

Studies have shown that berbamine suppresses the growth, migration and invasion in highly-metastatic human breast cancer cells by possibly inhibiting Akt and NF-kappaB signaling with their upstream target c-Met and downstream targets Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2.

BER has synergistic effects with anti-cancer agents trichostatin A, celecoxib and carmofur on inhibiting the growth of MDA-MB-231 cells and reducing the ratio of Bcl-2/Bax and/or VEGF expressions in the cancer cells. These findings suggest that berbamine may have wide therapeutic and/or adjuvant therapeutic application in the treatment of human breast cancer and other cancers (Wang, 2009).

MDR, Leukemia stem cells

Previous studies have shown that berbamine selectively induces apoptosis of imatinib (IM)-resistant-Bcr/Abl-expressing leukemia cells from the K562 cell line and CML patients. Berbamine derivatives obtained by synthesis were found to have very high activity in vitro. Six of these exhibited consistent high anti-tumor activity for imatinib-resistant K562 leukemia cells. Their IC(50) values at 48h were 0.36-0.55 microM, whereas berbamine IC(50) value was 8.9 microM. Cell cycle analysis results showed that compound 3h could reduce G0/G1 cells. In particular, these compounds displayed potent inhibition of the cytoplasm-to-nucleus translocation of NF-kappaB p65 which plays a critical role in the survival of leukemia stem cells (Xie, 2009).

Liver Cancer, Leukemia

Meng et al. (2013) reported that berbamine and one of its derivatives, bbd24, potently suppressed liver cancer cell proliferation and induced cancer cell death by targeting Ca2+/calmodulin-dependent protein kinase II (CAMKII). Furthermore, berbamine inhibited the in vivo tumorigenicity of liver cancer cells in NOD/SCID mice and downregulated the self-renewal abilities of liver cancer-initiating cells. Berbamine inhibits proliferation and induces apoptosis of KU812 leukaemia cells by increasing Smad3 activity (Kapoor, 2012).

Chronic Myeloid Leukemia, Leukopenia

During imatinib therapy, many patients with chronic myeloid leukemia (CML) develop severe neutropenia, leading to treatment interruptions, and potentially compromising response to imatinib. Berbamine (a bisbenzylisoquinoline alkaloid) has been widely used in Asian countries for managing leukopenia associated with chemotherapy. With berbamine support, the time to achieve complete cytogenetic response was significantly shorter (median, 6.5 vs. 10 months, p = 0.007). There were no severe adverse events associated with berbamine treatment. In conclusion, the present study reveals the potential clinical value of berbamine in the treatment of CML with imatinib-induced neutropenia (Zhao et al., 2011).

References

Kapoor S. (2012). Emerging role of berbamine as an anti-cancer agent in systemic malignancies besides chronic myeloid leukemia. Zhejiang Univ Sci B, 13(9):761-2.


Meng Z, Li T, Ma X, et al. (2013). Berbamine Inhibits the Growth of Liver Cancer Cells and Cancer-Initiating Cells by Targeting Ca2+/Calmodulin-Dependent Protein Kinase II. Mol Cancer Ther.


Wang S, Liu Q, Zhang Y, et al. (2009). Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action. Mol Cancer, 8:81.


Xie J, Ma T, Gu Y, et al. (2009). Berbamine derivatives: A novel class of compounds for anti-leukemia activity. Eur J Med Chem, 44(8):3293-8. doi: 10.1016/j.ejmech.2009.02.018


Zhao Y, Tan Y, Wu G, et al. (2011). Berbamine overcomes imatinib-induced neutropenia and permits cytogenetic responses in Chinese patients with chronic-phase chronic myeloid leukemia. Int J Hematol, 94(2):156-62. doi: 10.1007/s12185-011-0887-7.

Anti-cancer, Anti-cancer effect, apoptosis, Apoptotic, BAX, Breast cancer, CDC2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, chemo-preventive, chemo-sensitizing, Chemotherapy, Cytostatic, ER, G1, G2/M, Glioblastoma, H460, Liver cancer, Lung cancer, Oral cancer, p21, p53, PARP, PKC, radio-sensitizing, S, U87

Aloe-emodin (See also Emodin)

Cancer:
Nasopharyngeal., ER α degradation, Lung, breast, oral., glioblastoma, liver cancer prevention

Action: Cytostatic, radio-sensitizing, chemo-sensitizing

Nasopharyngeal Carcinoma

Aloe-emodin (AE), a natural., biologically active compound from Aloe vera leaves has been shown to induce apoptosis in several cancer cell lines in vitro. Investigation showed that AE induced G2/M phase arrest by increasing levels of cyclin B1 bound to Cdc2, and also caused an increase in apoptosis of nasopharyngeal carcinoma (NPC) cells, which was characterized by morphological changes, nuclear condensation, DNA fragmentation, caspase-3 activation, cleavage of poly (ADP-ribose) polymerase (PARP) and increased sub-G(1) population. Treatment of NPC cells with AE also resulted in a decrease in Bcl-X(L) and an increase in Bax expression.

Collectively, results indicate that the caspase-8-mediated activation of the mitochondrial death pathway plays a critical role in AE-induced apoptosis of NPC cells (Lin et al., 2010).

Glioblastoma

Aloe emodin arrested the cell-cycle in the S phase and promoted the loss of mitochondrial membrane potential in glioblastoma U87 cells that indicated the early event of the mitochondria-induced apoptotic pathway. It plays an important role in the regulation of cell growth and death (Ismail et al., 2013).

Breast Cancer

The anthraquinones emodin and aloe-emodin are also abundant in the rhizome Rheum palmatum and can induce cytosolic estrogen receptor α (ER α) degradation; it primarily affected nuclear ER α distribution similar to the action of estrogen when protein degradation was blocked. In conclusion, our data demonstrate that emodin and aloe-emodin specifically suppress breast cancer cell proliferation by targeting ER α protein stability through distinct mechanisms (Huang et al., 2013).

Lung Cancer

Photoactivated aloe-emodin induced anoikis and changes in cell morphology, which were in part mediated through its effect on cytoskeleton in lung carcinoma H460 cells. The expression of protein kinase Cδ (PKCδ) was triggered by aloe-emodin and irradiation in H460 cells. Furthermore, the photoactivated aloe-emodin-induced cell death and translocation of PKCδ from the cytosol to the nucleus was found to be significantly inhibited by rottlerin, a PKCδ-selective inhibitor (Chang et al., 2012).

Oral Cancer; Radio-sensitizing, Chemo-sensitizing

The treatment of cancer with chemotherapeutic agents and radiation has two major problems: time-dependent development of tumor resistance to therapy (chemoresistance and radioresistance) and nonspecific toxicity toward normal cells. Many plant-derived polyphenols have been studied intensively for their potential chemo-preventive properties and are pharmacologically safe.

These compounds include genistein, curcumin, resveratrol, silymarin, caffeic acid phenethyl ester, flavopiridol, emodin, green tea polyphenols, piperine, oleandrin, ursolic acid, and betulinic acid. Recent research has suggested that these plant polyphenols might be used to sensitize tumor cells to chemotherapeutic agents and radiation therapy by inhibiting pathways that lead to treatment resistance. These agents have also been found to be protective from therapy-associated toxicities.

Treatment with aloe-emodin at 10 to 40 microM resulted in cell-cycle arrest at G2/M phase. The alkaline phosphatase (ALP) activity in KB cells increased upon treatment with aloe-emodin when compared to controls. This is one of the first studies to focus on the expression of ALP in human oral carcinomas cells treated with aloe-emodin. These results indicate that aloe-emodin has anti-cancer effect on oral cancer, which may lead to its use in chemotherapy and chemo-prevention of oral cancer (Xiao et al., 2007).

Liver Cancer Prevention

In Hep G2 cells, aloe-emodin-induced p53 expression and was accompanied by induction of p21 expression that was associated with a cell-cycle arrest in G1 phase. In addition, aloe-emodin had a marked increase in Fas/APO1 receptor and Bax expression. In contrast, with p53-deficient Hep 3B cells, the inhibition of cell proliferation of aloe-emodin was mediated through a p21-dependent manner that did not cause cell-cycle arrest or increase the level of Fas/APO1 receptor, but rather promoted aloe-emodin-induced apoptosis by enhancing expression of Bax.

These findings suggest that aloe-emodin may be useful in liver cancer prevention (Lian et al., 2005).

References

Chang WT, You BJ, Yang WH, et al. (2012). Protein kinase C delta-mediated cytoskeleton remodeling is involved in aloe-emodin-induced photokilling of human lung cancer cells. Anti-cancer Res, 32(9):3707-13.

Huang PH, Huang CY, Chen MC, et al. (2013). Emodin and Aloe-Emodin Suppress Breast Cancer Cell Proliferation through ER α Inhibition. Evid Based Complement Alternat Med, 2013:376123. doi: 10.1155/2013/376123.

Ismail S, Haris K, Abdul Ghani AR, et al. (2013). Enhanced induction of cell-cycle arrest and apoptosis via the mitochondrial membrane potential disruption in human U87 malignant glioma cells by aloe emodin. J Asian Nat Prod Res.

Lian LH, Park EJ, Piao HS, Zhao YZ, Sohn DH. (2005). Aloe Emodin‐Induced Apoptosis in Cells Involves a Mitochondria‐Mediated Pathway. Basic & Clinical Pharmacology & Toxicology, 96(6):495–502.

Lin, ML, Lu, YC, Chung, JG, et al. (2010). Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway. Cancer Letters, 291(1), 46-58. doi: 10.1016/j.canlet.2009.09.016.

Xiao B, Guo J, Liu D, Zhang S. (2007). Aloe-emodin induces in vitro G2/M arrest and alkaline phosphatase activation in human oral cancer KB cells. Oral Oncol, 43(9):905-10.

Anti-cancer, Anti-cancer effect, anti-proliferative, Apoptotic, Chapter 8 Injectables and Cancer Research, Chemo-sensitizer, Chemotherapy, cytotoxic, Fissistigma glaucescens, Gastric cancer or Stomach cancer, Liver cancer, Lung cancer, metastasis, Ovarian cancer, PAK1, Pro-apoptotic, radiotherapy

Xiao Ai Ping

Cancer: Lung, gastric, ovarian, liver

Action: Anti-proliferative, chemo-sensitizer, pro-apoptotic

Ingredients: wu gu teng (Fissistigma glaucescens)

TCM functions: Clearing Heat, removing Toxin, dissolving Phlegm and softening the hardness.

Indications: Esophagus cancer, stomach cancer, lung cancer, ovarian cancer and liver cancer.

Dosage and usage:

Intravenous drip: 20-100ml mixed with 5% or 10% glucose injection, once daily.

Xiaoaiping Injection (XAP) is made from extracts from wu gu teng (Fissistigma glaucescens). Its TCM functions are Clearing Heat, removing Toxin, dissolving Phlegm and softening the hardness. It is used in the treatment of esophagus cancer, stomach cancer, lung cancer and liver cancer. It can be used as an adjuvant therapy for radiotherapy or chemotherapy (Drug Information Reference in Chinese: See end, 2006).

Lung Cancer

Lewis lung cancer (LLC) bearing mice were injected intraperitoneally daily with various doses of cisplatin, Xiao-Ai-Ping, or cisplatin plus Xiao-Ai-Ping, respectively. The combination of Xiao-Ai-Ping and cisplatin yielded significantly better anti-growth and pro-apoptotic effects on LLC xenografts than sole drug treatment did. In addition, Xiao-Ai-Ping triggered the infiltration of CD8+ T cells, a group of cytotoxic T cells, to LLC xenografts. In vitro studies showed that Xiao-Ai-Ping markedly upregulated the mRNA levels of ifn-?, prf-1, and gzmb in CD8+ T cells in a concentration-dependent manner, suggesting that Xiao-Ai-Ping augments the function of CD8+ T cells.

Xiao-Ai-Ping promotes the infiltration and function of CD8+ T cells and thus enhances the anti-growth effects of cisplatin on LLC xenografts, which provides new evidence for the combination of Xiao-Ai-Ping and cisplatin in clinic in China (Li et al., 2013).

Hepatocellular Carcinoma

Xiao-Ai-Ping (XAP) enhances the quality of life (QOL) of patients with advanced HCC, improves their immunity and extends their PFS. XAP was administered daily by i.v. and the treatment course lasted for 30 days for both groups. The progression-free survival (PFS) rate and overall survival (OS) rate in the 2 groups were analyzed. The 6-months cumulative survival rates in the treatment and control groups were 33.3% and 25.0%, respectively, with no significant difference (P > 0.05). The PFS was 18 weeks in the treatment group and 15 weeks in control group (P < 0.05) (Huang et al., 2013).

NSCLC

Seventy nine patients with terminal NSCLC patients were divided into the control group and the treatment group. The control group: paclitaxel 135 mg/m2,the 1st day intravenous drip, cisplatin 30 mg/m2, the 1st day ~ 3rd day, intravenous drip (TP regimen). The treatment group: Xiaoaiping injection combined with TP regimen. The clinical data of two groups was compared.

The short-term  curative effect and quality of life in the treatment group was better than the control group. The adverse effect of treatment group was slightly lower. Xiaoaiping injection in combination with TP regimen in the treatment of non-small-cell lung cancer has better efficacy, effectively improves the clinical symptoms and improves quality of life with fewer adverse reactions (Guoan, 2013).

Gastric Cancer

To investigate the effect and toxicities of xiaoaiping injection in the treatment of the elderly patients with advanced gastric carcinoma, forty-six elderly patients with advanced gastric carcinoma in the test group were treated with xiaoaiping injection plus supportive care, and the 30 patients of the control group were treated with supportive care alone. The total effective rate, the excellence plus effectiveness rate and the improvement rate of quality of life of the test group were better than those of the control group (P<0.05). Xiaoaiping injection is effective and safe in the treatment of the elderly patients with advanced gastric carcinoma (Liu et al., 2012).

Ovarian Cancer; Metastasis

The ovarian cancer Caov-3 cells were treated with xiaoaiping (XAP) in vitro. The inhibitor doxycyclin was also applied to the metalloproteinase-9 (MMP) as the positive control, whereas phosphate-buffered saline served as the negative control. XAP effectively inhibited Caov-3 cell migration and invasion and decreased the MMP-9 gene and protein expression levels (P<0.05). Moreover, the inhibitory effect of XAP was similar to that of doxycyclin (P>0.05). Conclusion: XAP inhibits Caov-3 cell migration by decreasing the MMP-9 expression (Wang et al., 2012).

Hepatoma

Zhao at al. (2011) researched the inhibitory effect of the combination of octreotide acetate and Xiaoaiping injection on hepatoma Hepal-6 cells and the expression of PAK1 protein. The different concentrations (10, 30, 50mg/ml), the different times (-24, -16, -8, 0 hours, 8, 16 & 24 hours), and the inhibition of the combination of oetreotide acetate and Xiaoaiping injection on Hepal-6 cells were detected by MTT assay.

Xiaoaiping of 50mg/ml combined with octreotide acetate was the best concentration of pharmacodynamie action for treating liver cancer (P<0. 05). Xiaoaiping of 50mg/nd combined with octreotide acetate was the best concentration for anti-cancer effect. Using oetreotide acetate 8 hours early was the best time for anti-cancer treatment, and its motility decreased significantly. Above all, down-regulating the PAK1 protein could restrain the proliferation of tumors and reduce motility. This provided the theoretical basis in targeted treatment for hepatocellular carcinoma.

References

Guoan X. (2013). Effect of xiaoaiping injection combined with TP regimen in the treatment of advanced non-small-cell lung cancer. Lin Chuang Yi Yao Shi Jian, 22(2): 83-85.


Huang, Z., Wang, Y., Chen, J., Wang, R., Chen, Q. (2013) Effect of Xiaoaiping injection on advanced hepatocellular carcinoma in patients. J Tradit Chin Med, 33(1):34-8.


Li, W.S., Yang, Y., Ouyang, Z.J. (2013). Xiao-Ai-Ping, a TCM injection, enhances the anti-growth effects of cisplatin on Lewis lung cancer cells through promoting the infiltration and function of CD8+ T lymphocytes. Evidence-Based Complementary and Alternative Medicine, 2013(2013):879512. doi:10.1155/2013/879512.


Liu X, Su Q, Mao X, Xue L, et al. (2012). Effect of Xiaoaiping Injection in the Treatment of the Elderly Patients with Advanced Gastric Carcinoma. Zhong Liu Ji Chu Yu Lin Chuang, 15(6): 513-514.


Wang. C., Dong, X., Wang, M., Wang, X. (2012). Xiaoaiping Injection Inhibits Cell Migration by Reducing MMP-9 Gene Expression in Human Ovarian Cancer Cells. Zhong Guo Zhong Liu Lin Chuang, 29(13): 886-888.


Xiao G. (2013). Effect of xiaoaiping injection combined with TP regimen in the treatment of advanced non-small-cell lung cancer. Lin Chuang Yi Yao Shi Jian, 22(2): 83-85.


Zhao HP, Liang LQ, Xie YR. (2011). Growth inhibition effect of Xiaoaiping injection combined with octreotide acetate on Hepal-6 cells and the expression of PAK1. Lin Chuang Zhong Liu Xue Za Zhi, 16(1): 19-22.

Anti-cancer, anti-tumor, anti-tumor immunity, apoptosis, Breast cancer, Breast cancer cell lines, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, Damages DNA, G2/M, Pancreatic cancer

Ukrain

Cancer: Breast, pancreatic, bladder, colorectal

Action: Damages DNA

Ukrain has been described as a semi-synthetic Chelidonium majus alkaloid derivative, consisting of three chelidonine alkaloids combined to triaziridide. Panzer et al. (2000) found the actions of Ukrain to be similar to the Chelidonium majus alkaloids from which it is prepared. Chelidonium majus contains a range of more than 30 alkaloids, most notably isochinolin derivatives (chelidonine, coptisine, berberin etc.). Chemical analyzes of Ukrain were inconsistent with the proposed trimeric structure and demonstrated that at least some commercial preparations of Ukrain consist of a mixture of C. majus alkaloids (including chelidonine) (Panzer et al., 2000).

Ukrain was developed in 1978 by Dr. Wassil J. Nowicky, director of the Ukrainian Anti-Cancer Institute of Vienna, Austria, and was first presented at the 13th International Congress of Chemotherapy in Vienna in August 1983. In 2004 and 2006, Nowicky was nominated for the Nobel Prize in Chemistry. The manufacturer of Ukrain is Nowicky Pharma, A-1040 Vienna, Austria.

Several reports describe Eastern European clinical trials using Ukrain for people with various types of cancer (Susak et al., 1996). The mechanism of action of Ukrain is unknown whereas the mechanism of action of thiotepa is known. The drug works by damaging the DNA of cells, leaving the cell unable to divide.

The proposed activity of Ukrain includes cytotoxicity from effects on cellular oxygen consumption, inhibition of DNA, RNA, and protein synthesis, and induction of apoptosis. In vitro studies demonstrate weak inhibition of tubulin polymerization causing arrest at G2/M phase of the cell-cycle. Limited in vitro data support the claim that Ukrain has selective cytotoxicity against cancer cells. Ukrain also is promoted for its claimed ability to increase total T-cell count and T-helper lymphocytes, while decreasing T-suppressor cells. In vitro activation of splenic lymphocytes also was reported (Colombo et al., 1996; Panzer et al., 2000; Uglyanitsa et al., 1998).

Ukrain has no drug approval in the EU. In the UK, Ukrain neither hasmarketing authorization nor is it registered under the “traditional use” label. It is not FDA-approved in the US but is approved in Mexico, and in the United Arab Emirates, as a standard anti-cancer medication. According to the manufacturer, NSC 631570 (=Ukrain) has drug licences in several states of the former Soviet Union (Ukraine, Georgia, Turkmenistan, Belarus/White Russia, Azerbaijan Republic, Tadshikistan, and the Ukraine. They also claim, without validation, that Ukrain has also been designated as an Orphan Drug for pancreatic cancer in the USA and in Australia (Human life Science Holding, n.d.).

There are seven RCTs assessing the efficacy of Ukrain for various cancer types (Ernst & Schmidt, 2005). The majority of these studies were published in two different journals between 1995 and 2002 by four different groups of authors, three from  Belarus and one from Germany. They relate to colorectal (Susak et al., 1995; Susak et al., 1996) rectal (Bondar et al., 1998), bladder (Uglyanitsa et al., 1998), pancreatic (Zemskov et al., 2000; Zemskov et al., 2002), and breast cancers (Uglyanitsa et al., 2000). Ukrain exposure induced apoptosis in a dose- and time-dependent manner with 50 µg/mL Ukrain leading to >50% cell death after 48 hour exposure for all three breast cancer cell lines.

Ukrain administration (12.5 mg/kg) led to significant inhibition of 4T07 tumor growth in vivo and sustained protective anti-tumor immunity following secondary challenge. Findings demonstrate the in vitro and in vivo cytotoxic effects of Ukrain on breast cancer cells and may provide insight into designing Ukrain-based therapies for breast cancer patients (Bozeman et al., 2012).

While common anti-cancer drugs are toxic both against cancer and normal cells (cytostatics), Ukrain is allegedly only toxic against cancer cells (“malignocytolytic”). Some studies suggest that there was no evidence to suggest selective cytotoxicity previously reported for Ukrain (Panzer et al., 2000). Research carried out at the National Cancer Institute where Ukrain was tested on the screening panel with 60 cell lines from eight human cancer types, it was revealed to be cytotoxic against all the solid cancer cell lines tested (Boehm & Ernst, 2013).

References

Boehm, K., Ernst, E. (2013) CAM-Cancer Consortium. Ukrain [online document]. http://cam-cancer.org/CAM-Summaries/Herbal-products/Ukrain. August 21, 2013.


Bondar, G.V., Borota, A.V., Yakovets, Y.I., Zolotukhin, S.E.(1998)  Comparative evaluation of the complex treatment of rectal cancer patients (chemotherapy and X-ray therapy, Ukrain monotherapy). Drugs Exp Clin Res 1998;24:221-6.

Bozeman, E.N., Srivatsan, S., Mohammadi, H., et al. (2012) Ukrain, a plant derived semi-synthetic compound, exerts anti-tumor effects against murine and human breast cancer and induce protective anti-tumor immunity in mice.  Exp Oncol. 2012 Dec;34(4):340-7.


Colombo, M.L., Bosisio, E.. (1996) Pharmacological activities of Chelidonium majus L. (papaveracea). Pharmacol Res 1996;33:127-34.


Ernst, E., Schmidt, K. (2005) Ukrain – a new cancer cure? A systematic review of randomised clinical trials. BMC Cancer 2005;5:69-75.


Human life Science Holding. (n.d) http://www.open-cc.com/English/1_04.asp Accessed 2 December 2013


Panzer, A., Hamel, E., Joubert, A.M., Bianchi, P.C., Seegers, J.C.. (2000) Ukrain (TM), a semisynthetic Chelidonium majus alkaloid derivative, acts by inhibition of tubulin polymerization in normal and malignant cell lines. Cancer Lett 2000;160(2):149-57.


Susak, Y.M., Yaremchuk, O.Y., Zemskov, V.S., Kravchenko, O.B., et al. (1995) Randomised clinical study of Ukrain on colorectal cancer. Eur J Cancer 1995;31:S153 Abstract 733.


Susak, Y.M., Zemskov, V.S., Yaremchuk, O.Y., et al. (1996) Comparison of chemotherapy and x-ray therapy with Ukrain monotherapy for colorectal cancer. Drugs Exptl Clin Res 1996;22:115–22.


Uglyanitsa, K.N., Nechiporenko, N.A., Nefyodov, L.I., Brzosko, W.J. (1998) Ukrain therapy of stage T1NOMO bladder cancer patients. Drugs Exp Clin Res 1998;24:227-30.

Anti-tumoral, Chapter 8 Injectables and Cancer Research, Chemotherapy, chemotherapy support, CYP1A2, inhibits chemotherapy-induced cardiotoxicity, inhibits CYP activity, Nausea and Vomiting

Shenmai

Cancers: Lung, stomach

Action: Anti-tumoral., chemotherapy support, inhibits CYP activity, inhibits chemotherapy-induced cardiotoxicity

Shenmai injection (SMI) is a mixture of Radix Ginseng and Radix Ophiopogonis, comprised of total ginsenoside (TG), ophiopogon total saponins (OTS), ophiopogon total flavone (OTF), ginsenoside Rd, ophiopogonin D and ophiopogonone A.

NSCLC

Forty-five NSCLC patients, with stages IIIb-IV, were randomly divided into two groups: the treatment group (treated with chemotherapy combined with Shenmai injection) and the control group (treated with chemotherapy only). There was no significant difference between the two groups in acute curative effects (P > 0.05). However, there were significant differences between them in Karnofsky score and weight (P < 0.05). The treatment group was significantly better than the control group in preventing leukopenia and decreased hemoglobin (P < 0.05). The incidence of thrombocytopenia, nausea and vomiting, hepatic, and renal dysfunction in the treatment group was lower than that in the control group.

Shenmai injection would not influence the efficacy of chemotherapy in advanced NSCLC patients. However, it could improve the quality of life, increase the body weight of patients, and alleviate adverse reactions of chemotherapy, such as myelosuppression, to improve chemotherapy tolerance (Cao, Li, & Tan, 2006).

Hepatic CYP Enzymes

These in vivo and in vitro results demonstrated that Shenmai had the potential to inhibit the activities of hepatic CYP3A1/2 and CYP2C6, but might not significantly affect CYP1A2 and CYP2E1-mediated metabolism in rats (Xia et al., 2010).

Gastric Cancer; Chemotherapy

Sixty-seven patients with gastric cancer in medium to advanced stage were randomly divided into two groups: 33 cases in the treatment group and 34 cases in the control group. The control group was treated with docetaxel, oxaliplatin and fluorouracil (DOF), while the treatment group was treated with DOF and Shenmai injection (40 mL / day). One treatment course included 21 days, and after 2 treatment courses the results were observed.

There was significant difference between the two groups (X2=4.327 6, P < 0.05). Additionally, there was statistically significant difference in the Karnofsky score (u=2.7033, P=0.008 4) and syndrome evaluation (u=2.375 9, P=0.018 0).

Shenmai injection, combined with chemotherapy, has better effect on gastric cancer in medium to advanced stage than single chemotherapy alone. It has a reliable effect on tumor mass but the benefits in regards to the rate of chemotherapy completion and Kanorfsky animation score is not definite (OR and 95% CI are over 1) (Hao, Liu, Wang, Li, & Li, 2013).

Cardiotoxicity

Six RCTs were included, totaling 615 patients (307 in the experimental group and 308 in the control group). Current evidence suggests that Shenmai injection is potentially effective in the prevention and treatment of cardiotoxicity in tumor patients induced by anthracyclines (Yang, Lu, Mou, & Xu, 2012).

NSCLC

All patients were treated with the Navelbine and Cisplatin (NP) chemotherapy, but to the treatment group the Chinese drugs Shengmai Injection by intravenous drip and Gujin Granule by oral intake were given additionally. The main observation indexes were response rate (RR), median survival time, 1-year survival rate and median time to progression (TTP); secondary observation indexes were side-effects and cycles of chemotherapy.

RR was 48.5% in the treatment group and 32.2% in the control group, and the median survival times were 13 months and 9 months, respectively. However, the differences between groups were insignificant in terms of 1-year survival rate [51.5% vs 46.4%, P=0.4042], median TTP (5.95 months vs 4.64 months, P=0.3242), grade III or IV bone marrow inhibition occurrence rate [33.3% (11/33) vs 39.3% (11/28), P=0.3500], and mean cycles of chemotherapy applied (2.94+/-0.94 cycles vs 2.75+/-0.75 cycles, P=0.4100).

Combined Chinese drugs and chemotherapy can enhance the short-termtherapeutic efficacy in the treatment of NSCLC and prolong patients” median survival time (Chen et al., 2009).

References

Cao, Y., Li, P., & Tan, K.J. (2006). Clinical observation on Shenmai injection in preventing and treating adverse reaction of chemotherapy on advanced non-small-cell lung cancer. Chinese Journal of Integrated Traditional and Western Medicine, 26(6), 550-552.


Chen YZ, Li ZD, Gao F, Zhang Y, Sun H, Li PP. (2009) Effects of combined Chinese drugs and chemotherapy in treating advanced non-small-cell lung cancer. Chin J Integr Med, 15(6):415-9.


Hao, S.L, Liu, L.K., Wang, X.X., Li, J., & Li, Y.F. (2013). Clinical research of Shenmai injection combined with chemotherapy on gastric cancer in medium-advanced stage, A Report of 33 Cases. Shaanxi Journal of Chinese Traditional Medicine, 29(2), 9-11.


Xia, C.H., Sun, J.G., Wang, G.J., Shang, L.L., Zhang, X.X., Zhang, R., Peng, Y., Wang, X.J., Hao, H.P., Xie, L., & Roberts, M.S. (2010). Herb-drug interactions: in vivo and in vitro effect of Shenmai injection, a herbal preparation, on the metabolic activities of hepatic cytochrome P450 3A1/2, 2C6, 1A2, and 2E1 in rats. Planta Medica, 76(3), 245-50. doi: 10.1055/s-0029-1186082.


Yang, M., Lu, J., Mou, J.J., & Xu, T. (2012). Systematic review of Shenmai injection for cardiotoxicity induced by anthracyclines. Chinese Journal of Pharmacovigilance, 9(11), 666-669.

Anti-metastatic, Chapter 8 Injectables and Cancer Research, Chemotherapy, chemotherapy support, Fatigue, Immune, Lung cancer, Nausea and Vomiting, radiotherapy

Shen qi fu zheng (Vital-qi Fortify)

Cancers: Stomach, lung

Action: Anti-metastatic, chemotherapy support

Ingredients: dang shen (Codonopsis pilosula), huang qi (Astragalus membranaceus).

TCM functions: Invigorating qi and supporting Vital-qi,

Indications: Adjuvant treatment for late-stage lung cancer not suitable for radiotherapy or chemotherapy, of qi deficiency type. It can be combined with chemotherapy for the adjuvant treatment of lung cancer and stomach cancer of qi deficiency type.

Dosage and usage:

Combination with radiotherapy or chemotherapy: Be administrated 3 days before chemotherapy, then be used synchronously with chemotherapy. 1 bottle daily for intravenous drip. The course is the same as that of radiotherapy or chemotherapy.

The clinical efficacy of Shenqifuzheng injection, combined with Bozhi glycopeptide, in treating aged lung cancer patients was observed.

NSCLC; Chemotherapy

In China, Shenqi Fuzheng, a newly developed injection concocted from Chinese medicinal herbs has been reported that may increase efficacy and reduce toxicity when combined with platinum-based chemotherapy, but little is known about it outside of China.

Twenty nine studies were included in this review based on our selection criteria. Of them, ten studies were of high quality and the rest were of low quality, according to the modified Jadad scale. The meta-analysis showed there was a statistically significant higher tumor response when the SFI plus platinum-based chemotherapy treatment group was compared with the platinum-based chemotherapy control group (Dong et al., 2010).

NSCLC

Sixty patients with advanced non-small-cell lung cancer were randomly divided into a treatment group or control group. The treatment group was treated by Shenqi Fuzheng injection combined with chemotherapy, and the control group with chemotherapy alone.

The effect of Shenqi Fuzheng injection combined with chemotherapy vs the chemotherapy alone showed no significant difference. However, in reducing toxicity and side-effects of chemotherapy, such as gastrointestinal reaction and leukopenia, it was superior to the chemotherapy alone (P < 0. 05).

The effect of Shenqi Fuzheng injection combined with chemotherapy in the treatment of advanced non-small-cell lung cancer can improve the quality of life of patients, reduce the toxic side-effects of chemotherapeutic agents, and enhance immunity (Qiao, 2012).

Lung Cancer

In the treatment group; symptoms of fatigue, anorexia, and nausea and vomiting were lower versus the control group. Also, the occurrence of leukopenia and thrombocytopenia in the treatment group was lower than that of the control group.

Shenqi Fuzheng injection plus chemotherapy for advanced lung cancer can reduce drug toxicity, improve the patient”s fatigue, loss of appetite, gastrointestinal symptoms and improve the quality of life of patients (Jiang, 2012).

Lung Cancer; Chemotherapy

Seventy four lung cancer patients diagnosed on their initial visit were chosen, and randomly divided into 3 groups: chemotherapy alone group (control group) of 21 cases, Shenqifuzheng injection combined with chemotherapy (single drug treatment) group of 25 cases, and Shenqifuzheng injection combined with Bozhi glycopeptide and chemotherapy (combined treatment) group of 28 cases.

The difference in short-term  effect, Karnofsky score, and clinical symptoms among the three groups had statistical significance (P < 0.05). The CD4, CDs, CD4/CD8, NK in peripheral blood lymphocytes, and percentage of natural killer cells were decreased significantly after chemotherapy in the control group; while the same indexes in the treatment group with Shenqifuzheng injection and Bozhi glycopeptide and chemotherapy improved significantly (P < 0.05).

Shenqifuzheng injection combined with Bozhi glycopeptide and chemotherapy can relieve adverse reactions in treating aged lung cancer patients. The combined treatment could also enhance the quality of life, immune function, and reduce complications, and thus is worthy of application in clinical settings (Wang, Zhou, Chang & Shao, 2013).

Gastric Cancer

Rats were injected with different dosages of Shenqi Fuzheng injection (0.04 g/m1, 0.08 g/ml and O. 16 g/ml) for 1 week. Matrigel TM test was performed to detect invasion ability of cells, and RT-PCR was used to check Tn-C mRNA expression.

In treated groups, invasiveness of cells was most significant (the inhibit ratio was 34.7% in 0.16 g/ml group). The expressions of Tenascin-C were lower than those of the control. There was significant difference between the high concentration group and the control.

The expressions of Tenascin-C are down-regulated when gastric cancer MGC-803 cells were treated with Shenqi Fuzheng injection at high concentration, therefore the invasiveness of gastric tumors may be reduced (Ma et al., 2013).

Fifty-three patients with advanced gastric cancer were randomly divided into a treatment group (26 cases) or a control group (27 cases). The treatment group received S-1/cisplatin (SP) chemotherapy plus Shenqi-Fuzheng injection, while the control group was treated with SP chemotherapy only. After 2 cycles of chemotherapy, the efficacy, cellular immune function index, and adverse reactions were observed.

Shenqi-Fuzheng injection plus SP chemotherapy can improve cellular immune function, tolerance to chemotherapy, and reduce toxicity in patients with advanced gastric cancer (Yin & Jiang, 2013).

References

Dong, J., Su, S-Y., Wang, M-Y., Zhan, Z. (2010). Shenqi fuzheng, an injection concocted from chinese medicinal herbs, combined with platinum-based chemotherapy for advanced non-small-cell lung cancer: a systematic review. J Exp Clin Cancer Res, 29(1):137. doi:  10.1186/1756-9966-29-137


Jiang, H. (2012). Clinical observation of the Shenqi Fuzheng injection on the response to chemotherapy in advanced lung cancer patients. Zhong Yi Lin Chuang Yan Jiu, 4(14), 11-12.


Ma, J.W., Song, Y.C., Zhang, Y., Jia, Y., Dang, C.X., & Hou, J. (2013). Effects of Shenqi Fuzheng injection on the invasiveness of cells and expression of Tenascin-C in human gastric cancer MGC- 803 cells. Journal of Modern Oncology, 21(2), 263-266.


Qiao, S. (2012). Effect of Shenqi Fuzheng injection combined with chemotherapy in treatment of advanced non small cell lung cancer clinical observation. Chinese Journal of Practical Medicine, 7(34), 25-26.


Wang, D.H., Zhou, L.H., Chang, C., & Shao, N. (2013). Observation of clinical effects of Shenqifuzheng injection combined with Bozhi glycopeptide and chemotherapy in treating aged lung cancer patients. Medical Review, 19(4), 733-735.


Yin, L.L., & Jiang, C.Y. (2013). Observation on the influence of Shenqi-Fuzheng injection on T-lymphocyte subsets, NKcell and the leukocyte of the patients with advanced gastric cancer. International Journal of Traditional Chinese Medicine, 35(1), 22-24.

angiogenesis, Anti-angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, anti-proliferative, anti-tumor, apoptosis, Apoptotic, BAX, Bcl-2, bFGF, Breast cancer, c-Jun, Chapter 8 Injectables and Cancer Research, Chemo-sensitizer, Chemotherapy, chemotherapy support, Colon Cancer or Colorectal cancer, Cytostatic, Diarrhea or Constipation, ERK, Hair Loss, IAP, IL-10, IL-2, IL-6, IL-8, immunotolerance, JNK, Liver cancer, Lung cancer, Osteosarcoma, Pancreatic cancer, radiation support, RANK, Rectal cancer, Sarcoma, sIL-2R, TNF, tumor-inhibitory, VEGF, VEGF

Oxymatrine or Compound Matrine (Ku Shen)

Cancer: Sarcoma, pancreatic, breast, liver, lung, oral., rectal., stomach, leukemia, adenoid cystic carcinoma

Action: Anti-inflammatory, anti-proliferative, chemo-sensitizer, chemotherapy support, cytostatic, radiation support, anti-angiogenesis

Ingredients: ku shen (Sophora flavescens), bai tu ling (Heterosmilax chinensis).

TCM functions: Clearing Heat, inducing diuresis, cooling Blood, removing Toxin, dispersing lumps and relieving pain (Drug Information Reference in Chinese: See end, 2000-12).

Indications: Pain and bleeding caused by cancer.

Dosage and usage:

Intramuscular injection: 2-4 ml each time, twice daily; intravenous drip: 12 ml mixed in 200 ml NaCl injection, once daily. The total amount of 200 ml administration makes up a course of treatment. 2-3 consecutive courses can be applied.

Anti-cancer

Oxymatrine, isolated from the dried roots of Sophora flavescens (Aiton), has a long history of use in traditional Chinese medicine to treat inflammatory diseases and cancer. Kushen alkaloids (KS-As) and kushen flavonoids (KS-Fs) are well-characterized components in kushen. KS-As containing oxymatrine, matrine, and total alkaloids have been developed in China as anti-cancer drugs. More potent anti-tumor activities were identified in KS-Fs than in KS-As in vitro and in vivo (Sun et al., 2012). The four major alkaloids in compound Ku Shen injection are matrine, sophoridine, oxymatrine and oxysophocarpine (Qi, Zhang, & Zhang, 2013).

Sarcoma

When a high dose was used, the tumor-inhibitory rate of oxymatrine was 31.36%, and the vascular density of S180 sarcoma was lower than that in the control group and the expression of VEGF and bFGF was down-regulated. Oxymatrine hence has an inhibitory effect on S180 sarcoma and strong inhibitory effects on angiogenesis. Its mechanism may be associated with the down-regulating of VEGF and bFGF expression (Kong et al., 2003).

T Cell Leukemia

Matrine, a small molecule derived from the root of Sophora flavescens AIT was demonstrated to be effective in inducing T cell anergy in human T cell leukemia Jurkat cells.

The results showed that passage of the cells, and concentration and stimulation time of ionomycin on the cells could influence the ability of T cell anergy induction.

The cells exposed to matrine showed markedly decreased mRNA expression of interleukin-2, an indicator of T cell anergy. Pre-incubation with matrine or ionomycin could also shorten extracellular signal-regulated kinase (ERK) and suppress c-Jun NH(2)-terminal kinase (JNK) expression on the anergic Jurkat cells when the cells were stimulated with anti-OKT-3 plus anti-CD28 antibodies. Thus, matrine is a strong candidate for further investigation as a T cell immunotolerance inducer (Li et al., 2010).

Osteosarcoma

Results showed that treatment with oxymatrine resulted in a significant inhibition of cell proliferation and DNA synthesis in a dose-dependent manner, which has been attributed to apoptosis. Oxymatrine considerably inhibited the expression of Bcl-2 whilst increasing that of Bax.

Oxymatrine significantly suppressed tumor growth in female BALB/C nude mice bearing osteosarcoma MNNG/HOS xenograft tumors. In addition, no evidence of drug-related toxicity was identified in the treated animals by comparing the body weight increase and mortality (Zhang et al., 2013).

Pancreatic Cancer

Oxymatrine decreased the expression of angiogenesis-associated factors, including nuclear factor κB (NF-κB) and vascular endothelial growth factor (VEGF). Finally, the anti-proliferative and anti-angiogenic effects of oxymatrine on human pancreatic cancer were further confirmed in pancreatic cancer xenograft tumors in nude mice (Chen et al., 2013).

Furthermore, oxymatrine treatment led to the release of cytochrome c and activation of caspase-3 proteins. Oxymatrine can induce apoptotic cell death of human pancreatic cancer, which might be attributed to the regulation of Bcl-2 and IAP families, release of mitochondrial cytochrome c and activation of caspase-3 (Ling et al., 2011).

Rectal Carcinoma

Eighty-four patients diagnosed with rectal carcinoma at the People”s Hospital of Yichun city in Jiangxi province from September 2006 to September 2011, were randomly divided into two groups: therapeutic group and control group. The patients in the therapeutic group were treated with compound matrine and intensity modulated radiation therapy (IMRT) (30 Gy/10 f/2 W), while the patients in control group were treated with IMRT.

The clinical effect and survival rate in the therapeutic group were significantly higher (47.6%) than those in the control group (21.4%). All patients were divided by improvement, stability, and progression of disease in accordance with Karnofsky Performance Scale (KPS). According to the KPS, 16 patients had improvement, 17 stabilized and 9 had disease progress in the therapeutic group.

However, the control group had 12 improvements, 14 stabilized, and 16 disease progress. Quality of life in the therapeutic group was higher than that in the control group by rank sum test. The level of sIL-2R and IL-8 in the therapeutic group was lower on the first and 14th day, post radiation, when compared to the control group. However, there was no significant difference on the first day and 14th day, between both experimental groups post therapy, according to the student test. Compound matrine can decrease the side-effects of IMRT, significantly inhibit sIL-2R and IL-8 in peripheral blood from radiation, and can improve survival quality in patients with rectal cancer (Yin et al., 2013).

Gastric Cancer

Seventy-six cases of advanced gastric cancer were collected from June 2010 to November 2011, and randomly divided into either an experimental group or control group. Patients in the two groups were treated with matrine injection combined with SP regimen, or SP regimen alone, respectively. The effectiveness rate of the experimental group and control group was 57.5% and 52.8% respectively.

The treatment of advanced gastric cancer with matrine injection, combined with the SP regimen, can significantly improve levels of white blood cells and hemoglobin, liver function, incidence of diarrhea and constipation, and neurotoxicity, to improve the quality of life in patients with advanced gastric cancer (Xia, 2013).

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC-2) cells were cultured in vitro. MTT assay was used to measure the cell proliferative effect. Compound radix Sophorae flavescentis injection could inhibit the proliferation of ACC-2 cells in vitro, and the dosage effect relationship was significant (P < 0.01). Radix Sophorae flavescentis injection could enhance ACC-2 cells Caspase-3 protein expression (P < 0.05 or P < 0.01), in a dose-dependent manner. It also could effectively restrain human adenoid cystic carcinoma ACC-2 cells Caspases-3 protein expression, and induce apoptosis, inhibiting tumor cell proliferation (Shi & Hu, 2012).

Breast Cancer; Chemotherapy

A retrospective analysis of oncological data of 70 postoperative patients with breast cancer from January 2008 to August 2011 was performed. According to the treatment method, the patients were divided into a therapy group (n=35) or control group (n=35). Patients in the control group were treated with the taxotere, adriamycin and cyclophosphamide regimen (TAC). The therapy group was treated with a combination of TAC and sophora root injection. Improved quality of life and incidence of adverse events, before and after treatment, for 2 cycles (21 days for a cycle) were compared.

The improvement rate of total quality of life in the therapy group was higher than that of the control group (P < 0.05). The drop of white blood cells and platelets, gastrointestinal reaction, elevated SGPT, and the incidence of hair loss in the therapy group were lower than those of the control group (P < 0.05).

Sophora root injection combined with chemotherapy in treatment of breast cancer can enhance the effect of chemotherapy, reduce toxicity and side-effects, and improve quality of life (An, An, & Wu, 2012).

Lung cancer; Pleural Effusion

The therapeutic efficiency of Fufang Kushen Injection Liquid (FFKSIL), IL-2, α-IFN on lung cancer accompanied with malignancy pleural effusions, was observed.

One hundred and fifty patients with lung cancer, accompanied with pleural effusions, were randomly divided into treatment and control groups. The treatment group was divided into three groups: injected FFKSIL plus IL-2, FFKSIL plus α-tFN, and IL-2 plus α>-IFN, respectively. The control group was divided into three groups and injected FFKSIL, IL-2 and α>-IFN, respectively. The effective rate of FFKSIL, IL-2, and α-IFN in a combination was significantly superior to single pharmacotherapy. The effective rate of fufangkushen plus ct-IFN was highest. The effect of FFKSIL, IL-2, and α-IFN, in a combination, on lung cancer with pleural effusions was significantly better than single pharmacotherapy. Moreover, the effect of FFKSIL plus IL-2 or α-IFN had the greatest effect (Hu & Mei, 2012).

Gastric Cancer

Administration of FFKSIL significantly enhanced serum IgA, IgG, IgM, IL-2, IL-4 and IL-10 levels, decreased serum IL-6 and TNF-αlevels, lowered the levels of lipid peroxides and enhanced GSH levels and activities of GSH-dependent enzymes. Our results suggest that FFKSIL blocks experimental gastric carcinogenesis by protecting against carcinogen-induced oxidative damage and improving immunity activity (Zhou et al., 2012).

Colorectal Cancer; Chemotherapy

Eighty patients after colorectal cancer resection were randomly divided into two groups: 40 patients in the control group were treated with routine chemotherapy including 5-fluorouridine(5-FU), calcium folinate(CF) and oxaliplatin, and 40 patients in the experimental group were treated with the same chemotherapy regime combined with 20 mLád-1 compound Kushen injection, for 10d during chemotherapy. In the control group the numbers of CD3+,CD4+T cells,NK cells and CD4+/CD8+ ratio significantly declined relative to prior to chemotherapy (P < 0.05), while CD8+T lymphocyte number increased significantly. In the experimental group, there were no significant differences between the numbers of CD3+,CD4+,CD8+T cells ,NK cells, and CD4+/CD8+ ratio, before and after chemotherapy (P > 0.05).

Compound Kushen injection can improve the immunologic function of patients receiving chemotherapy after colorectal cancer resection (Chen, Yu, Yuan, & Yuan, 2009).

NSCLC; Chemotherapy

A total of 286 patients with advanced NSCLC were enrolled for study. The patients were treated with either compound Kushen injection in combination with NP (NVB + CBP) chemotherapy (vinorelbine and carboplatin, n = 144), or with NP (NVB + CBP) chemotherapy alone (n = 142). The following indicators were observed: levels of Hb, WBC, PLT and T cell subpopulations in blood, serum IgG level, short-term  efficacy, adverse effects and quality of life.

The gastrointestinal reactions and the myelosuppression in the combination chemotherapy group were alleviated when compared with the chemotherapy alone group, showing a significant difference (P < 0.05). CD (8)(+) cells were markedly declined in the combination chemotherapy group, and the CD (4)(+)/CD (8)(+) ratio showed an elevation trend in the chemotherapy alone group. The Karnofsky Performance Scale (KPS) scores and serum IgM and IgG levels were higher in the combination chemotherapy group than those in the chemotherapy alone group (P < 0.01 and P < 0.05).

The compound Kushen injection plus NP chemotherapy regimen showed better therapeutic effect, reduced adverse effects of chemotherapy and improved the quality of life in patients with stage III and IV NSCLC (Fan et al., 2010).

Lung Adenocarcinoma

Different concentrations of matrine injection could inhibit the growth of SPCA/I human lung adenocarcinoma cells. There was a positive correlation between the inhibition rate and the drug concentration. Different concentrations of matrine injection combined with anti-tumor drugs had a higher growth inhibition rate than anti-tumor drugs alone. Matrine injection has direct growth suppression effect on SPCA/I human lung adenocarcinoma cells and SS+ injection combined with anti-tumor drugs shows a significant synergistic effect on tumor cells (Zhu, Jiang, Lu, Guo, & Gan, 2008).

Liver Cancer

Fifty-seven patients with unresectable primary liver cancer were randomly divided into 2 groups. The treatment group with 27 cases was treated by TACE combined with composite Kushen injection, and the control group with 30 cases was treated by TACE alone. One, two, and three year survival rates of the treatment group were 67%, 48%, and 37% respectively, and those of control group were 53%, 37%, and 20% respectively. There were significant differences between both groups (P < 0.05).

Combined TACE with composite Kushen injection can increase the efficacy of patients with unresectable primary liver cancer (Wang & Cheng, 2009).

Chemotherapy

Ten RCTs were included in a meta-analysis, whose results suggest that compared with chemotherapy alone, the combination had a statistically significant benefit in healing efficacy and improving quality of life. As well,  the combination also had a statistically significant benefit in myelosuppression, white blood cell, hematoblast, liver function and in reducing the gastroenteric reaction, decreasing the of CD3, CD4, CD4/CD8, and NK cells (Huang et al., 2011).

Colorectal Cancer, NSCLC, Breast Cancer; Chemotherapy

Fufang kushen Injection might improve the efficacies of chemotherapy in patients with colorectal cancer, NSCLC and breast cancer.

The results of a meta-analysis of 33 studies of randomized controlled trials with a total of 2,897 patients demonstrated that the short-term efficacies in patients with colorectal cancer, NSCLC, and breast cancer receiving Fufangkushen Injection plus chemotherapy were significantly better than for those receiving chemotherapy alone. However the results for patients with gastric cancer on combined chemotherapy were not significantly different from those for patients on chemotherapy alone (Fang, Lin, & Fan, 2011).

References

An, A.J., An, G.W., & Wu, Y.C. (2012). Observation of compound recipe light yellow Sophora root injection combined with chemotherapy in treatment of 35 postoperative patients with breast cancer. Medical & Pharmaceutical Journal of Chinese People”s Liberation Army, 24(10), 43-46. doi: 10.3969/j.issn.2095-140X.2012.10.016.


Chen, G., Yu, B., Yuan, S.J., & Yuan, Q. (2009). Effects of compound Kushen injection on the immunologic function of patients after colorectal cancer resection. Evaluation and Analysis of Drug-Use in Hospitals of China, 2009(9), R735.3. doi: cnki:sun:yypf.0.2009-09-025.


Chen H, Zhang J, Luo J, et al. (2013). Anti-angiogenic effects of oxymatrine on pancreatic cancer by inhibition of the NF-κB-mediated VEGF signaling pathway. Oncol Rep, 30(2):589-95. doi: 10.3892/or.2013.2529.


Fan, C.X., Lin, C.L., Liang, L., Zhao, Y.Y., Liu, J., Cui, J., Yang, Q.M., Wang, Y.L., & Zhang, A.R. (2010). Enhancing effect of compound Kushen injection in combination with chemotherapy for patients with advanced non-small-cell lung cancer. Chinese Journal of Oncology, 32(4), 294-297.


Fang, L., Lin, N.M., Fan, Y. (2011). Short-term  efficacies of Fufangkushen Injection plus chemotherapy in patients with solid tumors: a meta-analysis of randomized trials. Zhonghua Yi Xue Za Zhi, 91(35):2476-81.


Hu, D.J., & Mei, X.D. (2012). Observing therapeutic efficiency of fufangkushen injection, IL-2, α-IFN on lung cancer accompanied with malignancy pleural effusions. Journal of Clinical Pulmonology, 17(10), 1844-1845.


Huang S, Fan W, Liu P, Tian J. (2011). Meta-analysis of compound matrine injection combined with cisplatin chemotherapy for advanced gastric cancer. Zhongguo Zhong Yao Za Zhi, 36(22):3198-202.


Kong, Q-Z., Huang, D-S., Huang, T. et al. (2003). Experimental study on inhibiting angiogenesis in mice S180 by injections of three traditional Chinese herbs. Chinese Journal of Hospital Pharmacy, 2003-11. doi: CNKI:SUN:ZGYZ.0.2003-11-002


Li T, Wong VK, Yi XQ, et al. (2010). Matrine induces cell anergy in human Jurkat T cells through modulation of mitogen-activated protein kinases and nuclear factor of activated T-cells signaling with concomitant up-regulation of anergy-associated genes expression. Biol Pharm Bull, 33(1):40-6.


Ling Q, Xu X, Wei X, et al. (2011). Oxymatrine induces human pancreatic cancer PANC-1 cells apoptosis via regulating expression of Bcl-2 and IAP families, and releasing of cytochrome c. J Exp Clin Cancer Res, 30:66. doi: 10.1186/1756-9966-30-66.


Qi, L., Zhang, J., Zhang, Z. (2013). Determination of four alkaloids in Compound Kushen Injection by high performance liquid chromatography with ionic liquid as mobile phase additive. Chinese Journal of Chromatography, 31(3): 249-253. doi: 10.3724/SP.J.1123.2012.10039.


Shi, B., & Xu, H. (2012). Effects of compound radix Sophorae flavescentis injection on proliferation, apoptosis and caspase-3 expression in adenoid cystic carcinoma ACC-2 cells. Chinese Pharmacological Bulletin, 5(10), 721-724.


Sun M, Cao H, Sun L, et al. (2012). Anti-tumor activities of kushen: literature review. Evid Based Complement Alternat Med, 2012:373219. doi: 10.1155/2012/373219.


Wang, H.M., & Cheng, X.M. (2009). Composite Ku Shen injection combined with hepatic artery embolism on unresectable primary liver cancer. Modern Journal of Integrated Traditional Chinese and Western Medicine, 18(2), 1334–1335.


Xia, G. (2013). Clinical observation of compound matrine injection combined with SP regimen in advanced gastric cancer. Journal of Liaoning Medical University, 2013(1), 37-38.


Yin, W.H., Sheng, J.W., Xia, H.M., Chen, J., Wu, Y.W., & Fan, H.Z. (2013). Study on the effect of compound matrine on the level of sIL-2R and IL-8 in peripheral blood cells of patients with rectal cancer to radiation. Global Traditional Chinese Medicine, 2013(2), 100-104.


Zhang Y, Sun S, Chen J, et al. (2013). Oxymatrine induces mitochondria dependent apoptosis in human osteosarcoma MNNG/HOS cells through inhibition of PI3K/Akt pathway. Tumor Biol.


Zhou, S-K., Zhang, R-L., Xu, Y-F., Bi, T-N. (2012) Anti-oxidant and Immunity Activities of Fufang Kushen Injection Liquid. Molecules 2012, 17(6), 6481-6490; doi:10.3390/molecules17066481


Zhu, M.Y., Jiang, Z.H., Lu, Y.W., Guo, Y., & Gan, J.J. (2008). Matrine and anti-tumor drugs in inhibiting the growth of human lung cancer cell line. Journal of Chinese Integrative Medicine, 6(2), 163-165. doi: 10.3736/jcim20080211.

anti-apoptotic, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Autophagy, BAX, Bcl-2, Breast cancer, cancer stem cells, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, CSCs, EpCAM, Esophageal cancer, FAK, G0/G1, G1, G2/M, Glioblastoma, induces apoptosis, Leukemia, Liver cancer, metastasis, Ovarian cancer, p21, p53, Prostate cancer, Prostate cancer cell lines, Rabdosia rubescens, Rectal cancer, TrxR

Oridonin

Cancer: Prostate

Action: Growth arrest, autophagy

To investigate the mechanism of oridonin (ORI)-induced autophagy in prostate cancer PC-3 cells, PC-3 cells cultured in vitro were treated with ORI, and the inhibitory ratio of ORI on PC-3 cells was assayed by 3-4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. After ORI treatment, the proliferation of PC-3 cells was inhibited significantly in a concentration and time-dependent manner. SEM examination revealed cellular shrinkage and disappearance of surface microvilli in ORI-treated cells. Under TEM examination, the nuclei exhibited chromatin condensation and the appearance of a large number of autophagosomes with double-membrane structure in cytoplasm. AO staining showed the existence of AVOs. The expression of LC3 and the mRNA level of beclin 1 was increased by ORI. Furthermore, autophagy inhibitor 3-methyladenine reversed the increase of beclin 1 mRNA. The growth of PC-3 cells was inhibited, and autophagy was induced by ORI, indicating ORI may have a potential antitumor effect.

Source
Ye LH, Li WJ, Jiang XQ, et al. Study on the autophagy of prostate cancer PC-3 cells induced by oridonin. Anat Rec (Hoboken). 2012 Mar;295(3):417-22. doi: 10.1002/ar.21528.

 

Cancer: Multiple myeloma

Action: Inhibits proliferation and induces apoptosis

This study was purposed to investigate the antitumor effect of oridonin on human multiple myeloma cell line U266 The results showed that the oridonin obviously inhibited the growth of U266 cell in dose-and time-dependent manners. As for morphological changes, characteristic apoptotic cells presented in U266 cells treated with 10 µmol/L oridonin for 24 hours. The apoptotic rate of U266 cells increased in dose and time dependent manners; after treatment of U266 cells with oridonin the mRNA levels of FGFR3, BCL2, CCND1 and MYC as well as the their protein levels decreased. Occasionally, the oridonin up-regulated the protein levels of P53 in the same manner. It is concluded that the oridonin can exert its anti-tumor effect by inhibiting proliferation and inducing apoptosis of U266 cell in dose dependent and time dependent manners, that maybe give the clues about new program of target therapy for multiple myeloma.

Source:

Duan HQ, Li MY, Gao L, et al. Mechanism concerning antitumor effect of oridonin on multiple myeloma cell line U266. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Apr;22(2):364-9. doi: 10.7534/j.issn.1009-2137.2014.02.018.

Cancer: Multiple myeloma

Action: Induces apoptosis and autophagy

Exposure to oridonin (1-64 μmol/L) inhibited the proliferation of RPMI8266 cells in a concentration-dependent manner with an IC(50) value of 6.74 μmol/L. Exposure to oridonin (7 μmol/L) simultaneously induced caspase 3-mediated apoptosis and Beclin 1-dependent autophagy of RPMI8266 cells. Both the apoptosis and autophagy were time-dependent, and apoptosis was the main effector pathway of cell death. Exposure to oridonin (7 μmol/L) increased intracellular ROS and reduced SIRT1 nuclear protein in a time-dependent manner.

Oridonin simultaneously induces apoptosis and autophagy of human multiple myeloma RPMI8266 cells via regulation of intracellular ROS generation and SIRT1 nuclear protein. The cytotoxicity of oridonin is mainly mediated through the apoptotic pathway, whereas the autophagy protects the cells from apoptosis.

Source

Zeng R, Chen Y, Zhao S, Cui GH.Autophagy counteracts apoptosis in human multiple myeloma cells exposed to oridonin in vitro via regulating intracellular ROS and SIRT1. Acta Pharmacol Sin. 2012 Jan;33(1):91-100. doi: 10.1038/aps.2011.143.

Cancer: Prostate, acute promyelocytic leukemia, breast, non-small-cell lung (NSCL), Ehrlich ascites, P388 lymphocytic leukemia, colorectal., ovarian, esphageal

Action: Chemoresistance, Ara-C, VP-16 

Cancer cell arises in part through the acquisition of apoptotic resistance. Leukemia cells resistant to chemotherapy-induced apoptosis have been found to be sensitive to oridonin, a natural agent with potent anticancer activity. Weng et al., (2014) compared the response of human leukemia cells with oridonin and the antileukemia drugs Ara-C and VP-16. Compared with HL60 cells, K562 and K562/ADR cells displayed resistance to apoptosis stimulated by Ara-C and VP-16 but sensitivity to oridonin. Mechanistic investigations revealed that oridonin upregulated BIM-S by diminishing the expression of miR-17 and miR-20a, leading to mitochondria-dependent apoptosis. In contrast, neither Ara-C nor VP-16 could reduce miR-17 and miR-20a expression or could trigger BIM-S–mediated apoptosis.

Notably, silencing miR-17 or miR-20a expression by treatment with microRNA (miRNA; miR) inhibitors or oridonin restored sensitivity of K562 cells to VP-16. Synergistic effects of oridonin and VP-16 were documented in cultured cells as well as mouse tumor xenograft assays. Inhibiting miR-17 or miR-20a also augmented the proapoptotic activity of oridonin. Taken together, our results identify a miRNA-dependent mechanism underlying the anticancer effect of oridonin and provide a rationale for its combination with chemotherapy drugs in addressing chemoresistant leukemia cells.

Reference

Weng Hy, Huang Hl, Dong B, et al. Inhibition of miR-17 and miR-20a by Oridonin Triggers Apoptosis and Reverses Chemoresistance by Derepressing BIM-S. Cancer Res; 74(16); 1–11. doi: 10.1158/0008-5472.CAN-13-1748

Action: Induces apoptosis

Oridonin is a tetracycline diterpenoid isolated from the plant Rabdosia rubescens (RR) [(Hemsl.). Hara (Lamiaceae)] (dong ling cao) is a Chinese medicinal herb used widely in provinces including Henan. The aerial parts of RR and other species of the same genus has been reported to have the functions of clearing “heat” and “toxicity”, nourishing “yin”, removing “blood stasis”, and relieving swelling. RR has been used to treat stomach-ache, sore throat and cough.

Gastric Cancer, Esophageal Cancer, Liver Cancer, Prostate Cancer

RR and its extracts have been shown to be able to suppress disease progress, reduce tumor burden, alleviate syndrome and prolong survival in patients with gastric carcinoma, esophageal., liver and prostate cancers (Tang & Eisenbrand, 1992). Interestingly, other Isodon plants including Isodon japonicus Hara (IJ) and I. trichocarpus (IT) are also applied as home remedies for similar disorders in Japan and Korea.

Induces Apoptosis

These reports suggest that Isodon plants should have at least one essential anti-tumor component. In the 1970s, a bitter tetracycline diterpenoid compound, oridonin, was isolated from RR, IJ, and IT separately, and was shown to be a potent apoptosis inducer in a variety of cancer cells (Fujita et al., 1970; Fujita et al., 1976; Henan Medical Institute, 1978; Fujita et al., 1988).

Anti-cancer

There is currently research being undertaken regarding the relationship between the chemical structure/modifications and the molecular mechanisms underlying its anti-cancer activity, such as suppression of tumor proliferation and induction of tumor cell death, and the cell signal transduction in anti-cancer activity of oridonin (Zhang et al., 2010).

Prostate Cancer, Breast Cancer, NSCLC, Leukemia, Glioblastoma

Oridonin has been found to effectively inhibit the proliferation of a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7, MDA-MB231), non-small-cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers, acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138).

Oridonin induced apoptosis and G0/G1 cell-cycle arrest in LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in a p53-dependent manner. Taken together, oridonin inhibited the proliferation of cancer cells via apoptosis and cell-cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies (Ikezoe et al., 2003).

Breast Cancer; Anti-metastatic

According to the flow cytometric analysis, oridonin suppressed MCF-7 cell growth by cell-cycle arrest at the G2/M phase and caused accumulation of MDA-MB-231 cells in the Sub-G1 phase. The induced apoptotic effect of oridonin was further confirmed by a morphologic characteristics assay and TUNEL assay. Meanwhile, oridonin significantly suppressed MDA-MB-231 cell migration and invasion, decreased MMP-2/MMP-9 activation and inhibited the expression of Integrin β1 and FAK. In conclusion, oridonin inhibited growth and induced apoptosis in breast cancer cells, which might be related to DNA damage and activation of intrinsic or extrinsic apoptotic pathways. Moreover, oridonin also inhibited tumor invasion and metastasis in vitro possibly via decreasing the expression of MMPs and regulating the Integrin β1/FAK pathway in MDA-MB-231 cells (Wang et al., 2013).

Gastric Cancer

The inhibitory effect of oridonin on gastric cancer HGC-27 cells was detected using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. After treated with oridonin (0, 1.25, 2.5, 5 and 10 µg/mL), HGC-27 cells were collected for anexin V-phycoerythrin and 7-amino-actinomycin D double staining and tested by flow cytometric analysis, and oridonin- induced apoptosis in HGC-27 cells was detected.

Oridonin significantly inhibited the proliferation of HGC-27 cells in a dose- and time-dependent manner. The inhibition rates of HGC-27 treated with four different concentrations of oridonin for 24 h (1.25, 2.5, 5 and 10 µg/mL) were 1.78% ± 0.36%, 4.96% ± 1.59%, 10.35% ± 2.76% and 41.6% ± 4.29%, respectively, which showed a significant difference (P < 0.05. Cells treated with oridonin showed typical apoptotic features with acridine orange/ethidium bromide staining. After treatment with oridonin, the cells became round, shrank, and developed small buds around the nuclear membrane while forming apoptotic bodies. However, the change in the release of LDH caused by necrosis was insignificant, suggesting that the major cause of oridonin-induced HGC-27 cell death was apoptosis. Flow cytometric analysis also revealed that oridonin induced significant apoptosis compared with the controls (P < 0.05).

Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1, caspase-3 and cytochrome c, which are highly dependent upon the mitochondrial pathway (Sun et al., 2012).

Ehrlich Ascites, Leukemia

Oridonin has been found to also increase lifespan of mice bearing Ehrlich ascites or P388 lymphocytic leukemia. Oridonin triggered apoptosis in more than 50% of t(8;21) leukemic cells in vitro at concentration of 2 M or higher accompanied by degradation of AE oncoprotein, and showed significant anti-leukemia efficacies with low adverse effects in vivo. These data suggest possible beneficial effects for patients with t(8;21) acute myeloid leukemia (AML) (Zhou et al., 2007).

Prostate Cancer, Breast Cancer, Ovarian Cancer

Oridonin exhibited anti-proliferative activity toward all cancer cell lines tested, with an IC50 estimated by the MTT cell viability assay ranging from 5.8+/-2.3 to 11.72+/-4.8 microM. The increased incidence of apoptosis, identified by characteristic changes in cell morphology, was seen in tumor lines treated with oridonin. Notably, at concentrations that induced apoptosis among tumor cells, oridonin failed to induce apoptosis in cultures of normal human fibroblasts. Oridonin up-regulated p53 and Bax and down-regulated Bcl-2 expression in a dose-dependent manner and its absorption spectrum was measured in the presence and absence of double stranded (ds) DNA. Oridonin inhibits cancer cell growth in a cell-cycle specific manner and shifts the balance between pro- and anti-apoptotic proteins in favor of apoptosis. The present data suggest that further studies are warranted to assess the potential of oridonin in cancer prevention and/or treatment (Chen et al., 2005).

Ovarian Cancer Stem Cells; Chemotherapy Resistance

Oridonin was suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these types of compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Colorectal Cancer

Oridonin induced potent growth inhibition, cell-cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice.

Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell-cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment as it has been shown to induce apoptosis and senescence of colon cancer cells in vitro and in vivo (Gao et al., 2010).

Colon Cancer; Apoptosis

Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin.

Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process.

Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate (Gao et al., 2012).

Prostate Cancer; Apoptosis

Oridonin (ORI) could inhibit the proliferation and induce apoptosis in various cancer cell lines. After ORI treatment, the proliferations of human prostate cancer (HPC) cell lines PC-3 and LNCaP were inhibited in a concentration and time-dependent manner. ORI induced cell-cycle arrest at the G2/M phase. Autophagy occurred before the onset of apoptosis and protected cancer cells in ORI-treated HPC cells. P21 was involved in ORI-induced autophagy and apoptosis (Li et al., 2012).

References

Chen S, Gao J, Halicka HD, et al. (2005). The cytostatic and cytotoxic effects of oridonin (Rubescenin), a diterpenoid from Rabdosia rubescens, on tumor cells of different lineage. Int J Oncol, 26(3):579-88.

 

Chen SS, Michael A, Butler-Manuel SA. (2012). Advances in the treatment of ovarian cancer: a potential role of anti-inflammatory phytochemicals. Discov Med, 13(68):7-17.

 

Fujita E, Fujita T, Katayama H, Shibuya M. (1970). Terpenoids. Part XV. Structure and absolute configuration of oridonin isolated from Isodon japonicus trichocarpus. J Chem Soc (Chem Comm), 21:1674–1681

 

Fujita E, Nagao Y, Node M, et al. (1976). Anti-tumor activity of the Isodon diterpenoids: structural requirements for the activity. Experientia, 32:203–206.

 

Fujita T, Takeda Y, Sun HD, et al. (1988). Cytotoxic and anti-tumor activities of Rabdosia diterpenoids. Planta Med, 54:414–417.

 

Henan Medical Institute, Henan Medical College, Yunnan Institute of Botany. (1978). Oridonin–a new anti-tumor subject. Chin Science Bull, 23:53–56.

 

Ikezoe T, Chen SS, Tong XJ, et al. (2003). Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int J Oncol, 23(4):1187-93.

 

Gao FH, Hu XH, Li W, Liu H, et al. (2010). Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc. BMC Cancer, 10:610. doi: 10.1186/1471-2407-10-610.

 

Gao FH, Liu F, Wei W, et al. (2012). Oridonin induces apoptosis and senescence by increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells. Int J Mol Med, 29(4):649-55. doi: 10.3892/ijmm.2012.895.

 

Li X, Li X, Wang J, Ye Z, Li JC. (2012) Oridonin up-regulates expression of P21 and induces autophagy and apoptosis in human prostate cancer cells. Int J Biol Sci. 2012;8(6):901-12. doi: 10.7150/ijbs.4554.

 

Sun KW, Ma YY, Guan TP, et al. (2012). Oridonin induces apoptosis in gastric cancer through Apaf-1, cytochrome c and caspase-3 signaling pathway. World J Gastroenterol, 18(48):7166-74. doi: 10.3748/wjg.v18.i48.7166.

 

Tang W, Eisenbrand G. (1992). Chinese drugs of plant origin: chemistry, pharmacology, and use in traditional and modern medicine. Berlin: Springer-Verlag, 817–847.

 

Wang S, Zhong Z, Wan J, et al. (2013). Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic human breast cancer cells. Am J Chin Med, 41(1):177-96. doi: 10.1142/S0192415X13500134.

 

Zhang Wj, Huang Ql, Hua Z-C. (2010). Oridonin: A promising anti-cancer drug from China. Frontiers in Biology, 5(6):540-545.

 

Zhou G-B, Kang H, Wang L, et al. (2007). Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent anti-tumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood, 109(8):3441-3450.

Akt, angiogenesis, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-oxidant, anti-proliferative, AP-1, apoptosis, apoptosis-inducing, Apoptotic, Bcl-xL, Breast cancer, CCNE2, CDK2, CDK4, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, chemo-preventive, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, CSCs, EpCAM, G2/M, hepato-protective, IL-6, Immunomodulatory, including Terminalia chebula, inflammation, inhibits VEGF, iNOS, JNK, Lung cancer, Mcl-1, metastasis, Nitric Oxide, Ovarian cancer, p53, p65, Pancreatic cancer, PGE2, Pro-apoptotic, Radio-protective, TAM chemo-sensitizer, TAM resistance, TNF, TRAIL, VEGF, VEGF

Luteolin

Cancer: Colorectal., pancreatic, ovarian, breast

Action: Anti-inflammatory, radio-protective, TAM chemo-sensitizer

Luteolin is a flavonoid found in many plants and foods, including Terminalia chebula (Retz.), Prunella vulgaris (L.) and Perilla frutescens [(L.) Britton].

Luteolin is contained in Ocimum sanctum L. or Ocimum tenuiflorum L, commonly known as Holy Basil in English or Tulsi in various Indian languages; it is an important medicinal plant in the various traditional and folk systems of medicine in Southeast Asia. Scientific studies have shown it to possess anti-inflammatory, anti-analgesic, anti-pyretic, anti-diabetic, hepato-protective, hypolipidemic, anti-stress, and immunomodulatory activities. It has been found to prevent chemical-induced skin, liver, oral., and lung cancers and mediates these effects by increasing the anti-oxidant activity, altering the gene expressions, inducing apoptosis, and inhibiting angiogenesis and metastasis.

Radio-protective

The aqueous extract of Tulsi has been shown to protect mice against γ-radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. The chemo-preventive and radio-protective properties of Tulsi emphasize aspects that warrant future research to establish its activity and utility in cancer prevention and treatment (Baliga et al., 2013).

Anti-inflammatory

Pre-treatment of RAW 264.7 with luteolin, luteolin-7-glucoside, quercetin, and the isoflavonoid genistein inhibited both the LPS-stimulated TNF-αand interleukin-6 release, whereas eriodictyol and hesperetin only inhibited TNF-αrelease. From the compounds tested luteolin and quercetin were the most potent in inhibiting cytokine production with an IC50 of less than 1 and 5 µM for TNF-αrelease, respectively. Pre-treatment of the cells with luteolin attenuated LPS-induced tyrosine phosphorylation of many discrete proteins. Luteolin inhibited LPS-induced phosphorylation of Akt. Treatment of macrophages with LPS resulted in increased IκB-αphosphorylation and reduced the levels of IκB-α. It was concluded that luteolin inhibits protein tyrosine phosphorylation, nuclear factor-κB-mediated gene expression and pro-inflammatory cytokine production in murine macrophages (Xagorari et al., 2001).

Luteolin (Lut) possesses significant anti-inflammatory activity in well established models of acute and chronic inflammation, such as xylene-induced ear edema in mice (ED50= 107 mg/ kg), carrageenin-induced swellingof the ankle, acetic acid-induced pleurisy and croton oil-induced gaseous pouch granuloma in rats. Its combined immunostimulatory and anti-inflammatory activity, and inhibitory effect upon immediate hypersensitive response provide the pharmacologic bases for the beneficial effects of Lut in the treatment of chronic bronchitis (Chen et al., 1986).

Anti-inflammatory; Lung

Luteolin dose-dependently inhibited the expression and production of nitric oxide (NO) and prostaglandin E2 (PGE2), as well as the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Luteolin also reduced the DNA binding activity of nuclear factor-kappa B (NF-κB) in LPS-activated macrophages. Moreover, luteolin blocked the degradation of IκB-α and nuclear translocation of NF-κB p65 subunit.

In sum, these data suggest that, by blocking NF-κ>B and AP-1 activation, luteolin acts to suppress the LPS-elicited inflammatory events in mouse alveolar macrophages, and this effect was mediated, at least in part, by inhibiting the generation of reactive oxygen species. These observations suggest a possible therapeutic application of this agent for treating inflammatory disorders in the lung (Chen et al., 2007).

Anti-inflammatory; Neuroinflammation

Pre-treatment of primary murine microglia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. Whereas luteolin had no effect on the LPS-induced increase in NF-κB DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 hours after injection. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation (Jang et al., 2008).

Colon Cancer

Activities of CDK4 and CDK2 decreased within 2 hours after luteolin treatment, with a 38% decrease in CDK2 activity (P < 0.05) observed in cells treated with 40 µmol/l luteolin. Luteolin inhibited CDK2 activity in a cell-free system, suggesting that it directly inhibits CDK2.

tLuteolin promoted G2/M arrest at 24 hours post-treatment  by down-regulating cyclin B1 expression and inhibiting cell division cycle (CDC)2 activity. Luteolin promoted apoptosis with increased activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and decreased expression of p21CIP1/WAF1, survivin, Mcl-1, Bcl-xL, and Mdm-2. Decreased expression of these key antiapoptotic proteins could contribute to the increase in p53-independent apoptosis that was observed in HT-29 cells. Lim et al., (2007) demonstrated that luteolin promotes both cell-cycle arrest and apoptosis in the HT-29 colon cancer cell line, providing insight about the mechanisms underlying its anti-tumorigenic activities.

Pancreatic Cancer; Chemotherapy

Simultaneous treatment or pre-treatment (0, 6, 24 and 42 hours) of flavonoids and chemotherapeutic drugs and various concentrations (0-50µM) were assessed using the MTS cell proliferation assay. Simultaneous treatment with either flavonoid (0,13, 25 or 50µM) and chemotherapeutic drugs 5-fluorouracil (5-FU, 50µM) or gemcitabine (Gem, 10µM) for 60h resulted in less-than-additive effect (p<0.05). Pre-treatment for 24 hours with 13µM of either Api or Lut, followed by Gem for 36 hours was optimal to inhibit cell proliferation.

Pre-treatment of cells with 11-19µM of either flavonoid for 24 hours resulted in 59-73% growth inhibition when followed by Gem (10µM, 36h). Lut (15µM, 24h) Pre-treatment followed by Gem (10µM, 36h), significantly decreased protein expression of nuclear GSK-3βand NF-κB p65 and increased pro-apoptotic cytosolic cytochrome c. Pre-treatment of human pancreatic cancer cells BxPC-3 with low concentrations of Lut effectively aid in the anti-proliferative activity of chemotherapeutic drugs (Johnson et al., 2013).

Ovarian Cancer

Luteolin has been found to repress NF-kappaB (NF-κ>B, a pro-inflammatory transcription factor) and inhibit pro-inflammatory cytokines such as TNF-αand IL-6. Additionally, it has been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance.

Recent studies further indicate that luteolin potently inhibits VEGF production and suppresses ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Chemo-sensitizer

The sensitization effect of luteolin on cisplatin-induced apoptosis is p53 dependent, as such effect is only found in p53 wild-type cancer cells but not in p53 mutant cancer cells. Moreover, knockdown of p53 by small interfering RNA made p53 wild-type cancer cells resistant to luteolin and cisplatin. Second, Shi et al., (2007) observed a significant increase of p53 protein level in luteolin-treated cancer cells without increase of p53 mRNA level, indicating the possible effect of luteolin on p53 posttranscriptional regulation.

In summary, data from this study reveal a novel molecular mechanism involved in the anti-cancer effect of luteolin and support its potential clinical application as a chemo-sensitizer in cancer therapy.

Breast Cancer; TAM Chemo-sensitizer

This study found that the level of cyclin E2 (CCNE2) mRNA was higher in tumor cells (4.89-fold, (∗)P=0.005) than in normal paired tissue samples as assessed using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis (n=257). Further, relatively high levels of CCNE2 protein expression were detected in tamoxifen-resistant (TAM-R) MCF-7 cells.

These results showed that the level of CCNE2 protein expression was specifically inhibited in luteolin-treated (5µM) TAM-R cells, either in the presence or absence of 4-OH-TAM (100nM). Combined treatment with 4-OH-TAM and luteolin synergistically sensitized the TAM-R cells to 4-OH-TAM. The results of this study suggest that luteolin can be used as a chemo-sensitizer to target the expression level of CCNE2 and that it could be a novel strategy to overcome TAM resistance in breast cancer patients (Tu et al., 2013).

References

Baliga MS, Jimmy R, Thilakchand KR, et al. (2013). Ocimum sanctum L (Holy Basil or Tulsi) and its phytochemicals in the prevention and treatment of cancer. Nutr Cancer, 65(1):26-35. doi: 10.1080/01635581.2013.785010.


Chen CY, Peng WH, Tsai KD and Hsu SL. (2007). Luteolin suppresses inflammation-associated gene expression by blocking NF-κB and AP-1 activation pathway in mouse alveolar macrophages. Life Sciences, 81(23-24):1602-1614. doi:10.1016/j.lfs.2007.09.028


Chen MZ, Jin WZ, Dai LM, Xu SY. (1986). Effect of luteolin on inflammation and immune function. Chinese Journal of Pharmacology and Toxicology, 1986-01.


Chen SS, Michael A, Butler-Manuel SA. (2012). Advances in the treatment of ovarian cancer: a potential role of anti-inflammatory phytochemicals. Discov Med, 13(68):7-17.


Jang S, Kelley KW, Johnson RW. (2008). Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. PNAS, 105(21):7534-7539


Johnson JL, Gonzalez de Mejia E. (2013). Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem Toxicol, S0278-6915(13)00491-2. doi: 10.1016/j.fct.2013.07.036.


Lim DY, Jeong Y, Tyner Al., Park JHY. (2007). Induction of cell-cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am J Physiol Gastrointest Liver Physiol, 292: G66-G75. doi:10.1152/ajpgi.00248.2006.


Shi R, Huang Q, Zhu X, et al. (2007). Luteolin sensitizes the anti-cancer effect of cisplatin via c-Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization. Molecular Cancer Therapeutics, 6(4):1338-1347. doi: 10.1158/1535-7163.MCT-06-0638.


Tu SH, Ho CT, Liu MF, et al. (2013). Luteolin sensitizes drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression. Food Chem, 141(2):1553-61. doi: 10.1016/j.foodchem.2013.04.077.


Xagorari A, Papapetropoulos A, Mauromatis A, et al. (2001). Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and pro-inflammatory cytokine production in macrophages. JPET, 296(1):181-187.

angiogenesis, anti-apoptotic, Anti-cancer, anti-tumor, Anti-tumoral, apoptosis, Apoptotic, Bcl-2, Chapter 8 Injectables and Cancer Research, Chemotherapy, chemotherapy support, EGFR, epidermal growth factor receptor, Esophageal cancer, Fas/APO-1, FasL, IKK, IL-1, IL-2, immunomodular, Liver cancer, Lung cancer, Lymphoma, MDR, metastasis, Pro-apoptotic, radiation support, radiotherapy

Kanglaite injection (KLT)

Cancer: Lung, stomach, liver, kidney, breast, nasopharynx, esophagus, pancreas, colon-rectum, ovarian, prostate, lymphoma, leukemia

Action: Anti-tumoral, immunomodular, chemotherapy support, radiation support

Ingredients: yi yi ren (Coix Lacryma-jobi seed oil, CLSO).

Indications: primary NSCLC and primary liver cancer, which are not suitable for surgery, of qi and yin deficiency, lingering “Dampness due to Spleen deficiency types”. It has synergic effect when combined with radiotherapy or chemotherapy. It has certain anti-cachexia and analgesic effects for middle or late-stage tumor patients.

Dosage and usage:

Slow intravenous drip: 200 ml, once daily, 21 days as a course of treatment with 3-5 days interval.

When combined with radiotherapy or chemotherapy, the dosage can be reduced according to the practical conditions. (Drug Information Reference in Chinese, 2000. See end).

Invented by the famous pharmacological professor, Prof. Li Dapeng, Kanglaite Injection (KLT) has been listed by the Chinese government as a “State Basic Drug”, a “State Basic Medical Insurance Drug” and a “State Key New Drug”.

Based on pre-clinical studies at John Hopkins University, USA, tumor-inhibitive rate of KLT on transplanted breast carcinoma induced by cell strain MDA-MB-231 was over 50%. KLT could inhibit the expression of COX2 of the strain in vitro and act as an inhibitor of fatty acid synthase.

The broad ranged basic studies in China also revealed KLT different mechanisms such as inducing cancer cell apoptosis, inhibiting angiogenesis, reversing MDR and regulating gene expression of Fas/Apo-1 and Bcl-2.

Both Chinese and overseas clinical experiences have shown that KLT has proven effect in the treatment of cancers mainly at the sites of lung, breast, liver, nasopharynx, esophagus, stomach, pancreas, kidney, colon-rectum, ovary and prostate. This agent is also applied in the treatment of malignant lymphoma and acute leukemia. KLT has brought great benefits to over 500,000 cancer patients in more than 2,000 big or medium hospitals in China since 1997.

The year 1995 witnessed KLT patent certificates granted from China and the USA. In August 1997 the phase III clinical study was successfully completed and the injection was officially launched in China after final approval from the Ministry of Public Health.

Doctors in America carried out a phase 1 study of Kanglaite in 2003. They gave it to 16 people who had different types of cancer including lung, prostate and oesophageal cancers. The results showed people did not have many side-effects but the effect on their cancer varied. Some people showed no response, and their cancers continued to grow. But in others, the cancer stopped growing for a few months.

Standard treatment course for KLT is 200 ml (2 bottles) per day via intravenous drip x 42 days (84 bottles). There is a break for 4-5 days after 21 days. Clinical experiences in China and Russia suggest 2 treatment courses for those with late stage advanced and metastatic tumors for better therapeutic effect and evident prolongation of life (Conti, n.d.).

A consecutive cohort of 60 patients was divided into two groups, the experimental group receiving Kanglaite” Injection combined with chemotherapy and the control group receiving chemotherapy alone. After more than two courses of treatment, efficacy, quality of life and side-effects were evaluated. The response rate and KPS score of the experimental group were significantly improved as compared with those of the control group(P<0.05). In addition, gastrointestinal reactions and bone marrow suppression were significantly lower than in the control group(P<0.05). Kanglaite” Injection enhanced efficacy and reduced the side-effects of chemotherapy, improving quality of life of gastric cancer patients (Zhan et al., 2012).

Lung Cancer

C57BL/6 mice with Lewis lung carcinoma were divided into four groups: the control group (C), cisplatin group (1 mg/kg, DDP), low KLT group (6.25 ml/kg body weight [L]), and high KLT group (12.5 ml/kg body weight [H]). T cell proliferation was determined by the MTT assay. Nuclear factor-kappa B (NF-κB), inhibitor kappa B alpha

(IκBα), IκB kinase (IKK) and epidermal growth factor receptor (EGFR) levels were measured by western blotting. An enzyme-linked immunosorbent assay was used to analyze the expression of interleukin-2 (IL-2).

Intraperitoneal KLT significantly inhibited the growth of Lewis lung carcinoma, and the spleen index was significantly higher in the L and H groups than in the C group. KLT stimulated T cell proliferation in a dose-dependent manner. Treatment with KLT at either 6.25 or 12.5 ml/kg decreased the level of NF-κB in the nucleus in a dose-dependent manner, and KLT markedly decreased the expression of IκBα, IKK and EGFR in the cytoplasm of tumor cells and overall. IL-2 was significantly increased in the supernatant of splenocytes in the H group.

These results demonstrate that KLT has pronounced anti-tumor and immunostimulatory activities in C57BL/6 mice with Lewis lung carcinoma. These may affect the regulation of NF-κB/IκB expression, in addition to cytokines such as IL-2 and EGFR. Further work needs to investigate the relevant signaling pathway effects, but our findings suggest that KLT may be a promising anti-tumor drug for clinical use (Pan et al., 2012).

Skin Keratinocytes

Ultraviolet (UV) radiation plays an important role in the pathogenesis of skin photoaging. Depending on the wavelength of UV, the epidermis is affected primarily by UVB. One major characteristic of photoaging is the dehydration of the skin. Membrane-inserted water channels (aquaporins) are involved in this process. In this study we demonstrated that UVB radiation induced aquaporin-3 (AQP3) down-regulation in cultured human skin keratinocytes. Kanglaite is a mixture consisting of extractions of Coix Seed, which is an effective anti-neoplastic agent and can inhibit the activities of protein kinase C and NF-κB. We demonstrated that Kanglaite inhibited UVB-induced AQP3 down-regulation of cultured human skin keratinocytes. Our findings provide a potential new agent for anti-photoaging (Shan et al., 2012).

Hepatocellular Carcinoma

KLT produced an obvious time and dose-dependent inhibitory effect on HepG2 cells, and marked apoptosis was detected by FCM. The protein of Fas increased by 11.01%, 18.71%, 28.71% and 37.15%; the protein of FasL increased by 1.49%, 1.91%, 3.27% and 3.38% in comparison with the control (P<0.05). Real-time fluorescent quantitative RT-PCR showed that treating HepG2 cells with KLT caused the up-regulation of Fas and FasL mRNA. KLT inhibits HepG2 growth by inducing apoptosis, which may be mediated through activation of the Fas/FasL pathway (Lu et al., 2009).

Glomerular Nephritis

MTT, telomere repeat amplification protocol (TRAP), ELISA, PAGE and silver-stain were applied to detect the growth rate and telomerase activity of mesengial cell (MC) after stimulation of Kang Lai Te (KLT) and IL-1. The growth rate of MC was enhanced by IL-1 stimulation, which was accompanied with a reduction of the activity of telomerase. Adversely, the growth rate of MC was reduced by KLT, which was accompanied with an enhancement of activity of telomerase. Moreover, the growth rate of MC and the activity of telomerase were both inhibited by the combinative use of IL-1 and KLT without any influence from the sequence of their administration. KLT could inhibit proliferation and telomerase activity of MC with or without pre-stimulation with IL-1. KLT might be useful to prevent and treat glomerular nephritis related to MC proliferation (Hu et al., 2005).

Lung Metastasis

To screen the differential expression genes of Kanglaite in anti-tumor metastasis mRNA was extracted and purified from the lung of the mouse with LA795 lung metastasis, and hybridized respectively on 4 096-gene chip. cDNA microarray was scanned for the fluorescent signals and analyzing difference expression. Twenty-seven differential expressed genes were obtained.

Among these genes, 25 were up-regulated and 2 were down-regulated. Twelve of them were Mus musculus cDNA clone. Six genes related with genesis, development and metastasis of tumor. cDNA microarray for analysis of gene expression patterns is a powerful method to identify differential expressed genes. In this study, 6 genes are thought to be associated genes of Kanglaite in anti-tumor metastasis (Wu et al., 2003).

Lung Cancer; Chemo Side Effects

Sixteen reports were included in the meta-analysis. The quality of 16 studies was low. Pooling data of 5 studies indicated that the effect of Kanglaite+NP (Vinorelbine+Cisplatin) was better than NP with RR 1.46, 95% Confidence Interval 1.13 to 1.91. Pooling data of 3 studies of MVP (Mitomycin+Vindsine+ Cisplatin) plus Kanglaite indicated that the effect was better with RR 1.84, 95%CI 1.22 to 2.76. Pooling data of 2 studies showed that the effect of GP (Gemcitabine+Cisplatin) plus Kanglaite was better than GP with RR 1.63, 95%CI 1.09 to 2.43.

Fourteen studies revealed that Kanglaite may reduce the side-effects induced by regular treatment. Ten studies showed regular treatment plus Kanglaite can stabilize/improve quality of life (Zhu et al., 2009).

Apoptosis

Some studies show Kanglaite could inhibit some anti-apoptotic genes and activate some pro-apoptotic genes. Its injection solution is one of the new anti-cancer medicines that can significantly inhibit various kinds of tumor cells, so it has become the core of research into how to further explore KLT injection to promote tumor cell apoptosis by impacting on related genes (Lu et al., 2008).

References

Conti, M. (n.d.). Anti-cancer Chinese herbal kanglaite. Cancer Evolution. Retrieved from: http://www.cancerevolution.info/cancer-therapies/alternative-therapies/83-anticancer-chinese-herbal-kanglaite.html.


Hu, Y,H., Liang, W.K. Gong, Z.F. Xu,Q.L. Zou. (2005). The effect of kanglaite injection (KLT) on the proliferation and telomerase activity of rat mesangial cells. Zhongguo Zhong Yao Za Zhi, 30(6):450-453.


Lu, Y., Li, C.S., Dong, Q. (2008) Chinese herb related molecules of cancer-cell-apoptosis: a mini-review of progress between Kanglaite injection and related genes. J Exp Clin Cancer Res, 27:31. doi: 10.1186/1756-9966-27-31.


Lu, Y., L.Q. Wu, Q. Dong,C.S. Li. (2009). Experimental study on the effect of Kang-Lai-Te induced apoptosis of human hepatoma carcinoma cell HepG2. Hepatobiliary Pancreat Dis Int, 8(3):267-272.


Pan, P.,Y. Wu,Z.Y. Guo,R. et al. (2012). Anti-tumor activity and immunomodulatory effects of the intraperitoneal administration of Kanglaite in vivo in Lewis lung carcinoma. J Ethnopharmacol, 143(2):680-685.


Shan, S.J., Xiao T., Chen J., et al. (2012). Kanglaite attenuates UVB-induced down-regulation of aquaporin-3 in cultured human skin keratinocytes. Int J Mol Med, 29(4):625-629.


Wu, Y., Yang Y., Wu D. (2003). Study on the gene expression patterns of Kanglaite in anti-lung metastasis of LA795 mouse. Zhongguo Fei Ai Za Zhi, 6(6):473-476.


Zhan, Y.P., Huang X.E., Cao J. (2012). Clinical safety and efficacy of Kanglaite(R) (Coix Seed Oil) injection combined with chemotherapy in treating patients with gastric cancer. Asian Pac J Cancer Prev, 13(10):5319-5321.


Zhu, L.Z. Yang, S. Wang, Y. Tang. (2009). Kanglaite for Treating Advanced Non-small-cell Lung Cancer: A Systematic Review. Zhongguo Fei Ai Za Zhi, 12(3):208-215.

anti-proliferative, Chapter 8 Injectables and Cancer Research, Chemotherapy, chemotherapy support, Fatigue, Immune, immunomodulary, Lymphoma, Nausea and Vomiting, Radio-sensitizer, radiotherapy, Weight Gain or Weight Loss

Kangai Injection

Cancers: Cervical., lung, non-Hodgkin”s lymphoma, stomach

Action: Anti-proliferative, chemotherapy support, immunomodulary, radio-sensitizer

Non-Hodgkin’s Lymphoma

The influence of Kangai injection on blood serum vascular endothelial growth factor of non-Hodgkin”s lymphoma patients, and its synergistic effect, attenuation and improvement of quality of life was evaluated.

Eighty-five non-Hodgkin”s lymphoma patients were randomized into a treatment group or control group. The patients in the treatment group were treated by Kangai injection and cyclophosphamide / doxorubicin / vincristine / prednisolone (CHOP) combined chemotherapy, while those in the control group were treated by CHOP chemotherapy only.

The concentration of vascular endothelial growth factor in blood serum of the patients of the treatment group decreased after therapy (P < 0.05), acute curative effect gradually increased, quality of life was raised significantly (P < 0.05), and adverse reactions of the combined chemotherapy decreased markedly (P < 0.05).

Kangai injection, with CHOP chemotherapy, has a synergistic effect. It can attenuate progression of non-Hodgkin”s lymphoma, and improve quality of life. Additionally, it can decrease the concentration of serum vascular endothelial growth (Tang, 2006).

Stomach Cancer; Chemotherapy

Eighty patients with advanced stomach cancer were randomly divided into treatment group (chemotherapy+ GAMA injection) and control group (chemotherapy only). Observation was conducted on cellular immunization, short-termeffect, quality of life improvement, and toxic side-effects in both groups.

In the treatment group, both NK cellular activity and CD4/CD8 ratios were higher after the treatment (P < 0.01). CD3 and CD4 were both increased (P < 0.05). In the control group, the NK cellular activity, CD3, CD4, CD4/CD8 ratio were all lower after the treatment (P < 0.05). The short-term  efficacy rate was 45% in the treatment group and 40% in the control group. The difference was not significant. The treatment group was apparently lower than the control group in leukopenia, nausea and/or vomiting, and peripheral nerve toxicity (P < 0.05). Compared with the control group, less fatigue, better appetite, and Karnofsky score increases were observed in the treatment group (P < 0.01). The treatment group was also more effective in relieving pain and promoting weight gain than the control group (P < 0.05).

Treating advanced stomach cancer, with the combination of Kangai injection and chemotherapy, may decrease the adverse effects of chemotherapy on patients′cellular immune functions and other side effects, and thereby, improve the quality of life of patients (Wu & Yang, 2007).

NSCLC; Chemotherapy

Seventy eight patients with stage IIIB/IV NSCLC were randomly divided into two groups: treatment group (n=40) received GAMA injection and chemotherapy, and control group (n=38) only received chemotherapy.

The short-termeffect, Karnofsky scores of life quality, and the incidence of pancytopenia in treatment group were superior to those in the control group (72.5% vs 47.4%, P<0.05; 87.5% vs 55.3%, P < 0.01; P < 0.01).

Kangai injection can improve the short-term effect, quality of life, and pancytopenia prevalence in patients with intermediate and advanced-stage NSCLC (Wen, Xie, Xie & Feng, 2006).

Radiotherapy side-effects

One hundred ten cases of patients with malignant tumors wasrandomly divided into the treatment group or the control group. The treatment group was given Kangai injection for 40 days after radiotherapy, while the control group was treated by radiotherapy only.

Tumor growth in the treatment group and the control group were 66.7% and 43.4%, respectively. Karnofsky score improvements were 52.6% and 32.1%, respectively. The incidence of leukopenia was 22.8% and 42.5%, respectively. All differences were significant (P < 0.05). There was no significant difference in levels of lymphocytres between the treatment group before and after therapy (P > 0.05). However, there was significant difference in the control group before and after therapy (P< 0.05).

Kangai injection can improve the curative effect and alleviate the side-effects of radiotherapy on treating malignant tumors (Cao et al., 2005).

Leukemia

Kangai injection combination of fludarabine (Flud), cytosine arabinoside (Ara-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) in refractory/relapsed acute leukemia (AL) patients was investigated. The remission rate of treatment and total effective rate treatment group were 57.1% (16/28) and 71.4% (21/28), the control group were 52.3% (11/21) and 61.9% (13/21); there were no significant differences in the two groups. Duration of neutrophils less than 0.5 x 10(9)/L in treatment group was (14 +/- 6) day, control group was (23 +/- 3) day, Duration of platelet less than 25 x 10(9)/L in treatment group was (17 +/- 6) day, control group was (31 +/- 2) day, treatment group of III-IV degree of infection was 6.9% (1/28) and control group was 23.8% (5/21) between the two groups were significantly different (P < 0.05). treatment group of III- IV degree of gastrointestinal; toxicity was 10.7% (3/28) and control group was 28. 5% (6/ 21).

Kangai injection plus FLAG regimen could increase the remission rate, shorten the period of bone marrow suppression, significantly reduced the incidence and degree of infection, play an important role in attenuated efficiency (Wan et al., 2011).

References

Cao, H. (2005). Treating 57 cases of malignant tumor by Kangai injection and radiotherapy. Zhejiang Journal of Integrated Traditional Chinese and Western Medicine, 2005(12), R730.5. doi: cnki:sun:zjzh.0.2005-12-005.


Tang, Q. (2006). Influence of Kangai injection on blood serum vascular endothelial growth factor of non-Hodgkin lymphoma patient. Journal of Leukemia & Lymphoma, 15(1).


Wan, Q., Xi, A., Zhang, C., Liu X.(2011) Clinical study of kangai injection plus FLAG regimen for refractory/relapsed acute leukemia. Zhongguo Zhong Yao Za Zhi, 36(22):3207-9.


Wen, J.Y., Xie, Z., Xie, J.R., & Feng, L.P. (2006). Kangai injection mixed with chemotherapy in intermediate and advanced-stage non-small-cell lung cancer. Journal of Guandong Medical College, 24(1), 1005-4057.


Wu, L., & Yang, Y. (2007). A clinical study of treating advanced gastric cancer with the combination of Kangai injection and chemotherapy. Proceeding of Clinical Medicine, 18(7), 1671-8631.

Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tumor, Apoptotic, BAX, Bcl-2, Chapter 8 Injectables and Cancer Research, Chemo-protective, Chemotherapy, Colon Cancer or Colorectal cancer, CSK, Doxorubicin-induced cardotoxicity, Hippophae rhamnoides, Lung cancer, Lymphoma, radiotherapy, Rectal cancer

Isorhamnetin

Cancer:
Lung, colon, acute myeloid leukemia, T lymphoma, Ehrlich carcinoma, gastric, esophageal squamous cell, chronic myelogenous leukemia

Action: Dox-induced cardiotoxicity, anti-oxidant

Isorhamnetin, the anti-tumor component of Hippophae rhamnoides Linn, is also a member of the ßavonoid class of compounds. Its chemical name is 3,5,7-trihydroxy-2-(4-hydroxy-3-methoxyphenyl) chromen-4-one and its molecular formula is C16H12O7.

Lung Cancer

Isorhamnetin shows good inhibitory effects on human lung adenocarcinoma A549 cells, human colon cancer HT-29 cells, human chronic myeloid leukemia K562 cells, human acute myeloid leukemia HL-60 cells, mouse T lymphoma YAC-1 cells and mouse Ehrlich carcinoma. In terms of its mechanism of action, it seems that isorhamnetin simultaneously reduces the expression of Bcl-2 and increases the expression of Bax, which activates caspase-9 and its downstream factor caspase-3, thus resulting in cell death (Zhu et al. 2005).

Colorectal Cancer

It was demonstrated that isorhamnetin prevents colorectal tumorigenesis. Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. Magnetic resonance imaging, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than control diet.

These observations suggest the chemo-protective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that are dependent on CSK expression (Saud et al., 2013).

Gastric Cancer

The potential effects of isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, were investigated on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, gastric cancer (GC) cell lines, and xenograft mice model.

It was observed that IH exerted a strong anti-proliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of gastric cancer cells, which could be reversed in the presence of PPAR-γ inhibitor.

Using molecular docking analysis, Ramachandran et al. (2013) demonstratd that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, these findings clearly indicate that anti-tumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC.

Cardiac-protective; Doxorubicin

Isorhamnetin is a natural anti-oxidant with obvious cardiac-protective effect. Its action against doxorubicin-induced cardotoxicity and underlying mechanisms were investigated. Doxorubicin (Dox) is an anthracycline antibiotic for cancer therapy with limited usage due to cardiotoxicity. The aim of this study is to investigate the possible protective effect of isorhamnetin against Dox-induced cardiotoxicity and its underlying mechanisms. In an in vivo investigation, rats were intraperitoneally (i.p.) administered with Dox to duplicate the model of Dox-induced chronic cardiotoxicity.

Daily pre-treatment with isorhamnetin (5 mg/kg, i.p.) for 7 days was found to reduce Dox-induced myocardial damage significantly, including the decline of cardiac index, decrease in the release of serum cardiac enzymes, and amelioration of heart vacuolation. In vitro studies on H9c2 cardiomyocytes, isorhamnetin was effective to reduce Dox-induced cell toxicity. Isorhamnetin also potentiated the anti-cancer activity of Dox in MCF-7, HepG2 and Hep2 cells. These findings indicated that isorhamnetin can be used as an adjuvant therapy for the long-term clinical use of Dox (Sun et al., 2013).

Chronic Myelogenous Leukemia

The isorhamnetin 3-o-robinobioside and its original extract, ethyl acetate extract, from Nitraria retusa leaves, were evaluated for their ability to induce anti-oxidant and anti-genotoxic effects in human chronic myelogenous leukemia cell line. They were shown to have a great anti-oxidant and anti-genotoxic potential on human chronic myelogenous leukemia cell line K562 (Boubaker et al., 2012).

Esophageal Cancer

The flavonol aglycone isorhamnetin shows anti-proliferative activity in a variety of cancer cells and it inhibits the proliferation of human esophageal squamous carcinoma Eca-109 cells in vitro (Shi et al., 2012).

References

Boubaker J, Ben Sghaier M, Skandrani I, et al. (2012). Isorhamnetin 3-O-robinobioside from Nitraria retusa leaves enhance anti-oxidant and anti-genotoxic activity in human chronic myelogenous leukemia cell line K562. BMC Complement Altern Med, 12:135. doi: 10.1186/1472-6882-12-135.


Ramachandran L, Manu KA, Shanmugam MK, et al. (2013). Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer. J Biol Chem, 288(26):18777. doi: 10.1074/jbc.A112.388702.


Saud SM, Young MR, Jones-Hall YL, et al. (2013). Chemo-preventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β -catenin. Cancer Res, 73:5473.


Shi C, Fan LY, Cai Z, Liu YY, Yang CL. (2012). Cellular stress response in Eca-109 cells inhibits apoptosis during early exposure to isorhamnetin. Neoplasma, 59(4):361-9. doi: 10.4149/neo_2012_047.


Sun J, Sun G, Meng X, et al. (2013). Isorhamnetin protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. PLoS One, 8(5):e64526. doi: 10.1371/journal.pone.0064526.


Zhu L, Wang ZR, Zhou LM, et al. (2005). Effects and mechanisms of isorhamnetin on lung carcinoma. Space Med Med Eng (Chin), 18:381-383.

180, Angelica gigas, Angelica gigas (Nakai), angiogenesis, Anti-cancer, anti-tumor, apoptosis, Apoptotic, AR, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, Chemotherapy, Fibrosarcoma, HT1080, IL-8, inflammation, JAK2, MDR, MTOR, p53, Pro-apoptotic, Prostate cancer, Sarcoma, STAT3, TNF

Decursin

Cancer: Prostate, breast, fibrosarcoma, sarcoma

Action: MDR, inflammation, anti-cancer, angiogenesis

Decursin is isolated from Angelica gigas (Nakai).

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The physicochemical and toxicological characterization of compounds in A. gigas NAKAI, decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin, have been extensively studied (Mahat et al., 2012).

Sarcoma; Anti-cancer

The in vivo anti-tumor activities of decursinol angelate (1) and decursin (2) isolated from the roots of Angelica gigas were investigated. These two compounds, when administered consecutively for 9 days at 50 and 100 mg/kg i.p. in mice, caused a significant increase in the life span and a significant decrease in the tumor weight and volume of mice inoculated with Sarcoma-180 tumor cells. These results suggest that decursinol angelate (1) and decursin (2) from A. gigas have anti-tumor activities (Lee et al., 2003).

Fibrosarcoma

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumor necrosis factor α) in the presence or absence of CSL-32. Treatment of HT1080 cells with a derivative of decursin (CSL-32) inhibited their proliferation, without affecting cell viability, and TNF α-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8) (Lee et al., 2012).

Prostate Cancer

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to patients. As current chemotherapy is largely ineffective for PCa and has serious toxic side-effects, a collaborative effort has been initiated to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. The discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent has been highlighted and the mechanisms to account for the specific anti-AR actions have been identified: rapid block of AR nuclear translocation, inhibition of binding of 5-dihydrotestesterone to AR, and increased proteasomal degradation of AR protein. Structure-activity analyzes reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell-cycle arrest and pro-apoptotic activities.

This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/AR agents from complex herbal mixtures (Lu et al., 2007).

MDR

Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, Jang et al (2013) investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. The combined treatment reduced mitochondrial membrane potential., suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells.

Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

Breast Cancer

Decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Kim et al (2013) found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between peptidyl-prolyl cis/trans isomerase Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, the study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1.

References

Jang J, Jeong SJ, Kwon HY, Jung JH, et al. (2013). Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells. Evid Based Complement Alternat Med. 2013:506324. doi: 10.1155/2013/506324.

Kim JH, Jung JH, Kim SH, Jeong SJ. (2013). Decursin Exerts Anti-cancer Activity in MDA-MB-231 Breast Cancer Cells Via Inhibition of the Pin1 Activity and Enhancement of the Pin1/p53 Association.Phytother Res. doi: 10.1002/ptr.4986.

Lee S, Lee YS, Jung SH, et al. (2003). Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch Pharm Res, 26(9):727-30.

Lee SH, Lee JH, Kim EJ, et al. (2012). A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF- κB activities in HT1080 cells. Cell Biol Int, 36(7):683-8. doi: 10.1042/CBI20110257.

Lu JX, Kim SH, Jiang C, Lee JJ, Guo JM. (2007). Oriental herbs as a source of novel anti-androgen and prostate cancer chemo-preventive agents. Acta Pharmacologica Sinica, 28, 1365–1372. doi:10.1111/j.1745-7254.2007.00683.x

Mahat B, Chae JW, Baek IH, et al. (2012). Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas. Biol Pharm Bull, 35(7):1084-90.

anti-tumor, apoptosis, CDK2, cell-cycle arrest, Cervical cancer, Chapter 8 Injectables and Cancer Research, Chemo-sensitizer, Chemotherapy, chemotherapy support, Cytostatic, Immune, induces apoptosis, inhibits proliferation, Liver cancer, Lung cancer, metastasis, radiotherapy, VEGFR

Cinobufacini Injection

Cancer: Liver, lung

Action: Chemo-sensitizer, chemotherapy support, cytostatic

Ingredients: chan su (Dried toad skin/Bufo bufo gargarizans)

TCM functions: Removing Toxin, reducing swelling, relieving pain.

Indications: Anti-tumor, immune enhancing and anti-viral effects, and can be used in middle and late-stage tumors, chronic hepatitis B.

Dosage and usage:

Intramuscular injection: 2-4 ml once, twice daily, 2-3 months as a course of treatment.

Cervical Cancer; Radiotherapy

Sixty patients with early cervical cancer were randomly divided into two groups. Twenty eight cases in treatment group were treated by intensity modulated radiation therapy combined with Brucea javanica oil emulsion injection. Thirty two cases in control group were treated only by intensity modulated radiation therapy. There was no significant difference between the two groups on the short-term  effect and lesion local control rate (P > 0.05). The 3-year overall survival rate in the treatment group was higher than that in control group (P<0.05). There was significant difference between the two groups on radiation proctitis (P<0.05).

Intensity modulated radiation therapy combined with Brucea javanica oil emulsion injection can improve efficacy and reduce adverse reactions in early cervical cancer, worthy of clinical application. 10-20 ml mixed with 500 ml of 5% glucose for slow intravenous drip. Four weeks as a course of treatment, and 1-2 days interval after each week”s treatment.

Cinobufacini Injection (CI) showed better tumor inhibition effects on tumor-bearing rats of with a “heat syndrome” constitution, indicating CI was of a “cold property”. It may potentially be used in tumor-bearing rats of a “heat syndrome” constitution (Wang et al., 2011).

Induces Apoptosis

Chan Su is a traditional Chinese medicine prepared from the dried white secretion of the auricular and skin glands of toads, and has been used as an oriental drug for the treatment of a number of diseases, including cancer. In lung carcinoma A549 cells, treatment with the skin of Venenum Bufonis (SVB) resulted in the inhibition of cell growth and viability, and the induction of apoptosis.

SBV treatment induced the proteolytic activation of caspases and the concomitant degradation of poly(ADP-ribose)-polymerase and beta-catenin protein. Cleavage of Bid and a down-regulation of the inhibitor of apoptosis family proteins were also observed in SBV-treated A549 cells. Data from this study indicates that SVB induces the apoptosis of A549 cells through a signaling cascade of death receptor-mediated extrinsic and mitochondria-mediated intrinsic caspase pathways (Yun et al., 2009).

Blocks Metastasis

The effect of Cinobufacini injection on proliferation, heterogeneous adhesion, and invasiveness of human hepatoma HepG-2 cells co-cultured with human lymphatic endothelial cells (HLEC) was studied.

A co-culture system of human hepatoma HepG-2 cells and HLEC was established by means of Transwell chamber. Cell proliferation was analyzed by Trypan blue stain assay. MTT assay was used to observe the heterogeneous adhesion capacity of HepG-2 cells co-cultured with HLEC. Transwell invasion chamber was used to observe the invasiveness capacity of HepG-2 cells co-cultured with HLEC.

Cinobufacini Injection significantly inhibits proliferation, heterogeneous adhesion and invasiveness of hepG-2 cells co-cultured with HLEC in dose-dependent ways (all P0.05). Cinobufacini injection can inhibit the capability of proliferation, invasiveness and heterogeneous adhesion of HepG-2 cells, which might contribute to the inhibiting mechanisms of Cinobufacini injection on tumor metastasis (Fu, Gao, Tian, Chen, & Cui, 2013).

Inhibits Human Lymphatic Endothelial Cells (HLEC)

The effect of Cinobufacini injection on proliferation, migration and tubulin formation of human lymphatic endothelial cells (HLEC) was investigated.

Cell growth curve was used to observe the effect of Cinobufacini injection on the proliferation of HLEC; migration assay was used to observe the effect of Cinobufacini injection on the migration of HLEC; Matrigel assay was used to observe the effect of Cinobufacini injection on the tubulin formation of HLEC; Western blot was used to analyze the expression of VEGFR-3 and HGF in HLEC.

As the dosage of Cinobufacini injection increased (0.105, 0.21 and 0.42 µg/mL), so did the inhibition of HLCE. Cinobufacini injection demonstrated significant inhibition of HLEC proliferation (P < 0.05), migration (P < 0.05) and tubulin formation, in a dose-dependent manner (P < 0.05). Cinobufacini injection significantly decreased the expression of VEGFR-3 and HGF in HLEC, in a dose-dependent manner (P < 0.05).

Cinobufacini injection significantly inhibits HLEC proliferation, migration, and tubulin formation. The down-regulation of VEGFR-3 and HGF may contribute to the inhibitory effect of Cinobufacini injection on HLEC (Gao, Chen, Xiu, Fu, & Cui, 2013).

NSCLC; Chemotherapy

The efficacy and safety of Cinobufacini injection, combined with chemotherapy, as a treatment for advanced non-small-cell lung cancer (NSCLC) was investigated. Based on existing clinical information, a search of databases, such as Medline (1966-2011), Cochrane Library (2011, Issue 11), CNKI (1978-2011), VIP (1989-2011), Wanfang Data (1988-2011), CBMdisc (1978-2011) was done.

A total of seven RCTs of 498 patients were included. Meta-analysis results show that the experimental group and control group have significant differences in the response rate [RR=1.29, 95% CI (1.07, 1.56)], Karnofsky score [RR=1.86, 95% CI (1.14, 3.05)], weight change [RR=1.56, 95% CI (1.20, 2.03)], gastrointestinal side-effects [RR=0.72, 95% CI (0.53, 0.99)], neutropenia [RR=0.70, 95%CI(0.54, 0.91)], thrombocytopenia [RR=0.53, 95% CI (0.38, 0.75)], and renal function [RR=0.37, 95% CI (0.17, 0.79).

Cinobufacini, combined with chemotherapy, is suitable for advanced NSCLC by improving the response rate, increasing Karnofsky score, gaining weight and reducing major side-effects (Tu, Yin, & He, 2012).

Liver Cancer

The clinical effect of Cinobufacini injection, combined with transcatheter arterial chemoembolization (TACE), on treating primary liver cancer was investigated.

Seventy-eight patients with moderate and advanced primary liver cancer were randomly divided. The treatment group (n=38) was treated by Cinobufacini injection combined with TACE, and the control group (n=40), was treated by TACE only.

Quality of life of patients in the treatment group was significantly higher than that in control group. The 12 months survival rate of the treatment group was significantly higher than that of control group. There was no statistical difference in the rate of effectiveness between the two groups. Laboratory tests, after three cycles, in the treatment group were better than that of the control group, and the difference between the two groups was statistically significant.

Cinobufacini injection, combined with TACE, can decrease TACE induced liver damage, prolong survival time, and improve body immunity (Ke, Lu, & Li, 2011).

Hepatoma

Cinobufacini injection significantly inhibited HepG-2 cells proliferation in a dose and time-dependent manner. FCM analysis showed Cinobufacini injection induced cell-cycle arrest at the S phase. RT-PCR assay showed Cinobufacini injection down-regulated Cyclin A, and CDK2 expression at mRNA levels. Quantitative colorimetric assay showed Cinobufacini injection deceased Cyclin A/CDK2 activity in HepG-2 cells.

Cinobufacini injection can inhibit human hepatoma HepG-2 cells growth, induce cell apoptosis and induce cell-cycle arrest at the S phase. Its mechanism might be partly related to the down-regulation of Cyclin A, CDK2 mRNA expression, and inhibition of Cyclin A/CDK2 activity (Sun, Lu, Liang, & Cui, 2011).

Cell-cycle Arrest

Studies in China by Sun et al., (2011), Ke et al., (2011) and Tu et al., (2012) demonstrated that Cinobufacini Injection induced cell-cycle arrest, and could be used in the treatment of primary liver cancer, as well as in conjunction with chemotherapy in the treatment of non-small-cell lung cancer.

Caution

Resibufogenin (RBG), one of the major components in chan su, significantly affected all parameters of transmembrane action potential., induced delayed response after depolarization, and triggered arrhythmias in sheep and canine Purkinje fibers. Chan su toxicity carries a high mortality rate in the United States and this study focused upon the cardiac electrophysiological and electro-toxicity effects of RBG (Xie et al., 2000).

References

Fu, H.Y., Gao, S., Tian, L.L., Chen, X.Y., & Cui, X.N. (2013). Effect of Cinobufacini injection on proliferation and invasiveness of human hepatoma HepG-2 cells co-cultured with human lymphatic endothelial cells. The Chinese Journal of Clinical Pharmacology, 29(3), 199-201.


Gao, S., Chen, X.Y., Fu, H.Y., & Cui, X.Z. (2013). The effect of Cinobufacini injection on proliferation and tube-like structure formation of human lymphatic endothelial cells. China Oncology, 23(1), 36-41.


Ke, J, Lu, K., & Li, Y. (2011). Clinical observation of patients with primary liver cancer treated by Cinobufagin Injection combined with transcatheter arterial chemoembolization. Chinese Journal of Clinical Hepatology.


Sun, Y., Lu, X.X., Liang, X.M., & Cui, X.N. (2011). Impact of Cinobufacini injection on proliferation and cell-cycle of human hepatoma HepG-2 cells. The Chinese-German Journal of Clinical Oncology, 10(6), 321-324.


Tu, C., Yin, J., & He, J. Meta-analysis of Cinobufacini injection plus chemotherapy in the treatment of non-small-cell lung cancer. Anti-tumor Pharmacy, 2(1), 67-72.


Wang, S.S., Zhai, X.F., Li, B. (2011) Effect of cinobufacini injection on the tumor growth of tumor-bearing rats of different constitutions. Zhongguo Zhong Xi Yi Jie He Za Zhi, 31(8):1101-3.


Xie, J-T., Wang, Hs., Attele A.S., Yuan, C-S. (2000). Effects of Resibufogenin from Toad Venom on Isolated Purkinje Fibers. American Journal of Chinese Medicine, 28(2):187-196.


Yun, H.R., Yoo, H.S., Shin, D.Y., et al. (2009). Apoptosis induction of human lung carcinoma cells by Chan Su (Venenum Bufonis) through activation of caspases. J Acupunct Meridian Stud, 2(3):210-7. doi: 10.1016/S2005-2901(09)60057-1.

Anti-cancer, apoptosis, Bcl-2, Breast cancer, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, G0/G1, G1, GM-CSF, IL-2, IL-6, IL-8, Lung cancer, TNF

Astragalus (huang qi)

Cancer: Non-small-cell lung cancer, breast, colon, stomach

NSCLC; Chemotherapy

Guo et al. (2012) reported that treatment with Astragalus polysaccharide (APS) injections integrated with vinorelbine and cisplatin significantly improved quality of life in patients with advanced non-small-cell lung cancer over vinorelbine and cisplatin alone.

NSCLC

Astragalus injection (AI) combined with chemotherapy can significantly improve the QOF in NSCLC patients of advanced stage. The effective rate in the treated group was 40.0% and in the control group was 36.7%, the mean remission rate in the treated and control group was 5.4 months and 3.3 months, the median survival period 11 months and 7 months, and the 1-year survival rate 46.75% and 30.0%, respectively; the differences of these indexes between the two groups were all significant (P < 0.05). Moreover, the clinical improving rate and QOF elevation rate in the treated group was 80.4% and 43.3%, as compared with those in the control group (50.0% and 23.3% respectively); the difference was also significant (P < 0.01) (Zou & Liu, 2003).

Breast Cancer

In physiological dose E2, Astragalus mongholicus injection inhibited MCF-7 breast cancer cells proliferation at all concentration groups. As time lasting, Astragalus mongholicus injection showed better inhibitory effect than TAM (P<0.05). Among 2 x 10(-1) g/mL-2 x 10(-4) g/mL concentration, Astragalus mongholicus injection significantly increased the proliferative percent of G0/G1 and S-phase cell, decreased percent of G2-M phase cell (P<0.05) at 24 hours. After cocultured 72 hours, Astragalus mongholicus injection increased the rate of apoptosis to 16.7% at 2 x 10(-1) g/mL concentration (Zhou, Liu, & Tan, 2009).

Acute Exacerbations, Respiratory Failure in Chronic Obstructive Pulmonary Disease

A total of 112 patients with acute chronic obstructive pulmonary disease (AECOPD)were randomly divided into the treatment group (56 cases) and control group (56 cases). The treatment group received a 40 mL astragalus injection, with 5% glucose, 250 mL intravenous drip once a day at the start of conventional therapy. The control group received conventional therapy only. The therapeutic course of both groups was 14 days, and clinical therapeutic effects were observed. Serum levels of TNF-α>, IL-8, IL-2, lung function and blood gas analysis index of both groups were measured before and after treatment. The treatment group”s effectiveness rate was 94.64%, compared to the control group”s 67.86%, which was statistically significant (P<0.05).

Astragalus injection may significantly decrease the serum levels of TNF-α and IL-8, and increase the level of IL-2. It may improve the lung function and the curative effect in the patients with AECOPD (Xiong, Guo, & Xiong, 2013).

Residual Renal Function

The effect of astragalus injection on hemodialysis patient”s RRF (residual renal function, RRF) was observed.

Sixty hemodialysis patients with a RRF of more than 2ml/min were randomly divided into either an astragalus injection treatment group or a control group treated with normal saline. One hour prior to hemodialysis completion, the treatment group was administered an astragalus injection of 30ml, while the control group was given 30 ml of normal saline. Follow up after 6 months compared data of daily urine output and RRF.

Astragalus injection can potentially delay the rate of daily urine output reduction and protect RRF to some extent (Qi et al., 2013).

Stomach Cancer, Colon Cancer; Oxaliplatin-induced Neurotoxicity

40 patients with stomach or colon cancer were enrolled in the study. Patients comprised of 23 men and 17 women, from the ages of 32-75 years (mean age 60 years), and were randomly divided into two groups: the test group and the control group (20 cases in each group). All patients were treated with one cycle of an Oxaliplatin-containing chemotherapy regimen, entailing: oxaliplatin 130 mg/m2 on day 1, fluorouracil 0.5 g on days 1-5, and calcium foliate 0.2 g on days 1-5. In the test group 30 ml of Huangqi injection was added to the regimen on days 1-7. The manifestation of peripheral neurotoxic reactions were observed and nerve growth factor levels were measured.

In the control group, 2 patients had grade 0 toxicity, 10 had grade 1 toxicity, 6 had grade 2 toxicity, and 2 had grade 3 toxicity. In the test group, 14 patients had grade 0 toxicity and 6 had grade 1 toxicity. The incidence rate of neurotoxicity in the test and control groups was 30% and 90%, respectively. In the test and control groups, the nerve growth factor levels were (167 ± 10) ng/ml and (204 ± 19) ng/ml before chemotherapy, as well as (152 ± 8) ng/ml and (133 ± 12) ng/ml 2 days after chemotherapy, respectively. In the control group, the nerve growth factor levels were markedly decreased 2 days after chemotherapy compared to before chemotherapy. The difference between the two groups was statistically significant (P < 0.01).

Huangqi injection has some degree of efficacy in the prevention and treatment of Oxaliplatin-induced neurotoxicity (Cui, Li, Tan, & Li, 2009).

Myelosuppression

Astragalus membranaceus injection (AMI), administered at (500 mg/kg) improved the hematopoietic microenvironment by enhancing the BMSC survival and proliferation of colony-forming unit-fibroblast (CFU-F) formation, production of IL-6 as well as Granulocyte-macrophage colony-stimulating factor (GM-CSF) by BMSC and bcl-2 protein and mRNA expression in BMSC, which promoted myelopoiesis. The data may provide a mechanistic basis for applying this ancient Chinese herb to promote hematopoiesis as an efficacious adjuvant therapy against myelosuppression induced by anti-cancer therapy (Zhu & Zhu, 2007).

References

Cui, H.J., Li, O.J., Ying, H.Y., & Li, Y. (2009). Clinical observation of efficacy of huangqi injection in the prevention and treatment of neurotoxicity induced by oxaliplatin-containing chemotherapy regimen. Adverse Drug Reactions Journal., 11(4), 1671-8585.


Guo, L., Bai, S.P., Zhao, L., Wang, X.H. (2012). Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small-cell lung cancer: effects on quality of life and survival. Med Oncol. http://dx.doi.org/10.1007/s12032-011-0068-9.


Qi, Y.H., Qu, X.L., Tang, Y.H., Dai, Q., Zhang, S.B., & Yao, C.Y. (2013). The impact of Astragalus injection on residual renal function in hemodialysis patients. New Medicine, 2013(2), 105-107.


Xiong, S., Guo, Y., & Xiong, X. (2013). Influence of astragalus injection on serum cytokines and lung function in acute exacerbation of chronic obstructive pulmonary disease. China Modern Doctor, 51(9), 43-45.


Zhou, R.F., Liu, P.X., Tan, M. (2009). Effect of Astragalus mongholicus injection on proliferation and apoptosis of hormone sensitive (MCF-7) breast cancer cell lines with physiological dose E2. Zhong Yao Cai, 32(5):744-7.


Zou, Y.H., Liu, X.M. (2003). Effect of astragalus injection combined with chemotherapy on quality of life in patients with advanced non-small-cell lung cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi, 23(10):733–735.


Zhu XL, Zhu BD. (2007). Mechanisms by which Astragalus membranaceus injection regulates hematopoiesis in myelosuppressed mice. Phytother Res, 21(7):663-7.

ABCG2, AIF, anti-apoptotic, Anti-cancer, Anti-metastatic, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Artemisia annua, Bcl-2, BCRP, Breast cancer, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, Derivative of artemisinin, Down-regulates, epidermal growth factor receptor, Esophageal cancer, G0/G1, G1, G2/M, ICAM-1, induces apoptosis, Lymphoma, MDR, metastasis, Multi-Drug Resistance, Multi-drug resistance, Osteosarcoma, Ovarian cancer, p21, p53, Pancreatic cancer, Prostate cancer, Radio-sensitizer, Sarcoma, Skin cancer

Artesunate

Cancer: Colon, esophageal., pancreatic, ovarian, multiple myeloma and diffuse large B-cell lymphoma, osteosarcoma, lung, breast, skin, leukemia/lymphoma

Action: Anti-metastatic, MDR, radio-sensitizer

Pulmonary Adenocarcinomas

Artesunate exerts anti-proliferative effects in pulmonary adenocarcinomas. It mediates these anti-neoplastic effects by virtue of activating Bak (Zhou et al., 2012). At the same time, it down-regulates epidermal growth factor receptor expression. This results in augmented non-caspase dependent apoptosis in the adenocarcinoma cells. Artesunate mediated apoptosis is time as well as dose-dependent. Interestingly, AIF and Bim play significant roles in this Bak-dependent accentuated apoptosis (Ma et al., 2011). Adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) expression is also attenuated while transcription of matrix metallopeptidase 7 (MMP-7) is also down-regulated (Zhao et al., 2011). In addition, arsenuate enhances the radio-sensitization of lung carcinoma cells. It mediates this effect by down-regulating cyclin B1 expression, resulting in augmented G2/M phase arrest (Rasheed et al., 2010).

Breast Cancer

Similarly, artesunate exhibits anti-neoplastic effects in breast carcinomas. Artesunate administration is typically accompanied by attenuated turnover as well as accentuated peri-nuclear localization of autophagosomes in the breast carcinoma cells. Mitochondrial outer membrane permeability is typically augmented. As a result, artesunate augments programmed cellular decline in breast carcinoma cells (Hamacher-Brady et al., 2011).

Skin Cancer

Artesunate also exerts anti-neoplastic effects in skin malignancies. It mediates these effects by up-regulating p21. At the same time it down-regulates cyclin D1 (Jiang et al., 2012).

Colon Cancer

Artemisunate significantly inhibited both the invasiveness and anchorage independence of colon cancer SW620 cells in a dose-dependent manner. The protein level of intercellular adhesion molecule 1 (ICAM-1) was down-regulated as relative to the control group.

Artemisunate could potentially inhibit invasion of the colon carcinoma cell line SW620 by down-regulating ICAM-1 expression (Fan, Zhang, Yao & Li, 2008).

Multi-drug resistance; Colon Cancer

A profound cytotoxic action of the antimalarial., artesunate (ART), was identified against 55 cancer cell lines of the U.S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC50 values) for ART correlated significantly to the cell doubling times (P = 0.00132) and the portion of cells in the G0/G1 (P = 0.02244) or S cell-cycle phases (P = 0.03567).

Efferth et al., (2003) selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data-base. These genes belong to different biological categories (drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (=12%) genes correlated significantly to the IC50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines (P = 0.00017).

Multi-drug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent and- independent pathways in isogenic p53+/+ p21WAF1/CIP1+/+, p53-/- p21WAF1/CIP1+/+, and p53+/+ p21WAF1/CIP1-/- colon carcinoma cells.

Multi-drug resistance; Esophageal Cancer

The present study aimed to investigate the correlation between ABCG2 expression and the MDR of esophageal cancer and to estimate the therapeutic benefit of down-regulating ABCG2 expression and reversing chemoresistance in esophageal cells using artesunate (ART).

ART is a noteworthy antimalarial agent, particularly in severe and drug-resistant cancer cases, as ART is able to reverse drug resistance. ART exerted profound anti-cancer activity. The mechanism for the reversal of multi-drug resistance by ART in esophageal carcinoma was analyzed using cellular experiments, but still remains largely unknown (Liu, Zuo, & Guo, 2013).

Pancreatic Cancer

The combination of triptolide and artesunate could inhibit pancreatic cancer cell line growth, and induce apoptosis, accompanied by expression of HSP 20 and HSP 27, indicating important roles in the synergic effects. Moreover, tumor growth was decreased with triptolide and artesunate synergy. Results indicated that triptolide and artesunate in combination at low concentrations can exert synergistic anti-tumor effects in pancreatic cancer cells with potential clinical applications (Liu & Cui, 2013).

Ovarian Cancer

Advanced-stage ovarian cancer (OVCA) has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.

Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations.

However, Marchion et al. (2013) identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral., and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration.

Multiple Myeloma, B-cell Lymphoma

Findings indicate that artesunate is a potential drug for treatment of multiple myeloma and diffuse large B-cell lymphoma (DLBCL) at doses of the same order as currently in use for treatment of malaria without serious adverse effects. Artesunate treatment efficiently inhibited cell growth and induced apoptosis in cell lines. Apoptosis was induced concomitantly with down-regulation of MYC and anti-apoptotic Bcl-2 family proteins, as well as with cleavage of caspase-3. The IC50 values of artesunate in cell lines varied between 0.3 and 16.6 µm. Furthermore, some primary myeloma cells were also sensitive to artesunate at doses around 10 µm. Concentrations of this order are pharmacologically relevant as they can be obtained in plasma after intravenous administration of artesunate for malaria treatment (Holien et al., 2013).

Osteosarcoma, Leukemia/Lymphoma

Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo (Xu et al. 2011). ART alone or combined with chemotherapy drugs could inhibit the proliferation of B/T lymphocytic tumor cell lines as well ALL primary cells in vitro, probably through the mechanism of apoptosis, which suggest that ART is likely to be a potential drug in the treatment of leukemia/lymphoma (Zeng et al., 2009).

References

Efferth, T., Sauerbrey, A., Olbrich, A., et al. (2003) Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol, 64(2):382-94.


Fan, Y., Zhang, Y.L., Yao, G.T., & Li, Y.K. (2008). Inhibition of Artemisunate on the invasion of human colon cancer line SW620. Lishizzhen Medicine and Materia Medica Research, 19(7), 1740-1741.


Hamacher-Brady, A., Stein, H.A., Turschner, S., et al. (2011). Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem. 2011;286(8):6587–6601. doi: 10.1074/jbc.M110.210047.


Holien, T., Olsen, O.E., Misund, K., et al. (2013). Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Eur J Haematol, 91(4):339-46. doi: 10.1111/ejh.12176.


Jiang, Z., Chai, J., Chuang, H.H., et al. (2012). Artesunate induces G0/G1 cell-cycle arrest and iron-mediated mitochondrial apoptosis in A431 human epidermoid carcinoma cells. Anti-cancer Drugs, 23(6):606–613. doi: 10.1097/CAD.0b013e328350e8ac.


Liu, L., Zuo, L.F., Guo, J.W. (2013). Reversal of Multi-drug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109/ABCG2 cell line. Oncol Lett, 6(5):1475-1481.


Liu, Y. & Cui, Y.F. (2013). Synergism of cytotoxicity effects of triptolide and artesunate combination treatment in pancreatic cancer cell lines. Asian Pac J Cancer Prev, 14(9):5243-8.


Ma, H., Yaom Q., Zhang, A.M., et al. (2011). The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model. Molecules, 16(12):10556–10569. doi: 10.3390/molecules161210556.


Marchion, D.C., Xiong, Y., Chon, H.S., et al. (2013). Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer. Am J Obstet Gynecol, S0002-9378(13)00827-2. doi: 10.1016/j.ajog.2013.08.004.


Rasheed, S.A., Efferth, T., Asangani, I.A., Allgayer, H. (2010). First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer, 127(6):1475–1485. doi: 10.1002/ijc.25315.


Xu, Q., Li, Z.X., Peng, H.Q., et al. (2011). Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 12(4):247–255. doi: 10.1631/jzus.B1000373.


Zhao, Y., Jiang, W., Li, B., et al. (2011). Artesunate enhances radiosensitivity of human non-small-cell lung cancer A549 cells via increasing no production to induce cell-cycle arrest at G2/M phase. Int Immunopharmacol, 11(12):2039–2046. doi: 10.1016/j.intimp.2011.08.017.


Zeng, Y., Ni, X., Meng, W.T., Wen, Q., Jia, Y.Q. (2009). Inhibitive effect of artesunate on human lymphoblastic leukemia/lymphoma cells. Sichuan Da Xue Xue Bao Yi Xue Ban, 40(6):1038-43.


Zhou, C., Pan, W., Wang, X.P., Chen, T.S. (2012). Artesunate induces apoptosis via a bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. J Cell Physiol, 227(12):3778–3786. doi: 10.1002/jcp.24086.

Breast cancer, Chapter 8 Injectables and Cancer Research, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, Cytostatic, G2/M, Immune, Liver cancer, Lung cancer, Lymphoma, Radio-sensitizer, radiotherapy, Rectal cancer

Ai Di Injection (ADI)

Cancers: Breast, colorectal., glioma, lung

Action: Chemo-sensitizer, cytostatic, radio-sensitizer

 

Ingredients: Mylabris phalerata (ban mao), Panax ginseng (ren shen), Astragalus membranaceus (huang qi).

TCM functions: Clearing Heat, removing Toxin, resolving stagnant Blood, dissolving lumps.

Indications: Primary liver cancer, lung cancer, colorectal cancer, malignant lymphoma, and gynecological malignancies.

Dosage and usage:

For adults: 50-100ml, mixed with 400-500ml of 0.9% NaCl injection or 5-10% glucose injection for intravenous drip, once daily.

When combined with radiotherapy or chemotherapy, the course of treatment is synchronized to radiotherapy or chemotherapy.

Application before or after the surgery: 10 days as a course of treatment.

Intervention treatment: 10 days as a course of treatment.

Single application: 15 days as a cycle, with 3 days interval., 2 cycles as a course of treatment.

 

Cachexia patients in advanced stage: 30 consecutive days as a course of treatment (Drug Information Reference in Chinese: See end).

 

Glioma; Radio-sensitization

The inhibition ratio was determined by MTT assay, the change in the cell-cycle was analyzed by flow cytometry and the expression of cyclin B1 and Wee1 was detected by Western blot analysis. The reproductive activity of the group treated with irradiation (IR) and Aidi injection was suppressed significantly, and the cloning efficiency and divisional index also declined. Aidi injection (15 µg/ml) induced G2/M phase arrest in the cell line after 48 h.

 

Aidi injection (ADI) is effective in radio-sensitization. The possible mechanisms involved may be associated with G2/M phase cell arrest, the down-regulation of cyclin B1 and up-regulation of Wee1 expression, which influences cell size by inhibiting the entry into mitosis, through inhibiting Cyclin-dependent kinase 1 (Xu, Song, Qin, Wang, & Zhou, 2012).

 

Breast Cancer

ADI significantly inhibited the proliferation of MCF-7 cells in a dose-dependent manner. The IC50 of ADI was 55.71 mg/mL after treatment for 48 h. The 60 mg/mL ADI was used as the therapeutic drug concentration. Microarray analysis identified 45 miRNAs that were up-regulated and 55 miRNAs that were down-regulated in response to ADI treatment. Many ADI-induced miRNAs were related to breast cancers. The 12 potential target genes of mir-126 were predicted by both TargetScan and PicTar software.

 

The miRNA may serve as therapeutic targets for ADI, and its modulation of expression is an important mechanism of ADI inhibition of breast cancer cell growth (Zhang, Zhou, Lu, Du, & Su, 2011).

 

Colorectal Cancer; FOLFOX4

A consecutive cohort of 100 patients was divided into two groups. The experimental group was treated with a combination of Aidi injection and FOLFOX4, while the control group was only administered FOLFOX4. After a minimum of two courses of treatment, efficacy, quality of life, and side-effects were evaluated.

 

The response rate of the experimental group was not significantly different compared to the control group (P > 0.05). However, there were significant differences in clinical benefit response and KPS score. In addition, adverse gastrointestinal reactions and the incidence of leukopenia were lower than that of the control group (P < 0.05).

Aidi injection, combined with FOLFOX4, is associated with reduced toxicity of chemotherapy, enhanced clinical benefit response, and improved quality of life in patients with advanced colorectal cancer (Xu, Huang, Li, Li, & Tang, 2011).

 

NSCLC

Ninety-eight cases of advanced NSCLC were randomly divided into two groups: a trial group and control group. In the trial group Navelbine/Cisplatin (NP) plus Ai Di Injection (ADI) (60-80 ml) was administered intravenously, via dissolution in 400 ml of normal saline, per day for 8-10 days. In the control group, only NP chemotherapy was administered at the dosages of: Navelbine (25 mg/m², d1, 8) and Cisplastin (40 mg/m², d1-3). Each patient received at least two cycles of treatment.

 

The effective rate in the trial group and the control group was 53.1% and 44.9% respectively, without significant difference between the two groups (P > 0.05). However, the rate of progression, adverse reactions in the bone marrow, digestive tract, and immune function in the trial group were all lower than those in the control group (P < 0.05). In addition, improvement in Karnofsky score in the trial group was higher than that in the control group (P < 0.05).

 

A chemotherapy regiment of NP, combined with ADI, shows benefit in the treatment of advanced NSCLC. AI could minimize the adverse reactions of chemotherapy, and improve the quality of life in patients with NSCLC (Wang et al., 2004).

 

NSCLC; Meta-analysis

PubMed (1980-2008), Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2008), EMBASE (1984-2008), CancerLit (1996-2003), CBMdisc (1980-2008), CNKI database (1980-2008), Wanfang database (1980-2008), and Chongqing VIP database (1980-2008) were searched. Relevant Chinese periodicals were manually searched as well. All randomized controlled trials comparing Aidi Injection with other treatment methods of NSCLC were included. Two reviewers selected studies, assessed the quality of studies, and extracted the data independently.

 

Fourteen randomized controlled trials were included in the meta-analysis, but unfortunately, the quality of reports of the 14 included studies were poor. Aidi Injection combined with cobalt-60, or navelbine and platinol (NP), showed statistically significant differences in improving the response rate, compared to the use of cobalt-60 alone (P = 0.0002) or NP alone (P = 0.04). However, Aidi Injection combined with etoposide and platinol (EP), taxinol and platinol (TP) or gamma knife showed no significant differences when compared with single use of EP (P=0.60), TP (P=0.16) or gamma knife (P=0.34), respectively. The RR and 95% CI of EP, TP, and gamma knife were 1.17 [0.65, 2.09], 1.27 [0.91, 1.78] and 1.08 [0.92, 1.26] respectively.

 

Six studies indicated that Aidi Injection, combined with NP or gamma knife, could improve quality of life. Six studies showed that Aidi Injection, combined with NP or TP, could improve the bone marrow’s hematopoietic function. The results of the meta-analysis indicate that Aidi Injection may have adjuvant therapeutic effects in the treatment of NSCLC patients. However, sample sizes are small, study quality is poor, and the existence of publication bias had been found. The effects of Aidi Injection need to be confirmed by large multicenter randomized controlled trials (Ma, Duan, Feng, She, Chen & Zhang, 2009).

 

NSCLC; Neo-adjuvant Chemotherapy

Sixty patients, with stage IIIA non-small-cell lung cancer (NSCLC), underwent two courses of bronchial arterial infusion (BAI) chemotherapy, before tumor incision. They were assigned to either the treatment or control group, using a random number table. Thirty patients were allocated to each. An ADI of 100 mL, added into 500 mL of 5% glucose, was given to the patients in the treatment group via intravenous drip. Treatment was once a day, beginning 3 days prior and throughout each of two 14-day courses of chemotherapy.

 

Levels of T-lymphocyte subsets, natural killer cell activity, and interleukin-2 in peripheral blood were measured before and after the treatment. The effective rate in the treatment group was higher than that in the control group (70.0% vs. 56.7%, P < 0.05).

 

Moreover, bone marrow suppression and liver function damage (P < 0.05) was less in the treatment group relative to the control. Cellular immune function was suppressed in NSCLC patients, but was ameliorated after treatment, showing a significant difference when compared to the control group (P < 0.05).

 

ADI could potentially act as an ideal auxiliary drug for patients with stage IIIA NSCLC, receiving BAI neo-adjuvant chemotherapy, before surgical operation. It could enhance the effectiveness of chemotherapy, ameliorate adverse reactions, and elevate patient’s cellular immune function (Sun, Pei, Yin, Wu & Yang, 2010).

 

References

Ma, W.H., Duan, K.N., Feng, M., She, B., Chen, Y., & Zhang, R.M. (2009). Aidi Injection as an adjunct therapy for non-small-cell lung cancer: a systematic review. Journal of Chinese Integrative Medicine, 7(4), 315-324.

Sun, X.F., Pei, Y.T., Yin, Q.W., Wu, M.S., & Yang, G.T. (2010). Application of Aidi injection in the bronchial artery infused neo-adjuvant chemotherapy for stage III A non-small-cell lung cancer before surgical operation. Chinese Journal of Integrative Medicine, 16(6), 537-541.

Wang, D., Chen, Y., Ren, J., Cai, Y., M. Liu, M., & Zhan, Q. (2004). A randomized clinical study on efficacy of Aidi injection combined with chemotherapy in the treatment of advanced non-small-cell lung cancer. Journal of Chinese Integrative Medicine, 7(3), 247-249.

Xu, H.X., Huang, X.E., Li, Y., Li, C.G., & Tang, J.H. (2011). A clinical study on safety and efficacy of Aidi injection combined with chemotherapy. Asian Pacific Journal of Cancer Prevention, 12(9), 2233-2236.

Xu, X.T., Song, Y., Qin, S., Wang, L.L., & Zhou, J.Y. (2012). Radio-sensitization of SHG44 glioma cells by Aidi injection in vitro. Molecular Medicine Reports, 5(6), 1415-1418.

Zhang, H., Zhou, Q.M., Lu, L.L., Du, J., & Su, S.B. (2011). Aidi injection alters the expression profiles of microRNAs in human breast cancer cells. Journal of Traditional Chinese Medicine, 31(1), 10-16.