Category Archives: G1

Anti-estrogenic, Breast cancer, Chapter 7 Isolates and Cancer Research, Chemoprevention, ER, G1, G1/S, Glycine max, growth-inhibitory, LNCaP, Ovarian cancer, Prostate cancer, S

Glyceolins

Cancer: Prostate, breast, ovarian

Action: Anti-estrogenic

Glyceollins are soy-derived phytoalexins isolated from activated soy ( Glycine max [(L.) Merr.] that have been proposed to be candidates for cancer-preventive compounds.

Prostate cancer

It has been found that the glyceollins inhibited prostate cancer cell LNCaP growth similar to that of the soy isoflavone genistein. The growth-inhibitory effects of the glyceollins appeared to be due to an inhibition of G1/S progression and correlated with an up-regulation of cyclin-dependent kinase inhibitor 1 A and B mRNA and protein levels. By contrast, genistein only up-regulates cyclin-dependent kinase inhibitor 1A.

In addition, glyceollin treatments led to down-regulated mRNA levels for androgen responsive genes. In contrast to genistein, this effect of glyceollins on androgen responsive genes appeared to be mediated through modulation of an estrogen- but not androgen-mediated pathway.

Hence, the glyceollins exerted multiple effects on LNCaP cells that may be considered cancer-preventive and the mechanisms of action appeared to be different from other soy-derived phytochemicals (Payton-Stewart et al., 2009).

Anti-estrogenic Effects; Breast Cancer, Ovarian Cancer

The phytoalexin compounds glyceollins I, II, and III have been identified to exhibit marked anti-estrogenic effects on estrogen receptor function and estrogen-dependent tumor growth in vivo. The interactions among the induced soy phytoalexins glyceollins I, II, and III on the growth of estrogen-dependent MCF-7 breast cancer and BG-1 ovarian cancer cells were studied. Four treatment groups for each cell line were used: vehicle control, 20 mg/kg/mouse/d glyceollin mixture injection, 0.72 mg estradiol (E2) implant, and E2 implant + 20 mg/kg/mouse/d glyceollin injection.

Treatment with glyceollin suppressed E2-stimulated tumor growth of MCF-7 cells (-53.4%) and BG-1 cells (-73.1%) in ovariectomized athymic mice. These tumor-inhibiting effects corresponded with significantly lower E2-induced progesterone receptor expression in the tumors. In contrast to tamoxifen, the glyceollins had no estrogen-agonist effects on uterine morphology and partially antagonized the uterotropic effects of estrogen. These findings identify glyceollins as anti-estrogenic agents that may be useful in the prevention or treatment of breast and ovarian carcinoma (Salvo et al., 2006).

Anti-estrogenic Effects

The soybean plant under stress produces a mixture of glyceollins I, II, and III that bind to the estrogen receptor (ER) and inhibit estrogen-induced tumor progression. In further in vitro studies, the glyceollin mixture exhibits potential anti-estrogenic, therapeutic activity preventing estrogen-stimulated tumorigenesis and displaying a differential pattern of gene expression from tamoxifen.

Glyceollin I was identified as the active anti-estrogenic component of the mixture. Ligand-receptor modeling (docking) of the isomers within the ERα ligand binding cavity demonstrated a unique type II anti-estrogenic confirmation adopted by glyceollin I, but not isomers II and III. Glyceollin I treatment in 17β- estradiol-stimulated MCF-7 breast cancer cells and BG-1 ovarian cancer cells resulted in a novel inhibition of ER-mediated gene expression and cell proliferation/ survival.

Glyceollin I may represent an important component of a phytoalexin-enriched food (activated) diet in terms of chemoprevention as well as a novel therapeutic (Tilghman et al., 2010).

References

Payton-Stewart F, Schoene NW, Kim YS, et al. (2009). Molecular effects of soy phytoalexin glyceollins in human prostate cancer cells LNCaP. Molecular Carcinogenesis, 48(9):862–71. doi: 10.1002/mc.20532.


Salvo VA, BouŽ SM, Fonseca JP, et al. (2006). Antiestrogenic glyceollins suppress human breast and ovarian carcinoma tumorigenesis. Clin Cancer Res, 12(23):7159-64. doi: 10.1158/1078-0432.CCR-06-1426.


Tilghman SL, BouŽ SM, Burow ME. (2010). Glyceollins, a novel class of antiestrogenic phytoalexins. Molecular and Cellular Pharmacology, 2(4):155-60. doi: 10.4255/mcpharmacol.10.21

AGS, anti-tumor, anti-tumor activity, apoptosis, BAX, Bcl-2, Breast cancer, Breast cancer cell lines, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, G0/G1, G1, G2/M, MCF-7, MDA-MB-231, PARP, PCNA, Rhizoma curcuma longa, S

Germacrone

Cancer: Breast, stomach

Action: Cell-cycle arrest

Traditional medicinal herbs are an untapped source of potential pharmaceutical compounds. Germacrone is a natural product isolated from Rhizoma curcuma longa (L.).

Breast Cancer

Germacrone has been investigated for its inhibition on the proliferation of breast cancer cell lines. Germacrone treatment significantly inhibited cell proliferation, increased lactate dehydrogenase (LDH) release, and induced mitochondrial membrane potential (ΔΨ m) depolarization in both MCF-7 and MDA-MB-231 cells in a dose-dependent manner. Germacrone induced MDA-MB-231 and MCF-7 cell-cycle arrest at the G0/G1 and G2/M phases respectively and induced MDA-MB-231 cell apoptosis.

In addition, germacrone treatment induced caspase-3, 7, 9, PARP cleavage. It was therefore concluded that germacrone inhibited the proliferation of breast cancer cell lines by inducing cell-cycle arrest and apoptosis through mitochondria-mediated caspase pathway. These results might provide some molecular basis for the anti-tumor activity of Rhizoma curcuma (Zhong et al., 2011).

Stomach Cancer

Germacrone, contained in zedoary oil from Rhizoma curcuma, significantly decreased the cell viability of AGS cells (P < 0.01) and MGC 803 cells (P < 0.01), and the inhibitory effects were attenuated by elevated concentrations of FBS. At high concentrations (>=90 mug/mL), zedoary oil killed GES-1 cells. At low concentrations (<=60 mug/mL), zedoary oil was less inhibitory toward gastric cancer cell lines. In AGS cells, zedoary oil inhibited cell proliferation in a dose- and time-dependent manner, with decreased PCNA protein expression in the zedoary oil-treated cells, and arrested the cell-cycle at S, G2/M and G0/G1 stages after treatment for 6–48 hours. At concentrations of 30, 60 and 90 mug/mL, which resulted in significant inhibition of proliferation and cell-cycle arrest, zedoary oil induced cell apoptosis.

Zedoary oil up-regulated the ratio of Bax/Bcl-2 protein expression (P < 0.01). Zedoary oil which contains germacrone was hence found to inhibit AGS cell proliferation through cell-cycle arrest and cell apoptosis promotion, which are related to Bax/Bcl-2 protein expression.

References

Shi H, Tan B, Ji G, et al. (2013). Zedoary oil (Ezhu You) inhibits proliferation of AGS cells. Chin Med, 8(1):13.


Zhong Z, Chen X, Tan W, et al. (2011). Germacrone inhibits the proliferation of breast cancer cell lines by inducing cell-cycle arrest and promoting apoptosis. Eur J Pharmacol, 667(1-3):50-55. doi:10.1016/j.ejphar.2011.03.041.

anti-proliferative, anti-tumor, apoptosis, AR, BAX, Bcl-2, Causes cell-cycle arrest, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, G0/G1, G1, G2/M, PC3, Prostate cancer, S, Sophora Flavescens

Gentianaceae

Cancer: Prostate, breast, lung, pancreatic

Action: Causes cell-cycle arrest

Gentianaceae is a naturally occurring alkaloid isolated from Sophora flavescens (Aiton).

Prostate Cancer; AR-

Gentianaceae has shown anti-proliferative properties in a number of types of cancer, including breast, gastric, lung and pancreatic tumors. Gentianaceae was also found to promote apoptosis and inhibit invasion of cancer cells.

The anti-tumor effects of gentianaceae were evaluated on androgen-independent PC-3 prostate cancer cells. The effects of gentianaceae on cell-cycle progression and apoptosis of PC-3 cells were tested. Gentianaceae-treated PC-3 cells underwent G0/G1 cell-cycle arrest. There was a significant reduction in the number of S phase and G2/M phase cells in the treated group when compared to untreated cells.

There was also an increase in the number of necrotic cells in the gentianaceae-treated group when compared to untreated cells. Gentianaceae treatment resulted in increased levels of caspase-3 and Bax and decreased levels of Bcl-2. The data suggest that gentianaceae inhibits the proliferation of androgen-independent prostate cancer cells by causing G0/G1 cell-cycle arrest and promoting apoptosis. Gentianaceae-induced apoptosis was mediated by down-regulation of Bcl-2/Bax ratios and up-regulation of caspase-3 levels (Zhang et al., 2012).

Reference

Zhang P, Wang Z, Chong T, Ji Z. (2012). Matrine inhibits proliferation and induces apoptosis of the androgen “American Typewriter”; “American Typewriter”;‑ independent prostate cancer cell line PC-3. Mol Med Report, 5(3):783-7. doi: 10.3892/mmr.2011.701.

anti-proliferative, anti-tumor, apoptosis, Apoptotic, BAX, c-Fos, c-Jun, CDK4, Cervical cancer, Chapter 7 Isolates and Cancer Research, Chemoprevention, Cytostatic, ERK1, FasL, G1, Hep3B, hepato-protective, induces apoptosis, JNK, Melanoma, Neuroblastoma, p21, p53, PI3K, PKC, Prostate cancer

Geniposide –Penta-acetyl Geniposide (Ac)5GP

Cancers:
Glioma, melanoma, liver, hepatocarcinogenesis, hepatoma, prostate, cervical

Action: Cytostatic, induces apoptosis

Gardenia, the fruit of Gardenia jasminoides Ellis, has been widely used to treat liver and gall bladder disorders in Chinese medicine. It has been shown recently that geniposide, the main ingredient of Gardenia fructus , exhibits anti-tumor effect.

Hepatocarcinogenesis, Glioma

It has been demonstrated that (Ac)5GP plays more potent roles than geniposide in chemoprevention. (Ac)5GP decreased DNA damage and hepatocarcinogenesis, induced by aflatoxin B1 (AFB1), by activating the phase II enzymes glutathione S-transferase (GST) and GSH peroxidase (GSH-Px). It reduced the growth and development of inoculated C6 glioma cells, especially in pre-treated rats. In addition to the preventive effect, (Ac)5GP exerts its actions on apoptosis and growth arrest.

Treatment of (Ac)5GP caused DNA fragmentation of glioma cells. (Ac)5GP induced sub- G1 peak through the activation of apoptotic cascades PKCdelta/JNK/Fas/caspase8 and caspase 3. It arrested the cell-cycle at G0/ G1 by inducing the expression of p21, thus suppressing the cyclin D1/cdk4 complex formation and the phosphorylation of E2F.

Data from in vivo experiments indicated that (Ac)5GP is not harmful to the liver, heart and kidney. (Ac)5GP is strongly suggested to be an anti-tumor agent for development in the future (Peng, Huang, & Wang, 2005).

Induces Apoptosis

Previous studies have demonstrated the apoptotic cascades protein kinase C (PKC) delta/c-Jun NH2-terminal kinase (JNK)/Fas/caspases induced by penta-acetyl geniposide [(Ac)5GP]. However, the upstream signals mediating PKCdelta activation have not yet been clarified. Ceramide, mainly generated from the degradation of sphingomyelin, was hypothesized upstream above PKCdelta in (Ac)5GP-transduced apoptosis.

After investigation, (Ac)5GP was shown to activate neutral sphingomyelinase (N-SMase) immediately, with its maximum at 15 min. The NGF and p75 enhanced by (Ac)5GP was inhibited when combined with GW4869, the N-SMase inhibitor, indicating NGF/p75 as the downstream signals of N-SMase/ceramide. To evaluate whether N-SMase is involved in (Ac)5GP-transduced apoptotic pathway, cells were treated with (Ac)5GP, alone or combined with GW4869. It was demonstrated that N-SMase inhibition blocked FasL expression and caspase 3 activation. Similarly, p75 antagonist peptide attenuated the FasL/caspase 3 expression. It indicated that N-SMase activation is pivotal in (Ac)5GP-mediated apoptosis.

SMase and NGF/p75 are suggested to mediate upstream above PKCdelta, thus transducing FasL/caspase cascades in (Ac)5GP-induced apoptosis (Peng, Huang, Hsu, & Wang, 2006).

Glioma

Penta-acetyl geniposide [(Ac)(5)GP], an acetylated geniposide product from Gardenia fructus, has been known to have hepato-protective properties and recent studies have revealed its anti-proliferative and apoptotic effect on C6 glioma cells. The anti-metastastic effect of (Ac)(5)GP in the rat neuroblastoma line C6 glioma cells were investigated.

Further (Ac)(5)GP also exerted an inhibitory effect on phosphoinositide 3-kinase (PI3K) protein expression, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and inhibition of activation of transcription factor nuclear factor kappa B (NF-kappaB), c-Fos, c-Jun.

Findings suggest (Ac)(5)GP is highly likely to be an inhibiting cancer migration agent to be further developed in the future (Huang et al., 2009).

Melanoma

A new iridoid glycoside, 10-O-(4'-O-methylsuccinoyl) geniposide, and two new pyronane glycosides, jasminosides Q and R, along with nine known iridoid glycosides, and two known pyronane glycosides, were isolated from a MeOH extract of Gardeniae Fructus, the dried ripe fruit of Gardenia jasminoides (Rubiaceae).

The structures of new compounds were elucidated on the basis of extensive spectroscopic analyzes and comparison with literature. Upon evaluation of these compounds on the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), three compounds, i.e., 6-O-p-coumaroylgeniposide (3), 7, and 6'-O-sinapoyljasminoside (12), exhibited inhibitory effects with 21.6-41.0 and 37.5-47.7% reduction of melanin content at 30 and 50 µM, respectively, with almost no toxicity to the cells (83.7-106.1% of cell viability at 50 µM) (Akisha et al., 2012).

Hepatoma, Prostate Cancer, Cervical Cancer

Genipin is a metabolite of geniposide isolated from an extract of Gardenia fructus. Some observations suggested that genipin could induce cell apoptosis in hepatoma cells and PC3 human prostate cancer cells. Genipin could remarkably induce cytotoxicity in HeLa cells and inhibit its proliferation. Induction of the apoptosis by genipin was confirmed by analysis of DNA fragmentation and induction of sub-G(1) peak through flow cytometry.

The results also showed that genipin-treated HeLa cells cycle was arrested at G(1) phase. Western blot analysis revealed that the phosphorylated c-Jun NH(2)-terminal kinase (JNK) protein, phospho-Jun protein, p53 protein and bax protein significantly increased in a dose-dependent manner after treatment of genipin for 24 hours; the activation of JNK may result in the increase of the p53 protein level; the increase of the p53 protein led to the accumulation of bax protein; and bax protein further induced cell apoptotic death eventually (Cao et al., 2010).

References

Akihisa T, Watanabe K, Yamamoto A, et al. (2012). Melanogenesis inhibitory activity of monoterpene glycosides from Gardeniae Fructus. Chemistry & Biodiversity, 9(8), 1490-9. doi: 10.1002/cbdv.201200030.


Cao H, Feng Q, Xu W, et al. (2010). Genipin induced apoptosis associated with activation of the c-Jun NH2-terminal kinase and p53 protein in HeLa cells. Biol Pharm Bull, 33(8):1343-8.


Huang HP, Shih YW, Wu CH, et al. (2009). Inhibitory effect of penta-acetyl geniposide on C6 glioma cells metastasis by inhibiting matrix metalloproteinase-2 expression involved in both the PI3K and ERK signaling pathways. Chemico-biological Interactions, 181(1), 8-14. doi: 10.1016/j.cbi.2009.05.009.


Peng CH, Huang CN, Hsu SP, Wang CJ. (2006). Penta-acetyl geniposide induce apoptosis in C6 glioma cells by modulating the activation of neutral sphingomyelinase-induced p75 nerve growth factor receptor and protein kinase Cdelta pathway. Molecular Pharmacology, 70(3), 997-1004.


Peng CH, Huang CN, Wang CJ. (2005). The anti-tumor effect and mechanisms of action of penta-acetyl geniposide. Current Cancer Drug Targets, 5(4), 299-305.

angiogenesis, Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, apoptosis, Apoptotic, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Colon Cancer or Colorectal cancer, G1, hepato-protective, Immunomodulatory, Liver cancer, Lung cancer, Melanoma, metastasis, Oral cancer, Osteosarcoma, p53, PARP, Radio-protective, ROS, Sarcoma, Skin cancer, Syzygium aromaticum

Eugenol

Cancer:
Melanoma, osteosarcoma, leukemia, gastric, colon, liver, oral., lung

Action: Radio-protective

Eugenol is a natural compound available in honey and various plants extracts; in particular, cloves (Syzygium aromaticum (L.) Merrill & Perry).

Melanoma, Skin Tumors, Osteosarcoma, Leukemia, Gastric Cancer

Eugenol (4-allyl-2-methoxyphenol), a phenolic phytochemicals, is the active component of Syzigium aromaticum (cloves). Aromatic plants like nutmeg, basil, cinnamon and bay leaves also contain eugenol. Eugenol has a wide range of applications like perfumeries, flavorings, essential oils and in medicine as a local antiseptic and anesthetic. Increasing volumes of literature show eugenol possesses anti-oxidant, anti-mutagenic, anti-genotoxic, anti-inflammatory and anti-cancer properties.

The molecular mechanism of eugenol-induced apoptosis in melanoma, skin tumors, osteosarcoma, leukemia, gastric and mast cells has been well documented and highlights the anti-proliferative activity and molecular mechanism of eugenol-induced apoptosis against the cancer cells and animal model (Jaganathan et al., 2012).

Colon Cancer

Since most of the drugs used in cancer are apoptosis-inducers, the apoptotic effect and anti-cancer mechanism of eugenol were investigated against colon cancer cells. MTT assay signified the anti-proliferative nature of eugenol against the tested colon cancer cells. PI staining indicated increasing accumulation of cells at sub-G1-phase. Eugenol treatment resulted in reduction of intracellular non-protein thiols and increase in the earlier lipid layer break. Further events like dissipation of MMP and generation of ROS (reactive oxygen species) were accompanied in the eugenol-induced apoptosis. Augmented ROS generation resulted in the DNA fragmentation of treated cells as shown by DNA fragmentation and TUNEL assay. Further activation of PARP (polyadenosine diphosphate-ribose polymerase), p53 and caspase-3 were observed in Western blot analyzes.

These results demonstrate the molecular mechanism of eugenol-induced apoptosis in human colon cancer cells. This research will further enhance eugenol as a potential chemo-preventive agent against colon cancer (Jaganathan et al., 2011).

Radio-protective, Skin Cancer, Liver Cancer, Oral Cancer, Lung Cancer

Ocimum sanctum L. or Ocimum tenuiflorum L , commonly known as Holy Basil in English or Tulsi in the various Indian languages, is an important medicinal plant in the various traditional and folk systems of medicine in Southeast Asia, and another plant from which eugenol is extracted. Scientific studies have shown it to possess anti-inflammatory, analgesic, anti-pyretic, anti-diabetic, hepato-protective, hypolipidemic, anti-stress, and immunomodulatory activities. Preclinical studies have also shown that Ocimum and some of its phytochemicals including eugenol prevented chemical-induced skin, liver, oral., and lung cancers and to mediate these effects by increasing the anti-oxidant activity, altering the gene expressions, inducing apoptosis, and inhibiting angiogenesis and metastasis.

The aqueous extract of Ocimum and its flavanoids, orintin and vicenin, are shown to protect mice against γ-radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. This action is related to the important phytochemicals it contains like eugenol, which are also shown to prevent radiation-induced DNA damage.

References

Baliga MS, Jimmy R, Thilakchan 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.


Jaganathan SK, Mazumdar A, Mondhe D, Mandal M. (2011). Apoptotic effect of eugenol in human colon cancer cell lines. Cell Biol Int, 35(6):607-15. doi: 10.1042/CBI20100118.


Jaganathan SK, Supriyanto E. (2012). Anti-proliferative and Molecular Mechanism of Eugenol-Induced Apoptosis in Cancer Cells. Molecules, 17(6):6290-6304. doi:10.3390/molecules17066290.

ABC, Anti-cancer, Anti-metastatic, apoptosis, apoptosis induction, Breast cancer, CDK2, Chapter 7 Isolates and Cancer Research, Cytostatic, G1, G2/M, KIP1, lymphangiogenesis inhibitors, Nausea and Vomiting, p27, PARP, Prostate cancer, S, Sarcoma, TIMP-2

Dehydrocostus (See also costunolide)

Cancers: Breast, cervical., lung, prostate, sarcoma

Action: Anti-metastatic, cytostatic, lymphangiogenesis inhibitors

Saussurea lappa has been used in Chinese traditional medicine for the treatment of abdominal pain, tenesmus, nausea, and cancer. Previous studies have shown that S. lappa also induces G2 growth arrest and apoptosis in gastric cancer cells.

Prostate Cancer

The effects of hexane extracts of S. lappa (HESLs) on the migration of DU145 and TRAMP-C2 prostate cancer cells were investigated. DU145 and TRAMP-C2 cells were cultured in the presence of 0-4 µg/mL HESL with or without 10 ng/mL epidermal growth factor (EGF).

The active compound, dehydrocostus lactone (DHCL), in fraction 7, dose-dependently inhibited the basal and EGF-induced migration of prostate cancer cells. HESL and DHCL reduced matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 secretion but increased TIMP-2 levels in both the absence and presence of EGF.

Results demonstrated that the inhibition of MMP-9 secretion, and the stimulation of TIMP-2 secretion, contribute to reduced migration of DU145 cells treated with HESL and DHCL. This indicates that HESL containing its active principle, DHCL, has potential as an anti-metastatic agent in the treatment of prostate cancer (Kim et al., 2012).

Sarcoma

Human soft tissue sarcomas represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment. The effects of the costunolide and dehydrocostus lactone, which have been isolated from Saussurea lappa using activity-guided isolation, were studied on three soft tissue sarcoma cell lines of various origins. The effects on cell proliferation, cell-cycle distribution, apoptosis induction, and ABC transporter expression were analyzed. Both compounds inhibited cell viability dose- and time-dependently.

IC50 values ranged from 6.2 µg/mL to 9.8 µg/mL. Cells treated with costunolide showed no changes in cell-cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 hours. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase.

These data demonstrate for the first time that dehydrocostus lactone affects cell viability, cell-cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumors (Kretschmer et al., 2012).

The effects of the sesquiterpene lactones, costunolide and dehydrocostus, on the cell-cycle, MMP expression, and invasive potential of three human STS cell lines of various origins. Both compounds reduced cell proliferation in a time- and dose-dependent manner.

Dehydrocostus lactone significantly inhibited cell proliferation, arrested the cells at the G2/M interface and caused a decrease in the expression of the cyclin-dependent kinase CDK2 and the cyclin-dependent kinase inhibitor p27 (Kip1).

In the presence of costunolide, MMP-2 and MMP-9 levels were significantly increased in SW-982 and TE-671 cells. Dehydrocostus lactone treatment significantly reduced MMP-2 and MMP-9 expression in TE-671 cells, but increased MMP-9 level in SW-982 cells. In addition, the invasion potential was significantly reduced after treatment with both sesquiterpene lactones as investigated by the HTS FluoroBlock insert system (Lohberger et al., 2013).

Breast Cancer

Several Chinese herbs, namely, pu gong ying (Taraxacum officinale), gan cao (Glycyrrhizae uralensis), chai hu (Bupleurum chinense), mu xiang (Auklandia lappa), gua lou (Trichosanthes kirilowii) and huang yao zi (Dioscoreae bulbiferae), are frequently used in complex traditional Chinese medicine formulas, for breast hyperplasia and breast tumor therapy. The effects of these Chinese herbs are all described as 'clearing heat-toxin and resolving masses' in traditional use. However, the chemical profiles of anti-breast cancer constituents in these herbs have not been investigated thus far.

Two potential anti-breast cancer compounds, costunolide (Cos) and dehydrocostus lactone (Dehy), were identified in mu xiang. The combination of the two compounds showed a synergistic effect on inhibiting the proliferation of MCF-7 cells in vitro, exhibiting potential application in the treatment of breast cancer (Peng, Wang, Gu, Wen & Yan, 2013).

Lymphangiogenesis Inhibitors

In this study, we investigated lymphangiogenesis inhibitors from crude drugs used in Japan and Korea. The three crude drugs Saussureae Radix, Psoraleae Semen and Aurantti Fructus Immaturus significantly inhibited the proliferation of temperature-sensitive rat lymphatic endothelial (TR-LE) cells in vitro. These compounds might offer clinical benefits as lymphangiogenesis inhibitors and may be good candidates for novel anti-cancer and anti-metastatic agents (Jeong, 2013).

References

Jeong D, Watari K, Shirouzu T, et al. (2013). Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs. Biological & Pharmaceutical Bulletin, 36(1), 152-7.


Kim EJ, Hong JE, Lim SS, et al. (2012). The hexane extract of Saussurea lappa and its active principle, dehydrocostus lactone, inhibit prostate cancer cell migration. Journal of Medicinal Food, 15(1), 24-32. doi: 10.1089/jmf.2011.1735.


Kretschmer N, Rinner B, Stuendl N, et al. (2012). Effect of costunolide and dehydrocostus lactone on cell-cycle, apoptosis, and ABC transporter expression in human soft tissue sarcoma cells. Planta Medica, 78(16), 1749-1756. doi: 10.1055/s-0032-1315385.


Lohberger B, Rinner B, Stuendl N, et al. (2013). Sesquiterpene lactones downregulate g2/m cell-cycle regulator proteins and affect the invasive potential of human soft tissue sarcoma cells. PLoS One, 8(6), e66300. doi: 10.1371/journal.pone.0066300.


Peng ZX, Wang Y, Gu X, Wen YY, Yan C. (2013). A platform for fast screening potential anti-breast cancer compounds in traditional Chinese medicines. Biomedical Chromatography. doi: 10.1002/bmc.2990.

anti-apoptotic, Anti-cancer, anti-inflammatory, anti-oxidative, anti-proliferative, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, AR, BAX, Bcl-2, Bcl-xL, Breast cancer, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, COX-2, CYP3A, DU145, G1, G2/M, hepato-protective, ICAM-1, inflammation, JNK, MAPK, metastasis, MMP2, MMP9, MTOR, p38, PGE2, Prostate cancer, STAT3, STAT3 (Tyr705), TNF, VCAM-1

Cryptotanshinone (See also Tanshinone)

Cancer:
Prostate, breast, cervical., leukemia, hepatocellular carcinoma

Action: Anti-inflammatory, cell-cycle arrest, inhibits dihydrotestosterone (DHT), anti-proliferative, hepato-protective

Cryptotanshinone is a major constituent of tanshinones from Salvia miltiorrhiza (Bunge).

Tanshinone IIA and cryptotanshinone could induce CYP3A activity (Qiu et al., 2103).

Anti-proliferative Agent

Cryptotanshinone (CPT), a natural compound, is a potential anti-cancer agent. Chen et al., (2010) have shown that CPT inhibited cancer cell proliferation by arresting cells in G(1)-G(0) phase of the cell-cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation.

Furthermore, they found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I- or 10% fetal bovine serum-stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration- and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel anti-proliferative agent.

Anti-inflammatory; COX-2, PGE2

Cyclooxygenase-2 (COX-2) is a key enzyme that catalyzes the biosynthesis of prostaglandins from arachidonic acid and plays a critical role in some pathologies including inflammation, neurodegenerative diseases and cancer. Cryptotanshinone is a major constituent of tanshinones and has well-documented anti-oxidative and anti-inflammatory effects.

This study confirmed the remarkable anti-inflammatory effect of cryptotanshinone in the carrageenan-induced rat paw edema model. Since the action of cryptotanshinone on COX-2 has not been previously described, in this study, Jin et al. (2006) examined the effect of cryptotanshinone on cyclooxygenase activity in the exogenous arachidonic acid-stimulated insect sf-9 cells, which highly express human COX-2 or human COX-1, and on cyclooxygenases expression in human U937 promonocytes stimulated by lipopolysaccharide (LPS) plus phorbolmyristate acetate (PMA).

Cryptotanshinone reduced prostaglandin E2 synthesis and reactive oxygen species generation catalyzed by COX-2, without influencing COX-1 activity in cloned sf-9 cells. In PMA plus LPS-stimulated U937 cells, cryptotanshinone had negligible effects on the expression of COX-1 and COX-2, at either a mRNA or protein level. These results demonstrate that the anti-inflammatory effect of cryptotanshinone is directed against enzymatic activity of COX-2, not against the transcription or translation of the enzyme.

Prostate Cancer

Cryptotanshinone was identified as a potent STAT3 inhibitor. Cryptotanshinone rapidly inhibited STAT3 Tyr705 phosphorylation in DU145 prostate cancer cells and the growth of the cells through 96 hours of the treatment. Inhibition of STAT3 Tyr705 phosphorylation in DU145 cells decreased the expression of STAT3 downstream target proteins such as cyclin D1, survivin, and Bcl-xL.

Cryptotanshinone can suppress Bcl-2 expression and augment Fas sensitivity in DU145 prostate cancer cells. Park et al. (2010) show that JNK and p38 MAPK act upstream of Bcl-2 expression in Fas-treated DU145 cells, and that cryptotanshinone significantly blocked activation of these kinases. Moreover, cryptotanshinone sensitized several tumor cells to a broad range of anti-cancer agents. Collectively, the data suggest that cryptotanshinone has therapeutic potential in the treatment of human prostate cancer (Park et al., 2010).

Cryptotanshinone was colocalized with STAT3 molecules in the cytoplasm and inhibited the formation of STAT3 dimers. Computational modeling showed that cryptotanshinone could bind to the SH2 domain of STAT3. These results suggest that cryptotanshinone is a potent anti-cancer agent targeting the activation STAT3 protein. It is the first report that cryptotanshinone has anti-tumor activity through the inhibition of STAT3 (Shin et al., 2009).

Prostate Cancer; Androgen Receptor Positive

Anti-androgens to reduce or prevent androgens binding to androgen receptor (AR) are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a short period of time. Xu et al., (2012) found that cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Their results indicated that 0.5 µM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells.

Furthermore, data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR-coregulator complex formation.

Furthermore, they showed that CTS effectively inhibits CWR22Rv1 cell growth and expressions of AR target genes in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa.

Breast Cancer, Cervical Cancer, Leukemia, Hepatocellular Carcinoma

The three tanshinone derivatives, tanshinone I, tanshinone IIA, and cryptotanshinone, exhibited significant in vitro cytotoxicity against several human carcinoma cell lines (Wang et al., 2007).

Tanshinone I was found to inhibit the growth and invasion of breast cancer cells both in vitro and in vivo through regulation of adhesion molecules including ICAM-1 and VCAM-1 (Nizamutdinova et al., 2008), and induce apoptosis of leukemia cells by interfering with the mitochondrial transmembrane potential (ΔΨm), increasing the expression of Bax, as well as activating caspase-3 (Liu et al., 2010). Tanshinone IIA has been reported to inhibit the growth of cervical cancer cells through disrupting the assembly of microtubules, and induces G2/M phase arrest and apoptosis (Pan et al., 2010).

This compound can also inhibit invasion and metastasis of hepatocellular carcinoma (HCC) cells both in vitro and in vivo, by suppressing the expression of the metalloproteinases, MMP2 and MMP9 and interfering with the NFκB signaling pathway (Xu et al., 2009).

Breast Cancer

Cryptotanshione was reported to induce cell-cycle arrest at the G1-G0 phase, which was accompanied by the inhibition of cyclin D1 expression, retinoblastoma (Rb) protein phosphorylation, and of the rapamycin (mTOR) signaling pathway (Chen et al., 2010).

Hepato-protective Effect

Cryptotanshinone (20 or 40mg/kg) was orally administered 12 and 1h prior to GalN (700mg/kg)/LPS (10µg/kg) injection. The increased mortality and TNF- α levels by GalN/LPS were declined by cryptotanshinone pre-treatment. In addition, cryptotanshinone attenuated GalN/LPS-induced apoptosis, characterized by the blockade of caspase-3, -8, and -9 activation, as well as the release of cytochrome c from the mitochondria. Furthermore, cryptotanshinone significantly inhibited the activation of NF-κB and suppressed the production of pro-inflammatory cytokines.

These findings suggest that the hepato-protective effect of cryptotanshinone is likely to be associated with its anti-apoptotic activity and the down-regulation of MAPKs and NF-κB associated at least in part with suppressing TAK1 phosphorylation (Jin et al., 2013).

References

Chen W, Luo Y, Liu L, Zhou H, Xu B, Han X, Shen T, Liu Z, Lu Y, Huang S. (2010). Cryptotanshinone Inhibits Cancer Cell Proliferation by Suppressing Mammalian Target of Rapamycin–Mediated Cyclin D1 Expression and Rb Phosphorylation. Cancer Prev Res (Phila), 3(8):1015-25. doi: 10.1158/1940-6207.CAPR-10-0020. Epub 2010 Jul 13.

Jin DZ, Yina LL, Jia XQ, Zhu XZ. (2006). Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression. European Journal of Pharmacology, 549(1-3):166-72. doi:10.1016/j.ejphar.2006.07.055

Jin VQ, Jiang S, Wu YL, et al. (2013). Hepato-protective effect of cryptotanshinone from Salvia miltiorrhiza in d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure. Phytomedicine. doi:10.1016/j.phymed.2013.07.016

Liu JJ, Liu WD, Yang HZ, et al. (2010). Inactivation of PI3k/Akt signaling pathway and activation of caspase-3 are involved in tanshinone I-induced apoptosis in myeloid leukemia cells in vitro. Ann Hematol, 89:1089–1097. doi: 10.1007/s00277-010-0996-z.

Nizamutdinova IT, Lee GW, Lee JS, et al. (2008). Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation of adhesion molecules. Carcinogenesis, 29(10):1885-1892. doi:10.1093/carcin/bgn151

Pan TL, Hung YC, Wang PW, et al. (2010). Functional proteomic and structural insights into molecular targets related to the growth-inhibitory effect of tanshinone IIA on HeLa cells. Proteomics,10:914–929.

Park IJ, Kim MJ, Park OJ, et al. (2010). Cryptotanshinone sensitizes DU145 prostate cancer cells to Fas(APO1/CD95)-mediated apoptosis through Bcl-2 and MAPK regulation. Cancer Lett, 298:88–98. doi: 10.1016/j.canlet.2010.06.006.

Qiu F, Jiang J, Ma Ym, et al. (2013). Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers. Evidence-Based Complementary and Alternative Medicine, 2013(2013) http://dx.doi.org/10.1155/2013/730734

Shin DS, Kim HN, Shin KD, et al. (2009). Cryptotanshinone Inhibits Constitutive Signal Transducer and Activator of Transcription 3 Function through Blocking the Dimerization in DU145 Prostate Cancer Cells. Cancer Research, 69:193. doi: 10.1158/0008-5472.CAN-08-2575

Wang X, Morris-Natschke SL, Lee KH. (2007). New developments in the chemistry and biology of the bioactive constituents of Tanshen. Med Res Rev, 27:133–148. doi: 10.1002/med.20077.

Xu D, Lin TH, Li S, Da J, et al. (2012). Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells. Cancer Lett, 316(1):11-22. doi: 10.1016/j.canlet.2011.10.006.

Xu YX, Feng T, Li R, Liu ZC. (2009). Tanshinone II-A inhibits invasion and metastasis of human hepatocellular carcinoma cells in vitro and in vivo. Tumori, 95:789–795.

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

Abe F, Yamauchi T, Nagao T, et al. (2002). Ursolic acid as a trypanocidal constituent in rosemary. Biological & Pharmaceutical Bulletin, 25(11):1485–7. doi:10.1248/bpb.25.1485. PMID 12419966.


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.


Cai WJ, Ma YQ, Qi YM et al. (2006). Ai bian ji bian tu bian can kao wen xian ge shi    Carcinogenesis,Teratogenesis & Mutagenesis,18(1):16-8.


Cheng YQ, Chen Y, Wu QL, Fang J, Yang LJ. (2009). Zhongguo Shi Yan Xue Ye Xue Za Zhi, 17(5):1224-9.


Chowdhury AR, Mandal S, Mittra B, et al. (2002). Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives. Medical Science Monitor, 8(7): BR254–65. PMID 12118187.


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.


Ji ZN, Ye WC, Liu GG, Hsiao WL. (2002). 23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2 expression and telomerase activity in HL-60 Cells. Life Sciences, 72(1):1–9. doi:10.1016/S0024-3205(02)02176-8. PMID 12409140.


Kontogianni VG, Tomic G, Nikolic I, et al. (2013). Phytochemical profile of Rosmarinus officinalis and Salvia officinalis extracts and correlation to their anti-oxidant and anti-proliferative activity. Food Chem,136(1):120-9. doi: 10.1016/j.foodchem.2012.07.091.


Kumar D, Mallick S, Vedasiromoni JR, Pal BC. (2010). Anti-leukemic activity of Dillenia indica L. fruit extract and quantification of betulinic acid by HPLC. Phytomedicine, 17(6):431-5.


Li L, Du Y, Kong X, et al. (2013). Lamin B1 Is a Novel Therapeutic Target of Betulinic Acid in Pancreatic Cancer. Clin Cancer Res, Epub July 9. doi: 10.1158/1078-0432.CCR-12-3630


Liu Y, Luo W. (2012). Betulinic acid induces Bax/Bak-independent cytochrome c release in human nasopharyngeal carcinoma cells. Molecules and cells, 33(5):517-524. doi: 10.1007/s10059-012-0022-5


Pisha E, Chai H, Lee I-S, et al. (1995). Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nature Medicine, 1:1046 – 1051. doi: 10.1038/nm1095-1046


Pyo JS, Roh SH, Kim DK, et al. (2009). Anti-Cancer Effect of Betulin on a Human Lung Cancer Cell Line: A Pharmacoproteomic Approach Using 2 D SDS PAGE Coupled with Nano-HPLC Tandem Mass Spectrometry. Planta Med, 75(2): 127-131. doi: 10.1055/s-0028-1088366


Reiner T, Parrondo R, de Las Pozas A, Palenzuela D, Perez-Stable C. (2013). Betulinic Acid Selectively Increases Protein Degradation and Enhances Prostate Cancer-Specific Apoptosis: Possible Role for Inhibition of Deubiquitinase Activity. PLoS One, 8(2):e56234. doi: 10.1371/journal.pone.0056234.


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Selzer E, Pimentel E, Wacheck V, et al. (2000). Effects of Betulinic Acid Alone and in Combination with Irradiation in Human Melanoma Cells. Journal of Investigative Dermatology, 114:935–940; doi:10.1046/j.1523-1747.2000.00972.x


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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.

Akt, Anti-cancer, anti-tumor, apoptosis, Apoptotic, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, CHK2, Colon Cancer or Colorectal cancer, ER, ER-positive, G0/G1, G1, HER-2, HER-2/neu, Ovarian cancer, PARP, PI3K, PI3K/Akt

Antrodia camphorata

 

Cancer: Leukemia, colorectal., ER+ ovarian cancer

Action: Anti-cancer

Antrodia Camphorata [(M. Zang & C.H. Su) Sheng H. Wu, Ryvarden & T.T.] is a native Taiwanese mushroom which is used in Asian folk medicine. It is also known as Ganoderma camphoratum (M. Zang & C.H. Su) and Taiwanofungus camphoratus [(M. Zang & C.H. Su) Sheng H. Wu, Z.H. Yu, Y.C. Dai & C.H. Su].

Anti-tumor

Mycotherapy is defined as the study of the use of extracts and compounds obtained from mushrooms as medicines or health-promoting agents. An increasing number of studies in the past few years have revealed mushroom extracts as potent anti-tumor agents. Also, numerous studies have been conducted on bioactive compounds isolated from mushrooms reporting the heteropolysaccharides, β-glucans, α-glucans, proteins, complexes of polysaccharides with proteins, fatty acids, nucleoside antagonists, terpenoids, sesquiterpenes, lanostanoids, sterols and phenolic acids, as promising anti-tumor agents (Popović et al., 2013).

Leukemia

Antrodia camphorata (AC) is a native Taiwanese mushroom, which is used in Asian folk medicine as a chemo-preventive agent. The triterpenoid-rich fraction (FEA) was obtained from the ethanolic extract of AC and characterized by high performance liquid chromatography (HPLC). FEA caused DNA damage in leukemia HL60 cells which was characterized by phosphorylation of H2A.X and Chk2. It also exhibited apoptotic effect which was correlated to the enhancement of PARP cleavage and to the activation of caspase 3.

Taken together, these results provide the first evidence that pure AC component inhibits tumor growth in an in vivo model, thereby backing the traditional anti-cancer use of AC in Asian countries (Du et al., 2012).

Colon Cancer

Antrodia camphorata (AC) grown on germinated brown rice (CBR) was studied in HT-29 human colon cancer cells. CBR 80% ethanol EtOAc fraction showed the strongest inhibitory activity against HT-29 cell proliferation. Induction of G0/G1 cell-cycle arrest on human colon carcinoma cell was observed in CBR EtOAc fraction-treated cells. We found that CBR decreased the level of proteins involved in G0/G1 cell-cycle arrest and apoptosis. CBR EtOAc fraction inhibited the β-catenin signaling pathway, supporting its suppressive activity on the level of cyclin D1 (Park, Lim, & Park, 2013).

A new enynyl-benzenoid, antrocamphin O (1,4,7-dimethoxy-5-methyl-6-(3'-methylbut-3-en-1-ynyl)benzo[d][1,3]dioxide), and the known benzenoids antrocamphin A and 7-dimethoxy-5-methyl-1,3-benzodioxole, were isolated from the fruiting bodies of Antrodia camphorata (Taiwanofungus camphoratus). The benzenoids were tested successfully for cytotoxicity against the HT29, HTC15, DLD-1, and COLO 205 colon cancer cell lines (Chen et al., 2013).

ER+ Ovarian Cancer

MTT and colony formation assays showed that Antrodia camphorata (AC) induced a dose-dependent reduction in SKOV-3 cell growth. Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC. Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector β-catenin (Yang et al., 2013).

References

Chen PY, Wu JD, Tang KY, et al. (2013). Isolation and synthesis of a bioactive benzenoid derivative from the fruiting bodies of Antrodia camphorata. Molecules, 18(7):7600-8. doi: 10.3390/molecules18077600.


Du YC, Chang FR, Wu TY, et al. (2012). Anti-leukemia component, dehydroeburicoic acid from Antrodia camphorata induces DNA damage and apoptosis in vitro and in vivo models. Phytomedicine. doi:10.1016/j.phymed.2012.03.014


Park DK, Lim YH, Park HJ. (2013). Antrodia camphorata Grown on Germinated Brown Rice Inhibits HT-29 Human Colon Carcinoma Proliferation Through Inducing G0/G1 Phase Arrest and Apoptosis by Targeting the β -Catenin Signaling. J Med Food, 16(8):681-91. doi: 10.1089/jmf.2012.2605.


Popovi ć V, Zivkovi ć J, Davidovi ć S, et al. (2013). Mycotherapy Of Cancer: An Update On Cytotoxic And Anti-tumor Activities Of Mushrooms, Bioactive Principles And Molecular Mechanisms Of Their Action. Curr Top Med Chem.


Yang HL, Lin KY, Juan YC, et al. (2013). The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway. J Ethnopharmacol, 148(1):254-65. doi: 10.1016/j.jep.2013.04.023.

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, apoptosis, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, G1, Rectal cancer

Alkanna

Cancer: Colorectal

Action: Anti-cancer effect, apoptosis

In a continuing program to discover new anti-cancer agents from plants, especially naphthoquinones from the Alkanna genus, Alkanna cappadocica was investigated. Bioassay-guided fractionation of a dichloromethane/methanol (1:1) extract of the roots led to the isolation of four new and four known naphthoquinones. The known compounds are 11-deoxyalkannin (1), beta,beta-dimethylacrylalkannin (2), 11-O-acetylalkannin (3), and alkannin (4). The new compounds 5-O-methyl-11-deoxyalkannin (5), 8-O-methyl-11-deoxyalkannin (6), 5-O-methyl-11-O-acetylalkannin (7), and 5-O-methyl-beta,beta-dimethylacrylalkannin (8) were characterized by spectroscopic analyzes (LC-ESIMS, 1D and 2D NMR).

Cytotoxicity of the isolated compounds was evaluated versus 12 human cancer cell lines, HT-29, MDA-MB-231, PC-3, AU565, Hep G2, LNCaP, MCF7, HeLa, SK-BR-3, DU 145, Saos-2, and Hep 3B together with two normal cell lines, VERO and 3T3, by using the MTT assay. Compound 7 showed remarkable cytotoxicity with IC(50) values between 0.09 and 14.07 muM. It was more potent than the other compounds in six out of 12 cancer cell lines and the positive controls doxorubicin and etoposide (Sevimli-Gur et al., 2010).

Colorectal Cancer

The isolation of active compounds against human colorectal cancer from the root of Alkanna tinctoria (L.) Tausch led to the isolation of two naphthoquinones, alkannin (1) and angelylalkannin (2). Both of the two compounds showed significant inhibitory effects on the cancer cells. For alkannin (1) and angelylalkannin (2), the median inhibitory concentration (IC₅₀) values were 2.38 and 4.76  µM for HCT-116 cells, while for SW-480 cells they were 4.53 and 7.03  µM, respectively. The potential anti-proliferative mechanisms were also explored. At concentrations between 1-10  µM, both compounds arrested the cell-cycle at the G1 phase and induced cell apoptosis (Tung et al., 2013a).

To explore active anti-colorectal cancer compounds, we carried out phytochemical studies on Alkanna tinctoria and isolated eight quinone compounds. Using different spectral methods, compounds were identified as alkannin (1), acetylalkannin (2), angelylalkannin (3), 5-methoxyangenylalkannin (4), dimethylacryl alkannin (5), arnebifuranone (6), alkanfuranol (7), and alkandiol (8).

Among the eight compounds, alkannin (1), angelylalkannin (3), and 5-methoxyangenylalkannin (4) showed strong anti-proliferative effects, whereas compound 4 showed the most potent effects.   The structural-functional relationship assay suggested that to increase anti-cancer potential., future modifications on alkannin (1) should focus on the hydroxyl groups at C-5 and C-8 (Tung et al., 2013b).

References

Sevimli-Gur, C, Akgun, IH, Deliloglu-Gurhan, I, Korkmaz, KS, Bedir, E. (2010). Cytotoxic naphthoquinones from Alkanna cappadocica (perpendicular). J Nat Prod, 73(5):860-4. doi: 10.1021/np900778j.


Tung, NH, Du, GJ, Wang, CZ, Yuan, CS, Shoyama, Y. (2013a). Naphthoquinone components from Alkanna tinctoria (L.) Tausch show significant anti-proliferative effects on human colorectal cancer cells. Phytother Res, 27(1):66-70. doi: 10.1002/ptr.4680.


Tung, NH, Du, GJ, Yuan, CS, Shoyama, Y, Wang, CZ. (2013b). Isolation and chemo-preventive evaluation of novel naphthoquinone compounds from Alkanna tinctoria. Anti-cancer Drugs, 24(10):1058-68. doi: 10.1097/CAD.0000000000000017.

Anti-cancer, apoptosis, apoptosis induction, Apoptotic, BAX, Bcl-2, Boswellia carterri Birdw, Boswellia serrata, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, DR5, G1, Gastric cancer or Stomach cancer, HT-29, induces apoptosis, LNCaP, PC-3, p21, p53, PARP, Prostate cancer, SGC-7901, MKN-45

Acetyl-keto-beta-boswellic acid (AKBA)

Cancer: Colorectal, prostate, gastric

Action: Anti-cancer

Apoptotic

Acetyl-keto-beta-boswellic acid (AKBA), a triterpenoid isolated from Boswellia carterri Birdw and Boswellia serrata, has been found to inhibit tumor cell growth and to induce apoptosis. Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation, and independent of Fas/Fas ligand interaction in colon cancer HT-29 cells (Liu et al., 2002).

Colon Cancer

Although there is increasing evidence showing that boswellic acid might be a potential anti-cancer agent, the mechanisms involved in its action are unclear. It has been shown that acetyl-keto-beta-boswellic acid (AKBA) inhibits cellular growth in several colon cancer cell lines. Cell cycle analysis by flow cytometry showed that cells were arrested at the G1 phase after AKBA treatment.

These results demonstrate that AKBA inhibits cellular growth in colon cancer cells. These findings may have implications for the use of boswellic acids as potential anti-cancer agents in colon cancer (Liu et al., 2006).

AKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell-cycle in G1-phase and induction of apoptosis. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity (Yuan et al., 2013).

Gastric Cancer

AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited gastric cancer cells line SGC-7901 and MKN-45 xenografts without toxicity.

This effect might be associated with its roles in cell-cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Upon AKBA treatment, β-catenin expression in nuclei was inhibited, and membrane β-catenin was activated (Zhang et al., 2013).

Prostate

The apoptotic effects and the mechanisms of action of AKBA were studied in LNCaP and PC-3 human prostate cancer cells. AKBA induced apoptosis in both cell lines at concentrations above 10 microg/mL. AKBA-induced apoptosis was correlated with the activation of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase (PARP) cleavage.

AKBA treatment increased the levels of CAAT/enhancer binding protein homologous protein (CHOP) and activated a DR5 promoter reporter but did not activate a DR5 promoter reporter with the mutant CHOP binding site. These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP (Lu et al., 2008).

References

Liu J-J, Nilsson A, Oredsson S, et al. (2002). Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. Carcinogenesis. 23(12): 2087–2093. doi:10.1093/carcin/23.12.2087.

 

 

Liu JJ, Huang B, Hooi SC. (2006). Acetyl-keto-beta-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells. Br J Pharmacol, 148(8):1099-107.

 

Lu M, Xia L, Hua H, Jing Y. (2008). Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells. Cancer Res, 68(4):1180-6. doi: 10.1158/0008-5472.CAN-07-2978.

 

Yuan Y, Cui SX, Wang Y, et al. (2013). Acetyl-11-keto-beta-boswellic acid (AKBA) prevents human colonic adenocarcinoma growth through modulation of multiple signaling pathways. Biochim Biophys Acta, 1830(10):4907-16. doi: 10.1016/j.bbagen.2013.06.039.

 

Zhang YS, Xie JZ, Zhong JL, et al. (2013) Acetyl-11-keto-β-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/β -catenin signaling pathway. Biochim Biophys Acta, 1830(6):3604-15. doi: 10.1016/j.bbagen.2013.03.003.

Akt, Anti-cancer, anti-inflammatory, anti-proliferative, apoptosis, Apoptotic, Bcl-2, Breast cancer, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Colon Cancer or Colorectal cancer, COX-2, G1, induces apoptosis, Induces cell-cycle arrest, inflammation, Lung cancer, MCP-1, Melanoma, Nigella sativa, Osteosarcoma, p21, p53, Pro-apoptotic, Sarcoma, TNF

Thymoquinone

Cancer: Osteosarcoma, pancreatic, colorectal., lung, liver, melanoma, breast

Action: Anti-inflammatory

For centuries, the black seed (Nigella sativa (L.)) herb and oil have been used in Asia, Middle East and Africa to promote health and fight disease. Thymoquinone (TQ) is the major phytochemical constituent of Nigella sativa (L.) oil extract. Phytochemical compounds are emerging as a new generation of anti-cancer agents with limited toxicity in cancer patients.

Osteosarcoma

The anti-proliferative and pro-apoptotic effects of TQ were evaluated in two human osteosarcoma cell lines with different p53 mutation status. TQ decreased cell survival dose-dependently and, more significantly, in p53-null MG63 cells (IC(50) = 17 muM) than in p53-mutant MNNG/HOS cells (IC(50) = 38 muM). Cell viability was reduced more selectively in MG63 tumor cells than in normal human osteoblasts.

It was therefore suggested that the resistance of MNNG/HOS cells to drug-induced apoptosis is caused by the up-regulation of p21(WAF1) by the mutant p53 (transcriptional activity was shown by p53 siRNA treatment) which induces cell-cycle arrest and allows repair of DNA damage.

Collectively, these findings show that TQ induces p53-independent apoptosis in human osteosarcoma cells. As the loss of p53 function is frequently observed in osteosarcoma patients, these data suggest the potential clinical usefulness of TQ for the treatment of these malignancies (Roepke et al., 2007).

Pancreatic Ductal Adenocarcinoma

Inflammation has been identified as a significant factor in the development of solid tumor malignancies. It has recently been shown that thymoquinone (Tq) induces apoptosis and inhibited proliferation in PDA cells. The effect of Tq on the expression of different pro-inflammatory cytokines and chemokines was analyzed by real-time polymerase chain reaction (PCR). Tq dose- and time-dependently significantly reduced PDA cell synthesis of MCP-1, TNF-alpha, interleukin (IL)-1beta and Cox-2. Tq also inhibited the constitutive and TNF-alpha-mediated activation of NF-kappaB in PDA cells and reduced the transport of NF-kappaB from the cytosol to the nucleus. Our data demonstrate previously undescribed anti-inflammatory activities of Tq in PDA cells, which are paralleled by inhibition of NF-kappaB. Tq as a novel inhibitor of pro-inflammatory pathways provides a promising strategy that combines anti-inflammatory and pro-apoptotic modes of action (Chehl et al., 2009).

Lung cancer, Hepatoma, Melanoma, Colon Cancer, Breast Cancer

The potential impact of thymoquinone (TQ) was investigated on the survival., invasion of cancer cells in vitro, and tumor growth in vivo. Exposure of cells derived from lung (LNM35), liver (HepG2), colon (HT29), melanoma (MDA-MB-435), and breast (MDA-MB-231 and MCF-7) tumors to increasing TQ concentrations resulted in a significant inhibition of viability through the inhibition of Akt phosphorylation leading to DNA damage and activation of the mitochondrial-signaling pro-apoptotic pathway. Administration of TQ (10 mg/kg/i.p.) for 18 days inhibited the LNM35 tumor growth by 39% (P < 0.05). Tumor growth inhibition was associated with significant increase in the activated caspase-3. In this context, it has been demonstrated that TQ treatment resulted in a significant inhibition of HDAC2 proteins. In view of the available experimental findings, it is contended that thymoquinone and/or its analogues may have clinical potential as an anti-cancer agent alone or in combination with chemotherapeutic drugs such as cisplatin (Attoub et al., 2012).

Colon Cancer

It was reported that TQ inhibits the growth of colon cancer cells which was correlated with G1 phase arrest of the cell-cycle. Furthermore, TUNEL staining and flow cytometry analysis indicate that TQ triggers apoptosis in a dose- and time-dependent manner. These results indicate that TQ is anti-neoplastic and pro-apoptotic against colon cancer cell line HCT116. The apoptotic effects of TQ are modulated by Bcl-2 protein and are linked to and dependent on p53. Our data support the potential for using the agent TQ for the treatment of colon cancer (Gali-Muhtasib et al., 2004).

References

Attoub S, Sperandio O, Raza H, et al. (2012). Thymoquinone as an anti-cancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam Clin Pharmacol, 27(5):557-569. doi: 10.1111/j.1472-8206.2012.01056.x


Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. (2009). Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford), 11(5):373-81. doi: 10.1111/j.1477-2574.2009.00059.x.


Gali-Muhtasib H, Diab-Assaf M, Boltze C, et al. (2004). Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol, 25(4):857-66


Roepke M, Diestel A, Bajbouj K, et al. (2007). Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol Ther, 6(2):160-9.

A431, Akt, Anti-cancer, anti-inflammatory, anti-proliferative, apoptosis, Apoptotic, Bcl-2, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, COX-2, G1, HCT-116, Hep2, HepG2, HT29, induces apoptosis, Induces cell-cycle arrest, inflammation, inhibits proliferation, Liver cancer, LNM35, MCP-1, MDA-MB-231 and MCF-7, MDA-MB-435, Melanoma, Nigella sativa, Osteosarcoma, p21, p53, Pancreatic cancer, Pro-apoptotic, Saos-2, Sarcoma, TNF

Thymoquinone

Cancer: Osteosarcoma, pancreatic, colorectal., lung, liver, melanoma, breast

Action: Anti-inflammatory

For centuries, the black seed (Nigella sativa (L.)) herb and oil have been used in Asia, Middle East and Africa to promote health and fight disease. Thymoquinone (TQ) is the major phytochemical constituent of Nigella sativa (L.) oil extract. Phytochemical compounds are emerging as a new generation of anti-cancer agents with limited toxicity in cancer patients.

Osteosarcoma

The anti-proliferative and pro-apoptotic effects of TQ were evaluated in two human osteosarcoma cell lines with different p53 mutation status. TQ decreased cell survival dose-dependently and, more significantly, in p53-null MG63 cells (IC(50) = 17 muM) than in p53-mutant MNNG/HOS cells (IC(50) = 38 muM). Cell viability was reduced more selectively in MG63 tumor cells than in normal human osteoblasts.

It was therefore suggested that the resistance of MNNG/HOS cells to drug-induced apoptosis is caused by the up-regulation of p21(WAF1) by the mutant p53 (transcriptional activity was shown by p53 siRNA treatment) which induces cell-cycle arrest and allows repair of DNA damage.

Collectively, these findings show that TQ induces p53-independent apoptosis in human osteosarcoma cells. As the loss of p53 function is frequently observed in osteosarcoma patients, these data suggest the potential clinical usefulness of TQ for the treatment of these malignancies (Roepke et al., 2007).

Pancreatic Ductal Adenocarcinoma

Inflammation has been identified as a significant factor in the development of solid tumor malignancies. It has recently been shown that thymoquinone (Tq) induces apoptosis and inhibited proliferation in PDA cells. The effect of Tq on the expression of different pro-inflammatory cytokines and chemokines was analyzed by real-time polymerase chain reaction (PCR). Tq dose- and time-dependently significantly reduced PDA cell synthesis of MCP-1, TNF-alpha, interleukin (IL)-1beta and Cox-2. Tq also inhibited the constitutive and TNF-alpha-mediated activation of NF-kappaB in PDA cells and reduced the transport of NF-kappaB from the cytosol to the nucleus. Our data demonstrate previously undescribed anti-inflammatory activities of Tq in PDA cells, which are paralleled by inhibition of NF-kappaB. Tq as a novel inhibitor of pro-inflammatory pathways provides a promising strategy that combines anti-inflammatory and pro-apoptotic modes of action (Chehl et al., 2009).

Lung cancer, Hepatoma, Melanoma, Colon Cancer, Breast Cancer

The potential impact of thymoquinone (TQ) was investigated on the survival., invasion of cancer cells in vitro, and tumor growth in vivo. Exposure of cells derived from lung (LNM35), liver (HepG2), colon (HT29), melanoma (MDA-MB-435), and breast (MDA-MB-231 and MCF-7) tumors to increasing TQ concentrations resulted in a significant inhibition of viability through the inhibition of Akt phosphorylation leading to DNA damage and activation of the mitochondrial-signaling pro-apoptotic pathway. Administration of TQ (10 mg/kg/i.p.) for 18 days inhibited the LNM35 tumor growth by 39% (P < 0.05). Tumor growth inhibition was associated with significant increase in the activated caspase-3. In this context, it has been demonstrated that TQ treatment resulted in a significant inhibition of HDAC2 proteins. In view of the available experimental findings, it is contended that thymoquinone and/or its analogues may have clinical potential as an anti-cancer agent alone or in combination with chemotherapeutic drugs such as cisplatin (Attoub et al., 2012).

Colon Cancer

It was reported that TQ inhibits the growth of colon cancer cells which was correlated with G1 phase arrest of the cell-cycle. Furthermore, TUNEL staining and flow cytometry analysis indicate that TQ triggers apoptosis in a dose- and time-dependent manner. These results indicate that TQ is anti-neoplastic and pro-apoptotic against colon cancer cell line HCT116. The apoptotic effects of TQ are modulated by Bcl-2 protein and are linked to and dependent on p53. Our data support the potential for using the agent TQ for the treatment of colon cancer (Gali-Muhtasib et al., 2004).

References

Attoub S, Sperandio O, Raza H, et al. (2012). Thymoquinone as an anti-cancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam Clin Pharmacol, 27(5):557-569. doi: 10.1111/j.1472-8206.2012.01056.x


Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. (2009). Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford), 11(5):373-81. doi: 10.1111/j.1477-2574.2009.00059.x.


Gali-Muhtasib H, Diab-Assaf M, Boltze C, et al. (2004). Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol, 25(4):857-66


Roepke M, Diestel A, Bajbouj K, et al. (2007). Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol Ther, 6(2):160-9.

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.

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.

Anti-cancer, Anti-tumoral, Breast cancer, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Chemotherapy, chemotherapy support, Esophageal cancer, G0/G1, G1, Gastric cancer or Stomach cancer, Glioblastoma, KIP1, Liver cancer, Lung cancer, MAPK, Nasopharyngeal cancer, Nausea and Vomiting, p27, p38, radiotherapy, VEGF, VEGF

β-Elemene

Cancer: Lung, malignant ascites, glioblastoma, gastric

Action: Anti-tumoral., chemotherapy support

Ingredients: Mixed liquid of β-, γ-, δ-elemene.

Indications: Increases the therapeutic effect and lowers the toxic and side-effects of radiotherapy and chemotherapy when in combination with routine regiments of radiotherapy or chemotherapy for lung cancer, liver cancer, esophageal cancer, nasopharyngeal cancer, brain tumors, metastatic bone cancer and other malignancies. It can also be used for intervention, intracavitary chemotherapy and pleural effusion or ascites caused by cancer.

Dosage and usage:

Intravenous injection: 0.4-0.6 g, once daily, 2-3 weeks as a course of treatment.

Pleural injection: 300 ml + 10 ml of 2% procaine. The treatment can be repeated once after 5-7 days if the pleural effusion does not reduce.

Abdominal injection: 500 ml + 10 ml of 2% procaine, 1-2 times every week for 2 consecutive weeks.

Topical administration: 25-50 mg, once daily, 5-10 times as a course of treatment.

Arterial infusion: 300-400 mg once.

Elemene Injection is made from mixed liquid of β-, γ-, δ-elemene. It can increase the therapeutic effect and lower the toxicity and side-effects of radiotherapy and chemotherapy when combined with routine regiments of radiotherapy or chemotherapy for lung cancer, liver cancer, esophageal cancer, nasopharyngeal cancer, brain tumors, metastatic bone cancer and other malignancies. It can also be used for intervention, intraperitoneal chemotherapy, and pleural effusion or ascites caused by cancer (Drug Information Reference in Chinese: See end. 2000-12).

NSCLC; Chemotherapy

Randomized controlled trials (RCTs) of elemene injection combined with cisplatin chemotherapeuties in treating small cell lung cancer (NSCLC) were collected by Xu et al., (2013). Their meta-analysis results suggested that compared with cisplatin chemotherapy alone, the combination of elemene injection and cisplatin chemotherapeutics showed a higher clinical benefit rate (OR = 2. 03, 95% CI:1.43-2. 88, P <0. 000 1) and a better quality of life (OR = 3.23, 95% CI:2. 20-4. 74, P <0. 000 01). As well, the combination could also reduce leucopenia (OR =0. 50, 95% CI:0. 33-0. 76, P <0. 001), and thrombocytopenia (OR =0. 38, 95% CI:0. 16-0. 85, P <0. 02), increase CD4 (MD = 3.32, 95% C1:2. 94-3.70, P <0. 000 01), and CD4/CD8 (MD = 0. 36, 95% CI:0. 28-0. 44, P < 0. 000 01), and relieve gastrointestinal reactions such as nausea and vomiting (OR = 0. 37, 95% CI: 0. 19-0. 71, P = 0. 003).

The analysis indicates that elemene can enhance the chemotherapeutic effect on NSCLC, improve the quality of life, and reduce adverse effect of platinum-contained chemotherapeutics, thereby being worth promoting in clinic.

Lung Cancer

Randomized controlled clinical trials related to the use of β>-elemene injection, as an adjunctive treatment for lung cancer, were retrieved from the Chinese Biomedical (CBMweb), Chinese Medical Current Content (CMCC), China National Knowledge Infrastructure (CNKI), ChinaInfo, Cochrane Central Register of Controlled Trials; MEDLINE, EMBASE, OVID and TCMLARS databases.

A total of 21 source documents (1,467 patients) matched pre-specified criteria for determining the effectiveness and safety of β>-elemene injection as an adjunctive treatment for lung cancer. Five studies involving 285 NSCLC patients reported a higher 24-month survival rate (39.09%) with the adjunctive treatment than with chemotherapy alone (26.17%; RR, 1.51; 95% CI, 1.03 to 2.21). Four studies involving 445 patients reported that the increased probability for improved performance status for patients treated with elemene-based combinations was higher than that of patients treated with chemotherapy alone (RR, 1.82; 95% CI, 1.45 to 2.29).

The results from a subgroup analysis on 12 studies involving 974 NSCLC patients and 9 studies involving 593 patients with both SCLC and NSCLC showed that the tumor control rate for NSCLC improved more in the elemene-based combinations treatment group (78.70%) than in the chemotherapy alone control group (71.31%; RR, 1.06; 95% CI, 1.00 to 1.12). The tumor response rate for NSCLC also improved more among patients treated with elemene based combinations (50.71%) than among patients treated with chemotherapy alone (38.04%; RR, 1.34; 95% CI, 1.17 to 1.54). The effectiveness of chemotherapy for the treatment of lung cancer may improve when combined with β-elemene injection as an adjunctive treatment. The combined treatment can result in an improved quality of life and prolonged survival (Wang et al., 2012).

Malignant Ascites

The effective combination therapy for malignant ascites, the therapeutic value of the combination of Endostar, a modified recombinant human endostatin, and β-elemene, an active component of a traditional Chinese herb, in an H22 mouse malignant ascites model was investigated by Jiang et al. (2012). The results of this study revealed that the combination therapy had significant synergistic effects on the inhibition of ascites formation and a deceased number of tumor cells and protein levels in ascites compared with the results of treatment with a single agent. A decreased peritoneal microvascular permeability and reduction in VEGF, MMP-2 and hypoxia inducible factor 1α(HIF1α) was noted in the combination group, when compared with single agent treatment.

These studies found that in the ascitic tumor cells, the protein levels of VEGF and MMP-2, as well as levels of VEGF mRNA, were significantly inhibited by the combination therapy. The potentiating effects of the combination of Endostar with β-elemene suggest that this novel therapy may yield an effective therapy for the treatment of malignant ascites.

Glioblastoma

Anti-proliferation of glioblastoma cells induced by beta-elemene was dependent on p38 MAPK activation. Treatment of glioblastoma cell lines with beta-elemene, led to phosphorylation of p38 MAPK, cell-cycle arrest in G0/G1 phase and inhibition of proliferation of these cells. Inhibition of p38 MAPK reversed beta-elemene-mediated anti-proliferation effect. Furthermore, the growth of glioblastoma cell-transplanted tumors in nude mice was inhibited by intraperitoneal injection of beta-elemene (Yao et al., 2008).

Breast Cancer; Chemotherapy

Beta-elemene had synergistic effect with Paclitaxel, and its possible mechanism might be correlated with down-regulating the cell-cycle protein cyclin-B1 expression and up-regulating the P27(kip1) expression. Beta-elemene (20 and 40 microg/mL respectively) and Paclitaxel (0.016 and 0.008 microg/mL respectively) synergistically inhibited cell proliferation of MB-468 breast cancer cells, with Q value > 1.15. Beta-elemene alone (52.59 microg/mL) apparently decreased the expression of cyclin-B1 protein. The expression of cyclin-B1 protein in the combined group was also lower than that in the PI group (1.698 microg/mL). The expression of P27(kip1) was up-regulated when compared with that in the betaI group or the PI group (Cai et al., 2013).

Gastric Cancer

TCM therapy applied in the 34 patients assigned in the TCM group (group I) included intravenous injection of Cinobufotalin, beta-elemene, or orally taking of anti-cancer Chinese herbs. The same TCM was also applied in the 36 patients of the combined treatment group (group II), but in combined use of FOLFOX chemotherapeutic protocol.

The median survival period in group II was 31 months, while it was 30 months in group I; the 1-, 2-, 3-year survival rates in group II were 88.89%, 84.38% and 59.26%, and those in the group I were 82.35%, 71.43% and 65.00%, respectively with insignificant difference between the two groups (chi2 = 0.298, P > 0.05); QOF in group I was significantly superior to that in group II (P < 0.05), and the adverse reaction occurrence was significantly less in group I than that in group II.

Chinese medicine treatment can improve the QOF and prolong the survival period of patients with progressive gastric cancer with few side-effects (Liu et al., 2008).

References

Jiang, Z.Y., Qin, S.K., Yin, X.J., Chen, Y.L., Zhu, L. (2012). Synergistic effects of Endostar combined with β-elemene on malignant ascites in a mouse model. Exp Ther Med, 4(2):277-284.

Liu X, Hua BJ. (2008). Effect of traditional Chinese medicine on quality of life and survival period in patients with progressive gastric cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi, 28(2):105-7.

Wang, B., Peng, X.X., Sun, R., Li, J., Zhan, X.R., Wu, L.J., Wang, S.L., & Xie, T. (2012). Systematic review of β-elemene injection as adjunctive treatment for lung cancer. Chinese Journal of Integrative Medicine, 18(11), 8313-823.

Xu, X.W., Yuan, Z.Z., Hu, W.H., Wang, X.K. (2013). Meta-analysis on elemene injection combined with cisplatin chemotherapeutics in treatment of non-small-cell lung cancer. Zhongguo Zhong Yao Za Zhi, 38(9):1430-7.

Yao, Y.Q., Ding, X., Jia, Y.C, et al. (2008). Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. Cancer Lett, 264(1):127-34. doi: 10.1016/j.canlet.2008.01.049.