Category Archives: p38

angiogenesis, Anti-angiogenic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Chapter 7 Isolates and Cancer Research, chemo-prevention, COX-2, COX-2 inhibitor, cytotoxic, Head and neck cancer, HIF, induces apoptosis, MAPK, MDR, metastasis, MMP9, Multi-Drug Resistance, Multi-drug resistance, Oral cancer, p38, p53, Pro-apoptotic, reduction of cardiotoxicity, ROS, Squamous cell carcinoma, TNF

Salvianolic acid-B / Salvinal

Cancer:
Head and neck squamous cell carcinoma, oral squamous cell carcinoma, glioma

Action: MDR, reduction of cardiotoxicity, COX-2 inhibitor, inflammatory-associated tumor development, anti-cancer

Salvia miltiorrhiza contains a variety of anti-tumor active ingredients, such as the water-soluble components, salvianolic acid A, salvianolic acid B, salvinal, and liposoluble constituents, tanshinone I, tanshinone IIA, dihydrotanshinone I, miltirone, cryptotanshinone, ailantholide, neo-tanshinlactone, and nitrogen-containing compounds. These anti-tumor active components play important roles in the different stages of tumor evolution, progression and metastasis (Zhang & Lu, 2010).

Anti-cancer/MDR

Aqueous extracts of Salvia miltiorrhizae Bunge have been extensively used in the treatment of cardiovascular disorders and cancer in Asia. Recently, a compound, 5-(3-hydroxypropyl)-7-methoxy-2-(3'-methoxy-4'-hydroxyphenyl)-3-benzo[b]furancarbaldehyde (salvinal), isolated from this plant showed inhibitory activity against tumor cell growth and induced apoptosis in human cancer cells. In the present study, we investigated the cytotoxic effect and mechanisms of action of salvinal in human cancer cell lines. Salvinal caused inhibition of cell growth (IC50 range, 4-17 microM) in a variety of human cancer cell lines.

In particular, salvinal exhibited similar inhibitory activity against parental KB, P-glycoprotein-overexpressing KB vin10 and KB taxol-50 cells, and multi-drug resistance-associated protein (MRP)-expressing etoposide-resistant KB 7D cells.

Taken together, our data demonstrate that salvinal inhibits tubulin polymerization, arrests cell-cycle at mitosis, and induces apoptosis. Notably, Salvinal is a poor substrate for transport by P-glycoprotein and MRP. Salvinal may be useful in the treatment of human cancers, particularly in patients with drug resistance (Chang et al., 2004).

Glioma

Salvianolic acid B (SalB) has been shown to exert anti-cancer effect in several cancer cell lines. SalB increased the phosphorylation of p38 MAPK and p53 in a dose-dependent manner. Moreover, blocking p38 activation by specific inhibitor SB203580 or p38 specific siRNA partly reversed the anti-proliferative and pro-apoptotic effects, and ROS production induced by SalB treatment.

These findings extended the anti-cancer effect of SalB in human glioma cell lines, and suggested that these inhibitory effects of SalB on U87 glioma cell growth might be associated with p38 activation mediated ROS generation. Thus, SalB might be concerned as an effective and safe natural anti-cancer agent for glioma prevention and treatment (Wang et al., 2013).

Reduced Cardiotoxicity

Clinical attempts to reduce the cardiotoxicity of arsenic trioxide (ATO) without compromising its anti-cancer activities remain an unresolved issue. In this study, Wang et al., (2013b) determined that Sal B can protect against ATO-induced cardiac toxicity in vivo and increase the toxicity of ATO toward cancer cells.

The combination treatment significantly enhanced the ATO-induced cytotoxicity and apoptosis of HepG2 cells and HeLa cells. Increases in apoptotic marker cleaved poly (ADP-ribose) polymerase and decreases in procaspase-3 expressions were observed through Western blot. Taken together, these observations indicate that the combination treatment of Sal B and ATO is potentially applicable for treating cancer with reduced cardiotoxic side effects.

Oral Cancer

Sal B has inhibitory effect on oral squamous cell carcinoma (OSCC) cell growth. The anti-tumor effect can be attributed to anti-angiogenic potential induced by a decreased expression of some key regulator genes of angiogenesis. Sal B may be a promising modality for treating oral squamous cell carcinoma.

Sal B induced growth inhibition in OSCC cell lines but had limited effects on premalignant cells. A total of 17 genes showed a greater than 3-fold change when comparing Sal B treated OSCC cells to the control. Among these genes, HIF-1α, TNFα and MMP9 are specifically inhibited; expression of THBS2 was up-regulated (Yang et al., 2011).

Head and Neck Cancer

Overexpression of cyclooxygenase-2 (COX-2) in oral mucosa has been associated with increased risk of head and neck squamous cell carcinoma (HNSCC). Celecoxib is a non-steroidal anti-inflammatory drug, which inhibits COX-2 but not COX-1. This selective COX-2 inhibitor holds promise as a cancer-preventive agent. Concerns about the cardiotoxicity of celecoxib limit its use in long-term chemo-prevention and therapy. Salvianolic acid B (Sal-B) is a leading bioactive component of Salvia miltiorrhiza Bge, which is used for treating neoplastic and chronic inflammatory diseases in China.

Tumor volumes in Sal-B treated group were significantly lower than those in celecoxib treated or untreated control groups (p < 0.05). Sal-B inhibited COX-2 expression in cultured HNSCC cells and in HNSCC cells isolated from tumor xenografts. Sal-B also caused dose-dependent inhibition of prostaglandin E(2) synthesis, either with or without lipopolysaccharide stimulation. Taking these results together, Sal-B shows promise as a COX-2 targeted anti-cancer agent for HNSCC prevention and treatment (Hao et al., 2009).

Inflammatory-associated tumor development

A half-dose of daily Sal-B (40 mg/kg/d) and celecoxib (2.5 mg/kg/d) significantly inhibited JHU-013 xenograft growth relative to mice treated with a full dose of Sal-B or celecoxib alone. The combination was associated with profound inhibition of COX-2 and enhanced induction of apoptosis. Taken together, these results strongly suggest that a combination of Sal-B, a multifunctional anti-cancer agent, with low-dose celecoxib holds potential as a new preventive strategy in targeting inflammatory-associated tumor development (Zhao et al., 2010).

Squamous Cell Carcinoma

The results showed that Sal B significantly decreased the squamous cell carcinoma (SCC) incidence from 64.7 (11/17) to 16.7% (3/18) (P=0.004); angiogenesis was inhibited in dysplasia and SCC (P<0.01), with a simultaneous decrease in the immunostaining of hypoxia-inducible factor 1alpha and vascular endothelium growth factor protein (P<0.05). The results suggested that Sal B had inhibitory effect against the malignant transformation of oral precancerous lesion and such inhibition may be related to the inhibition of angiogenesis (Zhou, Yang, & Ge, 2006).

References

Chang JY, Chang CY, Kuo CC, et al. (2004). Salvinal, a novel microtubule inhibitor isolated from Salvia miltiorrhizae Bunge (Danshen), with antimitotic activity in Multi-drug-sensitive and -resistant human tumor cells. Mol Pharmacol, 65(1):77-84.


Hao Y, Xie T, Korotcov A, et al. (2009). Salvianolic acid B inhibits growth of head and neck squamous cell carcinoma in vitro and in vivo via cyclooxygenase-2 and apoptotic pathways. Int J Cancer, 124(9):2200-9. doi: 10.1002/ijc.24160.


Wang ZS, Luo P, Dai SH, et al., (2013a). Salvianolic acid B induces apoptosis in human glioma U87 cells through p38-mediated ROS generation. Cell Mol Neurobiol, 33(7):921-8. doi: 10.1007/s10571-013-9958-z.


Wang M, Sun G, Wu P, et al. (2013b). Salvianolic Acid B prevents arsenic trioxide-induced cardiotoxicity in vivo and enhances its anti-cancer activity in vitro. Evid Based Complement Alternat Med, 2013:759483. doi: 10.1155/2013/759483.


Yang Y, Ge PJ, Jiang L, Li FL, Zhum QY. (2011). Modulation of growth and angiogenic potential of oral squamous carcinoma cells in vitro using salvianolic acid B. BMC Complement Altern Med, 11:54. doi: 10.1186/1472-6882-11-54.


Zhang W, Lu Y. (2010). Advances in studies on anti-tumor activities of compounds in Salvia miltiorrhiza. Zhongguo Zhong Yao Za Zhi, 35(3):389-92.


Zhao Y, Hao Y, Ji H, Fang Y, et al. (2010). Combination effects of salvianolic acid B with low-dose celecoxib on inhibition of head and neck squamous cell carcinoma growth in vitro and in vivo. Cancer Prev Res (Phila), 3(6):787-96. doi: 10.1158/1940-6207.CAPR-09-0243.


Zhou ZT, Yang Y, Ge JP. (2006). The preventive effect of salvianolic acid B on malignant transformation of DMBA-induced oral premalignant lesion in hamsters. Carcinogenesis, 27(4):826-32.

Akt, AMPK, angiogenesis, Anti-angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, anti-metastasis, Anti-metastatic, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, enhanced paclitaxel absorption, Glioblastoma, HO-1, HT-29, Lymphoma, MAPK, MDR, metastasis, P-gp, p21, p38, p53, PARP, Pro-apoptotic, Prostate cancer, ROS, S, VEGF, VEGF

RG3 (See also Ginsenosides)

Cancer: Glioblastoma, prostate, breast, colon

Action: Anti-angiogenesis, MDR, enhances chemotherapy, MDR, enhanced paclitaxel absorption, anti-metastatic

RG3 is a ginsenoside isolated from red ginseng (Panax ginseng (L.)), after being peeled, heated, and dried.

Angiosuppressive Activity

Aberrant angiogenesis is an essential step for the progression of solid tumors. Thus anti-angiogenic therapy is one of the most promising approaches to control tumor growth.

Rg3 was found to inhibit the proliferation of human umbilical vein endothelial cells (HUVEC) with an IC50 of 10 nM in Trypan blue exclusion assay.

Rg3 (1-10(3) nM) also dose-dependently suppressed the capillary tube formation of HUVEC on the Matrigel in the presence or absence of 20 ng/ml vascular endothelial growth factor (VEGF). The Matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, which play an important role in the degradation of basement membrane in angiogenesis and tumor metastasis present in the culture supernatant of Rg3-treated aortic ring culture were found to decrease in their gelatinolytic activities. Taken together, these data underpin the anti-tumor properties of Rg3 through its angiosuppressive activity (Yue et al., 2006).

Glioblastoma

Rg3 has been reported to exert anti-cancer activities through inhibition of angiogenesis and cell proliferation. The mechanisms of apoptosis by ginsenoside Rg3 were related with the MEK signaling pathway and reactive oxygen species. Our data suggest that ginsenoside Rg3 is a novel agent for the chemotherapy of glioblastoma multiforme (GBM) (Choi et al., 2013).

Sin, Kim, & Kim (2012) report that chronic treatment with Rg3 in a sub-lethal concentration induced senescence-like growth arrest in human glioma cells. Rg3-induced senescence was partially rescued when the p53/p21 pathway was inactivated. Data indicate that Rg3 induces senescence-like growth arrest in human glioma cancer through the Akt and p53/p21-dependent signaling pathways.

MDR/Enhanced Paclitaxel Absorption

The penetration of paclitaxel through the Caco-2 monolayer from the apical side to the basal side was facilitated by 20(s)-ginsenoside Rg3 in a concentration-dependent manner. Rg3 also inhibited P-glycoprotein (P-gp), and the maximum inhibition was achieved at 80 µM (p < 0.05). The relative bioavailability (RB)% of paclitaxel with 20(s)-ginsenoside Rg3 was 3.4-fold (10 mg/kg) higher than that of the control. Paclitaxel (20 mg/kg) co-administered with 20(s)-ginsenoside Rg3 (10 mg/kg) exhibited an effective anti-tumor activity with the relative tumor growth rate (T/C) values of 39.36% (p <0.05).

The results showed that 20(s)-ginsenoside Rg3 enhanced the oral bioavailability of paclitaxel in rats and improved the anti-tumor activity in nude mice, indicating that oral co-administration of paclitaxel with 20(s)-ginsenoside Rg3 could provide an effective strategy in addition to the established i.v. route (Yang et al., 2012).

Prostate Cancer

The anti-proliferation effect of Rg3 on prostate cancer cells has been well reported. Rg3 treatment triggered the activation of p38 MAPK; and SB202190, a specific inhibitor of p38 MAPK, antagonized the Rg3-induced regulation of AQP1 and cell migration, suggesting a crucial role for p38 in the regulation process. Rg3 effectively suppresses migration of PC-3M cells by down-regulating AQP1 expression through p38 MAPK pathway and some transcription factors acting on the AQP1 promoter (Pan et al., 2012).

Enhances Chemotherapy

The clinical use of cisplatin (cis-diamminedichloroplatinum II) has been limited by the frequent emergence of cisplatin-resistant cell populations and numerous other adverse effects. Therefore, new agents are required to improve the therapy and health of cancer patients. Oral administration of ginsenoside Rg3 significantly inhibited tumor growth and promoted the anti-neoplastic efficacy of cisplatin in mice inoculated with CT-26 colon cancer cells. In addition, Rg3 administration remarkably inhibited cisplatin-induced nephrotoxicity, hepatotoxicity and oxidative stress.

Rg3 promotes the efficacy of cisplatin by inhibiting HO-1 and NQO-1 expression in cancer cells and protects the kidney and liver against tissue damage by preventing cisplatin-induced intracellular ROS generation (Lee et al., 2012).

Colon Cancer

Rg3-induced apoptosis in HT-29 cells is mediated via the AMPK signaling pathway, and that 20(S)-Rg3 is capable of inducing apoptosis in colon cancer. Rg3-treated cells displayed several apoptotic features, including DNA fragmentation, proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) and morphological changes. 20(S)-Rg3 down-regulated the expression of anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl2), up-regulated the expression of pro-apoptotic protein of p53 and Bcl-2-associated X protein (Bax), and caused the release of mitochondrial cytochrome c, PARP, caspase-9 and caspase-3 (Yuan et al., 2010).

Anti-metastatic

Studies have linked Rg3 with anti-metastasis of cancer in vivo and in vitro and the CXC receptor 4 (CXCR4) is a vital molecule in migration and homing of cancer to the docking regions. At a dosage without obvious cytotoxicity, Rg3 treatment elicits a weak CXCR4 stain color, decreases the number of migrated cells in CXCL12-elicited chemotaxis and reduces the width of the scar in wound healing and Rg3 is a new CXCR4 inhibitor (Chen et al., 2011).

References

Chen XP, Qian LL, Jiang H, Chen JH. (2011). Ginsenoside Rg3 inhibits CXCR4 expression and related migrations in a breast cancer cell line. Int J Clin Oncol, 16(5):519-23. doi: 10.1007/s10147-011-0222-6.


Choi YJ, Lee HJ, Kang DW, et al. (2013). Ginsenoside Rg3 induces apoptosis in the U87MG human glioblastoma cell line through the MEK signaling pathway and reactive oxygen species. Oncol Rep. doi: 10.3892/or.2013.2555.


Lee CK, Park KK, Chung AS, Chung WY. (2012). Ginsenoside Rg3 enhances the chemosensitivity of tumors to cisplatin by reducing the basal level of nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1/NAD(P)H quinone oxidoreductase-1 and prevents normal tissue damage by scavenging cisplatin-induced intracellular reactive oxygen species. Food Chem Toxicol, 50(7):2565-74. doi: 10.1016/j.fct.2012.01.005.


Pan XY, Guo H, Han J, et al. (2012). Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells. Eur J Pharmacol, 683(1-3):27-34. doi: 10.1016/j.ejphar.2012.02.040.


Sin S, Kim SY, Kim SS. (2012). Chronic treatment with ginsenoside Rg3 induces Akt-dependent senescence in human glioma cells. Int J Oncol., 41(5):1669-74. doi: 10.3892/ijo.2012.1604.


Yang LQ, Wang B, Gan H, et al. (2012). Enhanced oral bioavailability and anti-tumor effect of paclitaxel by 20(s)-ginsenoside Rg3 in vivo. Biopharm Drug Dispos., 33(8):425-36. doi: 10.1002/bdd.1806.


Yuan HD, Quan HY, Zhang Y, et al. (2010). 20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway. Mol Med Rep., 3(5):825-31. doi: 10.3892/mmr.2010.328.


Yue PY, Wong DY, Wu PK, et al. (2006). The angiosuppressive effects of 20 (R)-ginsenoside Rg3. Biochem Pharmacol, 72(4):437-45.

Akt, Cervical cancer, Chapter 7 Isolates and Cancer Research, Down-regulates, EGFR, epidermal growth factor receptor, ERK1, HPV-associated, JNK, MAPK, p38

Retinoids

Cancer: none noted

Action: Down-regulates,epidermal growth factor receptor

Human papillomavirus (HPV) is an important etiological agent in the genesis of cervical cancer. HPV-positive cervical tumors and human papillomavirus-positive cell lines display increased epidermal growth factor receptor (EGFR) expression, which is associated with increased cell proliferation. ECE16-1 cells are an HPV-immortalized human ectocervical epithelial cell line that is a model of HPV-associated cervical neoplasia and displays elevated EGFR levels.

The effects of receptor-selective retinoid ligands on EGFR-associated signal transduction were examined. It has been shown that retinoic acid receptor (RAR)-selective ligands reduce EGFR level and the magnitude and duration of EGFR activation in EGF-stimulated cells.

These effects are reversed by co-treatment with an RAR antagonist. To identify the mechanism, Sah et al. (2002) examined the effects of retinoid treatments on EGF-dependent signaling. Stimulation with EGF causes a biphasic activation of the ERK1/2 MAPK.

This effect is specific as retinoid treatment does not alter the level or activity of other EGFR-regulated kinases, including AKT and the MAPKs p38 and JNK. Retinoid X receptor-selective ligands, in contrast, did not regulate these responses. These results suggest that RAR ligand-associated down-regulation of EGFR activity reduces cell proliferation by reducing the magnitude and duration of EGF-dependent ERK1/2 activation.

All-trans retinoic acid (RA), through binding to the retinoic acid receptors (RARs), alters interactions of the RARs with various protein components of the transcription complex at numerous genes in stem cells, and some of these protein components of the transcription complex then either place or remove epigenetic marks on histones or on DNA, altering chromatin structure and leading to an exit from the self-renewing, pluripotent stem cell state.

Different epigenetic mechanisms, i.e. first, primarily H3K27me3 marks and then DNA methylation, may be employed by embryonic stem cells and other stem cells for control of early vs. late stages of cell differentiation. Creating these stable epigenetic changes requires the actions of many molecules, including tet1, polycomb protein complexes (PRCs), miRNAs, DNA methyltransferases (DNMTs), and telomerase reverse transcriptase (Gudas, 2013).

References

Gudas LJ. (2013). Retinoids induce stem cell differentiation via epigenetic changes. Semin Cell Dev Biol, S1084-9521(13)00102-X. doi: 10.1016/j.semcdb.2013.08.002.


Sah JF, Eckert RL, Chandraratna RA, Rorke EA. (2002). Retinoids suppress epidermal growth factor-associated cell proliferation by inhibiting epidermal growth factor receptor-dependent ERK1/2 activation. J Biol Chem, 277(12):9728-35.

ameliorated myelosuppression, anti-apoptotic, apoptosis, Apoptotic, BAX, Bcl-2, Bcl-xL, c-Jun, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemotherapy, Colon Cancer or Colorectal cancer, EP2, EP4, ERK, Gastric cancer or Stomach cancer, HepG2, SMMC-7721, HT29, JNK, Liver cancer, MDR, Multi-Drug Resistance, Multi-drug resistance, p38, Paeonia suffruticosa, PCNA, PGE2, Radio-protective, radio-protective effect, Rectal cancer, ROS, SGC7901/VCR

Paeoniflorin

Cancer: Hepatocellular carcinoma, colorectal, liver

Action: Radio-protective, ameliorated myelosuppression, MDR

Radio-protective

The radio-protective effect of paeoniflorin (PF), a main bioactive component in the traditional Chinese herb peony, on irradiated thymocytes and the possible mechanisms of protection have been investigated. Ionizing radiation can induce DNA damage and cell death by generating reactive oxygen species (ROS).

It was found 60Co γ-ray irradiation increased cell death and DNA fragmentation in a dose-dependent manner while increasing intracellular ROS. Pre-treatment of thymocytes with PF (50–200 µg/ml) reversed this tendency and attenuated irradiation-induced ROS generation. Hydroxyl-scavenging action of PF in vitro was detected through electron spin resonance assay. Several anti-apoptotic characteristics of PF, including the ability to diminish cytosolic Ca2+ concentration, inhibit caspase-3 activation, and up-regulate Bcl-2 and down-regulate Bax in 4 Gy-irradiated thymocytes, were determined.

Extracellular regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 kinase, were activated by 4 Gy irradiation, with their activation partly blocked by pre-treatment of cells with PF. The presence of ERK inhibitor PD98059, JNK inhibitor SP600125 and p38 inhibitor SB203580 decreased cell death in 4 Gy-irradiated thymocytes. These results suggest PF protects thymocytes against irradiation-induced cell damage by scavenging ROS and attenuating the activation of the mitogen-activated protein kinases (Li et al., 2007).

Liver Cancer

Prostaglandin E2 (PGE2) has been shown to play an important role in tumor development and progression. PGE2 mediates its biological activity by binding any one of four prostanoid receptors (EP1 through EP4). Paeoniflorin, a monoterpene glycoside, significantly inhibited the proliferation of HepG2 and SMMC-7721 cells stimulated by butaprost at multiple time points (24, 48, and 72 hours). Paeoniflorin induced apoptosis in HepG2 and SMMC-7721 cells, which was quantified by annexin-V and propidium iodide staining. Our results indicate that the expression of the EP2 receptor and Bcl-2 was significantly increased, whereas that of Bax and cleaved caspase-3 was decreased in HepG2 and SMMC-7721 cells.

Paeoniflorin, which may be a promising agent in the treatment of liver cancer, induced apoptosis in hepatocellular carcinoma cells by down-regulating EP2 expression and also increased the Bax-to-Bcl-2 ratio, thus up-regulating the activation of caspase-3 (Hu et al., 2013).

Colorectal Cancer

Results showed that positive cells of Proliferating Cell Nuclear Antigen (PCNA) in paeoniflorin (PF) and docetaxel-treated group was decreased to 30% and 15% respectively, compared with control group of tumors. But apoptosis cells in docetaxel treated groups studied by TUNEL is increased to 40 ± 1.2% and 30 ± 1.5% respectively, compared with 24 ± 2.3% in negative control. Furthermore, the efficiency of tumor-bearing mice treated by PF was superior to docetaxel in vivo. Overall, PF may be an effective chemo-preventive agent against colorectal cancer HT29 (Wang et al., 2012).

Ameliorates Myelosuppression

The administration of paeoniflorin and albiflorin (CPA) extracted from Paeonia radix, significantly ameliorated myelosuppression in all cases. For the X-ray irradiated mice and the chemotherapy treated mice and rabbits, high dosages of CPA resulted in the recovery of, respectively, 94.4%, 95.3% and 97.7% of hemoglobin content; 67.7%, 92.0% and 94.3% of platelet numbers; 26.8%, 137.1% and 107.3% of white blood cell counts; as well as a reversal in the reduction of peripheral differential white blood cell counts.

There was also a recovery of 50.9%, 146.1% and 92.3%, respectively, in the animals' relative spleen weight. Additionally, a recovery of 35.7% and 87.2% respectively in the number of bone marrow nucleated cells was observed in the radio- and chemo -therapy-treated mice. Bone marrow white blood cell counts also resumed to normal levels (Xu et al., 2011).

MDR

Studies have shown that NF-κB activation may play an essential role in the development of chemotherapy resistance in carcinoma cells. Paeonißorin, a principal bioactive component of the root of Paeonia lactißora, has been reported to exhibit various pharmacological effects. In the present study, Fanh et al. (2012) reported for the first time that paeoniflorin at non-toxic concentrations may effectively modulate multi-drug resistance (MDR) of the human gastric cancer cell line SGC7901/vincristine (VCR) via the inhibition of NF-κB activation and, at least partly, by subsequently down-regulating its target genes MDR1, BCL-XL and BCL-2.

References

Fang S, Zhu W, Zhang Y, Shu Y, Liu P. (2012). Paeoniflorin modulates Multi-drug resistance of a human gastric cancer cell line via the inhibition of NF- κB activation. Mol Med Rep, 5(2):351-6. doi: 10.3892/mmr.2011.652.


Hu S, Sun W, Wei W, et al. (2013). Involvement of the prostaglandin E receptor EP2 in paeoniflorin-induced human hepatoma cell apoptosis. Anti-cancer Drugs, 24(2):140-9. doi: 10.1097/CAD.0b013e32835a4dac.


Li CR, Zhou Z, Zhu D, et al. (2007). Protective effect of paeoniflorin on irradiation-induced cell damage involved in modulation of reactive oxygen species and the mitogen-activated protein kinases. The International Journal of Biochemistry & Cell Biology, 39(2):426–438


Wang H, Zhou H, Wang CX, et al. (2012). Paeoniflorin inhibits growth of human colorectal carcinoma HT 29 cells in vitro and in vivo. Food Chem Toxicol, 50(5):1560-7. doi: 10.1016/j.fct.2012.01.035.


Xu W, Zhou L, Ma X, et al. (2011). Therapeutic effects of combination of paeoniflorin and albiflorin from Paeonia radix on radiation and chemotherapy-induced myelosuppression in mice and rabbits. Asian Pac J Cancer Prev, 12(8):2031-7.

Anti-angiogenic, anti-tumor, anti-tumor activity, apoptosis, BAX, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, Cytostatic, ER, G0/G1, G1, growth-inhibitory, Melanoma, Osteosarcoma, p21, p38, PARP, Sarcoma

Nelumbo Extract (NLE):Neferine

Cancer: Liver, osteosarcoma, breast, melanoma

Action: Anti-angiogenic, cytostatic

Neferine is a major bis-benzylisoquinoline alkaloid derived from the green seed embryos of the Indian lotus (Nelumbo nucifera (Gaertn.)).

Identification of natural products that have anti-tumor activity is invaluable to the chemo-prevention and therapy of cancer. The embryos of lotus (Nelumbo nucifera) seeds are consumed in beverage in some parts of the world for their presumed health-benefiting effects. Neferine is a major alkaloid component in lotus embryos.

Hepatitis

Experimental results suggest that neferine exhibited cytotoxicity against HCC Hep3B cells, but not against HCC Sk-Hep1 and THLE-3, a normal human liver cell line. Results demonstrated neferine induced ER stress and apoptosis, acting through multiple signaling cascades by the activation of Bim, Bid, Bax, Bak, Puma, caspases-3, -6, -7, -8 and PARP, and the protein expression levels of Bip, calnexin, PDI, calpain-2 and caspase-12 were also upregulated dramatically by neferine treatment.

These observations reveal that the therapeutic potential of neferine in treating HCC Hep3B cells, containing copies of hepatitis B virus (HBV) genomes (Yoon et al., 2013).

Osteosarcoma

It was found that neferine possessed a potent growth-inhibitory effect on human osteosarcoma cells, but not on non-neoplastic human osteoblast cells. The inhibitory effect of neferine on human osteosarcoma cells was largely attributed to cell-cycle arrest at G1. The up-regulation of p21 by neferine was due to an increase in the half-life of p21 protein. Zhang et al. (2012) showed that neferine treatment led to an increased phosphorylation of p21 at Ser130 that was dependent on p38. Their results for the first time showed a direct anti-tumor effect of neferine, suggesting that consumption of neferine may have cancer-preventive and cancer-therapeutic benefit.

Breast Cancer

Qualitative analysis showed that NLE contained several compounds, including polyphenols. The polyphenols identified in NLE consisted primarily of gallic acid, rutin, and quercetin. Cell cycle analysis revealed that breast cancer MCF-7 cells treated with NLE were arrested at the G0/G1 phase. In an in vivo analysis, treatment with NLE (0.5 and 1%) effectively reduced tumor volume and tumor weight in mice inoculated with MCF-7 cells compared to the control samples.

These results confirmed that cell-cycle arrest was sufficient to elicit tumor regression following NLE treatment (Yang et al., 2011).

Melanoma

Methanolic extracts from the flower buds and leaves of sacred lotus (Nelumbo nucifera) were found to show inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. 3-30 µM nuciferine and N-methylasimilobine inhibited the expression of tyrosinase mRNA, 3-30 µM N-methylasimilobine inhibited the expression of TRP-1 mRNA, and 10-30 µM nuciferine inhibited the expression of TRP-2 mRNA (Nakamura et al., 2013).

References

Nakamura S, Nakashima S, Tanabe G, et al. (2013). Alkaloid constituents from flower buds and leaves of sacred lotus (Nelumbo nucifera, Nymphaeaceae) with melanogenesis inhibitory activity in B16 melanoma cells. Bioorg Med Chem, 21(3):779-87. doi: 10.1016/j.bmc.2012.11.038.


Yang MY, Chang YC, Chan KC et al. (2011). Flavonoid-enriched extracts from Nelumbo nucifera leaves inhibits proliferation of breast cancer in vitro and in vivo. European Journal of Integrative Medicine, 3(3):153-163. doi:10.1016/j.eujim.2011.08.008


Yoon JS, Kim HM, Yadunandam AK, et al. (2013). Neferine isolated from Nelumbo nucifera enhances anti-cancer activities in Hep3B cells: Molecular mechanisms of cell-cycle arrest, ER stress induced apoptosis and anti-angiogenic response. Phytomedicine, 20(11):1013–1022. doi:10.1016/j.phymed.2013.03.024.


Zhang XY, Liu ZJ, Xu B, et al. (2012). Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization. European Journal of Pharmacology, 677(1–3):47–54.

Akt, Akt/mTOR/P70S6K, AMPK, angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, apoptosis, Apoptotic, BAX, Bladder cancer, CD31, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, ERK, ERK1, FAK, G0/G1, G1, Glioblastoma, HCT-116, HER-2, HIF, IL-6, induces apoptosis, inhibits angiogenesis, JAK1, JAK2, Lung cancer, Magnolia officinalis, metastasis, MMP2, MTOR, Ovarian cancer, p21, p21/Cip1, p38, p53, P70S6K, PC3, PI3K, PI3K/Akt, PI3K/Akt/MTOR, Pro-apoptotic, Prostate cancer, STAT3, VEGF, VEGF

Magnolol

Cancer:
Bladder, breast, colon, prostate, glioblastoma, ovarian, leukemia, lung

Action: Anti-inflammatory, apoptosis, inhibits angiogenesis, anti-metastatic

Magnolol (Mag), an active constituent isolated from the Chinese herb hou po (Magnolia officinalis (Rehder & Wilson)) has long been used to suppress inflammatory processes. It has anti-cancer activity in colon, hepatoma, and leukemia cell lines.

Anti-inflammatory

Magnolol (Mag) suppressed IL-6-induced promoter activity of cyclin D1 and monocyte chemotactic protein (MCP)-1 for which STAT3 activation plays a role. Pre-treatment of ECs with Mag dose-dependently inhibited IL-6-induced Tyr705 and Ser727 phosphorylation in STAT3 without affecting the phosphorylation of JAK1, JAK2, and ERK1/2. Mag pre-treatment of these ECs dose-dependently suppressed IL-6-induced promoter activity of intracellular cell adhesion molecule (ICAM)-1 that contains functional IL-6 response elements (IREs).

In conclusion, our results indicate that Mag inhibits IL-6-induced STAT3 activation and subsequently results in the suppression of downstream target gene expression in ECs. These results provide a therapeutic basis for the development of Mag as an anti-inflammatory agent for vascular disorders including atherosclerosis (Chen et al., 2006).

Bladder Cancer; Inhibits Angiogenesis

In the present study, Chen et al. (2013) demonstrated that magnolol significantly inhibited angiogenesis in vitro and in vivo, evidenced by the attenuation of hypoxia and vascular endothelial growth factor (VEGF)-induced tube formation of human umbilical vascular endothelial cells, vasculature generation in chicken chorioallantoic membrane, and Matrigel plug.

In hypoxic human bladder cancer cells (T24), treatment with magnolol inhibited hypoxia-stimulated H2O2 formation, HIF-1α induction including mRNA, protein expression, and transcriptional activity as well as VEGF secretion. Interestingly, magnolol also acts as a VEGFR2 antagonist, and subsequently attenuates the downstream AKT/mTOR/p70S6K/4E-BP-1 kinase activation both in hypoxic T24 cells and tumor tissues. As expected, administration of magnolol greatly attenuated tumor growth, angiogenesis and the protein expression of HIF-1α, VEGF, CD31, a marker of endothelial cells, and carbonic anhydrase IX, an endogenous marker for hypoxia, in the T24 xenograft mouse model.

Collectively, these findings strongly indicate that the anti-angiogenic activity of magnolol is, at least in part, mediated by suppressing HIF-1α/VEGF-dependent pathways, and suggest that magnolol may be a potential drug for human bladder cancer therapy.

Colon Cancer; Induces Apoptosis

Emerging evidence has suggested that activation of AMP-activated protein kinase (AMPK), a potential cancer therapeutic target, is involved in apoptosis in colon cancer cells. However, the effects of magnolol on human colon cancer through activation of AMPK remain unexplored.

Magnolol displayed several apoptotic features, including propidium iodide labeling, DNA fragmentation, and caspase-3 and poly(ADP-ribose) polymerase cleavages. Park et al. (2012) showed that magnolol induced the phosphorylation of AMPK in dose- and time-dependent manners.

Magnolol down-regulated expression of the anti-apoptotic protein Bcl2, up-regulated expression of pro-apoptotic protein p53 and Bax, and caused the release of mitochondrial cytochrome c. Magnolol-induced p53 and Bcl2 expression was abolished in the presence of compound C. Magnolol inhibited migration and invasion of HCT-116 cells through AMPK activation. These findings demonstrate that AMPK mediates the anti-cancer effects of magnolol through apoptosis in HCT-116 cells.

Ovarian Cancer

Treatment of HER-2 overexpressing ovarian cancer cells with magnolol down-regulated the HER-2 downstream PI3K/Akt signaling pathway, and suppressed the expression of downstream target genes, vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and cyclin D1. Consistently, magnolol-mediated inhibition of MMP2 activity could be prevented by co-treatment with epidermal growth factor. Migration assays revealed that magnolol treatment markedly reduced the motility of HER-2 overexpressing ovarian cancer cells. These findings suggest that magnolol may act against HER-2 and its downstream PI3K/Akt/mTOR-signaling network, thus resulting in suppression of HER-2mediated transformation and metastatic potential in HER-2 overexpressing ovarian cancers. These results provide a novel mechanism to explain the anti-cancer effect of magnolol (Chuang et al., 2011).

Lung Cancer

Magnolol has been found to inhibit cell growth, increase lactate dehydrogenase release, and modulate cell cycle in human lung carcinoma A549 cells. Magnolol induced the activation of caspase-3 and cleavage of Poly-(ADP)-ribose polymerase, and decreased the expression level of nuclear factor-κB/Rel A in the nucleus. In addition, magnolol inhibited basic fibroblast growth factor-induced proliferation and capillary tube formation of human umbilical vein endothelial cells. These data indicate that magnolol is a potential candidate for the treatment of human lung carcinoma (Seo et al., 2011).

Prostate Cancer; Anti-metastatic

Matrix metalloproteinases (MMPs) are enzymes involved in various steps of metastasis development. The objective of this study was to study the effects of magnolol on cancer invasion and metastasis using PC-3 human prostate carcinoma cells. Magnolol inhibited cell growth in a dose-dependent manner. In an invasion assay conducted in Transwell chambers, magnolol showed 33 and 98% inhibition of cancer cell at 10 microM and 20 microM concentrations, respectively, compared to the control. The protein and mRNA levels of both MMP-2 and MMP-9 were down-regulated by magnolol treatment in a dose-dependent manner.

These results demonstrate the anti-metastatic properties of magnolol in inhibiting the adhesion, invasion, and migration of PC-3 human prostate cancer cells (Hwang et al., 2010).

Glioblastoma Cancer

Magnolol has been found to concentration-dependently (0-40 microM) decrease the cell number in a cultured human glioblastoma cancer cell line (U373) and arrest the cells at the G0/G1 phase of the cell-cycle.

Pre-treatment of U373 with p21/Cip1 specific antisense oligodeoxynucleotide prevented the magnolol-induced increase of p21/Cip1 protein levels and the decrease of DNA synthesis. Magnolol at a concentration of 100 microM induced DNA fragmentation in U373. These findings suggest the potential applications of magnolol in the treatment of human brain cancers (Chen et al. 2011).

Inhibits Angiogenesis

Magnolol inhibited VEGF-induced Ras activation and subsequently suppressed extracellular signal-regulated kinase (ERK), phosphatidylinositol-3-kinase (PI3K)/Akt and p38, but not Src and focal adhesion kinase (FAK). Interestingly, the knockdown of Ras by short interfering RNA produced inhibitory effects that were similar to the effects of magnolol on VEGF-induced angiogenic signaling events, such as ERK and Akt/eNOS activation, and resulted in the inhibition of proliferation, migration, and vessel sprouting in HUVECs.

In combination, these results demonstrate that magnolol is an inhibitor of angiogenesis and suggest that this compound could be a potential candidate in the treatment of angiogenesis-related diseases (Kim et al., 2013).

References

Chen LC, Liu YC, Liang YC, Ho YS, Lee WS. (2009). Magnolol inhibits human glioblastoma cell proliferation through up-regulation of p21/Cip1. J Agric Food Chem, 57(16):7331-7. doi: 10.1021/jf901477g.


Chen MC, Lee CF, Huang WH, Chou TC. (2013). Magnolol suppresses hypoxia-induced angiogenesis via inhibition of HIF-1 α /VEGF signaling pathway in human bladder cancer cells. Biochem Pharmacol, 85(9):1278-87. doi: 10.1016/j.bcp.2013.02.009.


Chen SC, Chang YL, Wang DL, Cheng JJ. (2006). Herbal remedy magnolol suppresses IL-6-induced STAT3 activation and gene expression in endothelial cells. Br J Pharmacol, 148(2): 226–232. doi: 10.1038/sj.bjp.0706647


Chuang TC, Hsu SC, Cheng YT, et al. (2011). Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells. Cancer Lett, 311(1):11-9. doi: 10.1016/j.canlet.2011.06.007.


Hwang ES, Park KK. (2010). Magnolol suppresses metastasis via inhibition of invasion, migration, and matrix metalloproteinase-2/-9 activities in PC-3 human prostate carcinoma cells. Biosci Biotechnol Biochem, 74(5):961-7.


Kim KM, Kim NS, Kim J, et al. (2013). Magnolol Suppresses Vascular Endothelial Growth Factor-Induced Angiogenesis by Inhibiting Ras-Dependent Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways. Nutr Cancer.


Park JB, Lee MS, Cha EY, et al. (2012). Magnolol-induced apoptosis in HCT-116 colon cancer cells is associated with the AMP-activated protein kinase signaling pathway. Biol Pharm Bull, 35(9):1614-20.


Seo JU, Kim MH, Kim HM, Jeong HJ. (2011). Anti-cancer potential of magnolol for lung cancer treatment. Arch Pharm Res, 34(4):625-33. doi: 10.1007/s12272-011-0413-8.

Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Bladder cancer, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Cytostatic, cytotoxic, Down-regulates, ERK, ERK1, Hep3B, JNK, Liver cancer, MAPK, p21, p38, p53, PARP, Phellinus igniarius, pro-oxidative, ROS, S

Hispolon

Cancer: Bladder, breast, liver, gastric

Action: Anti-inflammatory, cytostatic, cytotoxic, pro-oxidative, anti-proliferative

Hispolon is an active phenolic compound of Phellinus igniarius , a mushroom that has recently been shown to have anti-oxidant, anti-inflammatory, and anti-cancer activities.

Liver Cancer

Hispolon inhibited cellular growth of Hep3B cells in a time-dependent and dose-dependent manner, through the induction of cell-cycle arrest at S phase measured using flow cytometric analysis and apoptotic cell death, as demonstrated by DNA laddering. Exposure of Hep3B cells to hispolon resulted in apoptosis as evidenced by caspase activation, PARP cleavage, and DNA fragmentation. Hispolon treatment also activated JNK, p38 MAPK, and ERK expression. Inhibitors of ERK (PB98095), but not those of JNK (SP600125) and p38 MAPK (SB203580), suppressed hispolon-induced S-phase arrest and apoptosis in Hep3B cells.

These findings establish a mechanistic link between the MAPK pathway and hispolon-induced cell-cycle arrest and apoptosis in Hep3B cells (Huang et al., 2011).

Gastric Cancer, Breast Cancer, Bladder Cancer

Hispolon extracted from Phellinus species was found to induce epidermoid and gastric cancer cell apoptosis. Hispolon has also been found to inhibit breast and bladder cancer cell growth, regardless of p53 status. Furthermore, p21(WAF1), a cyclin-dependent kinase inhibitor, was elevated in hispolon-treated cells. MDM2, a negative regulator of p21(WAF1), was ubiquitinated and degraded after hispolon treatment.

Lu et al. (2009) also found that activated ERK1/2 (extracellular signal-regulated kinase1/2) was recruited to MDM2 and involved in mediating MDM2 ubiquitination. The results indicated that cells with higher ERK1/2 activity were more sensitive to hispolon. In addition, hispolon-induced caspase-7 cleavage was inhibited by the ERK1/2 inhibitor, U0126.

In conclusion, hispolon ubiquitinates and down-regulates MDM2 via MDM2-recruited activated ERK1/2. Therefore, hispolon may be a potential anti-tumor agent in breast and bladder cancers.

Gastric Cancer

The efficacy of hispolon in human gastric cancer cells and cell death mechanism was explored. Hispolon induced ROS-mediated apoptosis in gastric cancer cells and was more toxic toward gastric cancer cells than toward normal gastric cells, suggesting greater susceptibility of the malignant cells.

The mechanism of hispolon-induced apoptosis was that hispolon abrogated the glutathione anti-oxidant system and caused massive ROS accumulation in gastric cancer cells. Excessive ROS caused oxidative damage to the mitochondrial membranes and impaired the membrane integrity, leading to cytochrome c release, caspase activation, and apoptosis. Furthermore, hispolon potentiated the cytotoxicity of chemotherapeutic agents used in the clinical management of gastric cancer.

These results suggest that hispolon could be useful for the treatment of gastric cancer either as a single agent or in combination with other anti-cancer agents (Chen et al., 2008).

Anti-proliferative Activity

Hispolon, which lacks one aromatic unit in relation to curcumin, exhibits enhanced anti-inflammatory and anti-proliferative activities. Dehydroxy hispolon was least potent for all three activities. Overall the results indicate that the substitution of a hydroxyl group for a methoxy group at the meta positions of the phenyl rings in curcumin significantly enhanced the anti-inflammatory activity, and the removal of phenyl ring at the 7(th) position of the heptadiene back bone and addition of hydroxyl group significantly increased the anti-proliferative activity of curcumin and hispolon (Ravindran et al., 2010).

References

Chen W, Zhao Z, Li L, et al. (2008). Hispolon induces apoptosis in human gastric cancer cells through a ROS-mediated mitochondrial pathway. Free Radic Biol Med, 45(1):60-72. doi: 10.1016/j.freeradbiomed.2008.03.013.


Huang GJ, Deng JS, Huang SS, Hu ML. (2011). Hispolon induces apoptosis and cell-cycle arrest of human hepatocellular carcinoma Hep3B cells by modulating ERK phosphorylation. J Agric Food Chem, 59(13):7104-13. doi: 10.1021/jf201289e.


Lu TL, Huang GJ, Lu TJ, et al. (2009). Hispolon from Phellinus linteus has anti-proliferative effects via MDM2-recruited ERK1/2 activity in breast and bladder cancer cells. Food Chem Toxicol, 47(8):2013-21. doi: 10.1016/j.fct.2009.05.023.


Ravindran J, Subbaraju GV, Ramani MV, et al. (2010). Bisdemethylcurcumin and structurally related hispolon analogues of curcumin exhibit enhanced prooxidant, anti-proliferative and anti-inflammatory activities in vitro. Biochem Pharmacol, 79(11):1658-66. doi: 10.1016/j.bcp.2010.01.033.

Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, Anti-oxidation, anti-proliferative, anti-tumor, anti-tumor activity, apoptosis, apoptosis-inducing, Apoptotic, AR, BAX, Bcl-2, BCR, Bladder cancer, Breast cancer, Breast cancer cell lines, CAM, cancer stem cells, CCNE2, CDC2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-enhancing, chemo-preventive, Chemo-protective, Chemo-sensitizer, chemo-sensitzer, Chemoprevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, CSCs, down-regulate COX-2, EGFR, ERK, G2/M, GSTP1, HER2, HIF, HO-1, IL-1, IL-6, IL-8, inflammation, inhibits angiogenesis, Liver cancer, Lymphoma, MAPK, Melanoma, metastasis, MTOR, Multi-Drug Resistance, Multi-drug resistance, Nitric Oxide, NQO1, Osteosarcoma, Ovarian cancer, p38, p65, P70S6K, Pancreatic cancer, PARP, PI3K, Pro-apoptotic, Prostate cancer, Rectal cancer, Rh-123, ROS, Sarcoma, SHH, TAM resistance, TNF, Topo-II, VEGF, VEGF

Dietary Flavones

Cancer:
Prostate, colorectal., breast, pancreatic, bladder, ovarian, leukemia, liver, glioma, osteosarcoma, melanoma

Action: Anti-inflammatory, TAM resistance, cancer stem cells, down-regulate COX-2, apoptosis, cell-cycle arrest, anti-angiogenic, chemo-sensitzer, adramycin (ADM) resistance

Sulforaphane, Phenethyl isothiocyanate (PEITC), quercetin, epicatechin, catechin, Luteolin, apigenin

Anti-inflammatory

The anti-inflammatory activities of celery extracts, some rich in flavone aglycones and others rich in flavone glycosides, were tested on the inflammatory mediators tumor necrosis factor α (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lipopolysaccharide-stimulated macrophages. Pure flavone aglycones and aglycone-rich extracts effectively reduced TNF-α production and inhibited the transcriptional activity of NF-κB, while glycoside-rich extracts showed no significant effects.

Celery diets with different glycoside or aglycone contents were formulated and absorption was evaluated in mice fed with 5% or 10% celery diets. Relative absorption in vivo was significantly higher in mice fed with aglycone-rich diets as determined by HPLC-MS/MS (where MS/MS is tandem mass spectrometry). These results demonstrate that deglycosylation increases absorption of dietary flavones in vivo and modulates inflammation by reducing TNF-α and NF-κB, suggesting the potential use of functional foods rich in flavones for the treatment and prevention of inflammatory diseases (Hostetler et al., 2012).

Colorectal Cancer

Association between the 6 main classes of flavonoids and the risk of colorectal cancer was examined using data from a national prospective case-control study in Scotland, including 1,456 incident cases and 1,456 population-based controls matched on age, sex, and residence area.

Dietary, including flavonoid, data were obtained from a validated, self-administered food frequency questionnaire. Risk of colorectal cancer was estimated using conditional logistic regression models in the whole sample and stratified by sex, smoking status, and cancer site and adjusted for established and putative risk factors.

The significant dose-dependent reductions in colorectal cancer risk that were associated with increased consumption of the flavonols quercetin, catechin, and epicatechin, remained robust after controlling for overall fruit and vegetable consumption or for other flavonoid intake. The risk reductions were greater among nonsmokers, but no interaction beyond a multiplicative effect was present.

This was the first of several a priori hypotheses to be tested in this large study and showed strong and linear inverse associations of flavonoids with colorectal cancer risk (Theodoratou et al., 2007).

Anti-angiogenic, Prostate Cancer

Luteolin is a common dietary flavonoid found in fruits and vegetables. The anti-angiogenic activity of luteolin was examined using in vitro, ex vivo, and in vivo models. Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis; hence, examination of this mechanism of tumor growth is essential to understanding new chemo-preventive targets. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay.

Pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the down-regulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions.

Taken together, these findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis (Pratheeshkumar et al., 2012).

Pancreatic Cancer; Chemo-sensitizer

The potential of dietary flavonoids apigenin (Api) and luteolin (Lut) were assessed in their ability to enhance the anti-proliferative effects of chemotherapeutic drugs on BxPC-3 human pancreatic cancer cells; additionally, the molecular mechanism of the action was probed.

Simultaneous treatment with either flavonoid (0,13, 25 or 50µM) and chemotherapeutic drugs 5-fluorouracil (5-FU, 50µM) or gemcitabine (Gem, 10µM) for 60 hours resulted in less-than-additive effect (p<0.05). Pre-treatment for 24 hours with 13µM of either Api or Lut, followed by Gem for 36 hours was optimal to inhibit cell proliferation. Pre-treatment of cells with 11-19µM of either flavonoid for 24 hours resulted in 59-73% growth inhibition when followed by Gem (10µM, 36h). Lut (15µM, 24h) pre-treatment followed by Gem (10µM, 36h), significantly decreased protein expression of nuclear GSK-3β and NF-κB p65 and increased pro-apoptotic cytosolic cytochrome c. Pre-treatment of human pancreatic cancer cells BxPC-3 with low concentrations of Api or Lut hence effectively aid in the anti-proliferative activity of chemotherapeutic drugs (Johnson et al., 2013).

Breast Cancer; Chemo-sensitizer, Tamoxifen

The oncogenic molecules in human breast cancer cells are inhibited by luteolin treatment and it was found that the level of cyclin E2 (CCNE2) mRNA was higher in tumor cells than in normal paired tissue samples as assessed using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis (n=257).

Combined treatment with 4-OH-TAM and luteolin synergistically sensitized the TAM-R cells to 4-OH-TAM. These results suggest that luteolin can be used as a chemo-sensitizer to target the expression level of CCNE2 and that it could be a novel strategy to overcome TAM resistance in breast cancer patients (Tu et al., 2013).

Breast Cancer

Consumers of higher levels of Brassica vegetables, particularly those of the genus Brassica (broccoli, Brussels sprouts and cabbage), reduce their susceptibility to cancer at a variety of organ sites. Brassica vegetables contain high concentrations of glucosinolates that can be hydrolyzed by the plant enzyme, myrosinase, or intestinal microflora to isothiocyanates, potent inducers of cytoprotective enzymes and inhibitors of carcinogenesis. Oral administration of either the isothiocyanate, sulforaphane, or its glucosinolate precursor, glucoraphanin, inhibits mammary carcinogenesis in rats treated with 7,12-dimethylbenz[a]anthracene. To determine whether sulforaphane exerts a direct chemo-preventive action on animal and human mammary tissue, the pharmacokinetics and pharmacodynamics of a single 150 µmol oral dose of sulforaphane were evaluated in the rat mammary gland.

Sulforaphane metabolites were detected at concentrations known to alter gene expression in cell culture. Elevated cytoprotective NAD(P)H:quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1) gene transcripts were measured using quantitative real-time polymerase chain reaction. An observed 3-fold increase in NQO1 enzymatic activity, as well as 4-fold elevated immunostaining of HO-1 in rat mammary epithelium, provide strong evidence of a pronounced pharmacodynamic action of sulforaphane. In a subsequent pilot study, eight healthy women undergoing reduction mammoplasty were given a single dose of a broccoli sprout preparation containing 200 µmol of sulforaphane. Following oral dosing, sulforaphane metabolites were readily measurable in human breast tissue enriched for epithelial cells. These findings provide a strong rationale for evaluating the protective effects of a broccoli sprout preparation in clinical trials of women at risk for breast cancer (Cornblatt et al., 2007).

In a proof of principle clinical study, the presence of disseminated tumor cells (DTCs) was demonstrated in human breast tissue after a single dose of a broccoli sprout preparation containing 200 µmol of sulforaphane. Together, these studies demonstrate that sulforaphane distributes to the breast epithelial cells in vivo and exerts a pharmacodynamic action in these target cells consistent with its mechanism of chemo-protective efficacy.

Such efficacy, coupled with earlier randomized clinical trials revealing the safety of repeated doses of broccoli sprout preparations , supports further evaluation of broccoli sprouts in the chemoprevention of breast and other cancers (Cornblatt et al., 2007).

CSCs

Recent research into the effects of sulforaphane on cancer stem cells (CSCs) has drawn a great deal of interest. CSCs are suggested to be responsible for initiating and maintaining cancer, and to contribute to recurrence and drug resistance. A number of studies have indicated that sulforaphane may target CSCs in different types of cancer through modulation of NF- κB, SHH, epithelial-mesenchymal transition and Wnt/β-catenin pathways. Combination therapy with sulforaphane and chemotherapy in preclinical settings has shown promising results (Li et al., 2013).

Anti-inflammatory

Sulforaphane has been found to down-regulate COX-2 expression in human bladder transitional cancer T24 cells at both transcriptional- and translational levels. Cyclooxygenase-2 (COX-2) overexpression has been associated with the grade, prognosis and recurrence of transitional cell carcinoma (TCC) of the bladder. Sulforaphane (5-20 microM) induced nuclear translocation of NF-kappaB and reduced its binding to the COX-2 promoter, a key mechanism for suppressing COX-2 expression by sulforaphane. Moreover, sulforaphane increased expression of p38 and phosphorylated-p38 protein. Taken together, these data suggest that p38 is essential in sulforaphane-mediated COX-2 suppression and provide new insights into the molecular mechanisms of sulforaphane in the chemoprevention of bladder cancer (Shan et al., 2009).

Bladder Cancer

An aqueous extract of broccoli sprouts potently inhibits the growth of human bladder carcinoma cells in culture and this inhibition is almost exclusively due to the isothiocyanates. Isothiocyanates are present in broccoli sprouts as their glucosinolate precursors and blocking their conversion to isothiocyanates abolishes the anti-proliferative activity of the extract.

Moreover, the potency of isothiocyanates in the extract in inhibiting cancer cell growth was almost identical to that of synthetic sulforaphane, as judged by their IC50 values (6.6 versus 6.8 micromol/L), suggesting that other isothiocyanates in the extract may be biologically similar to sulforaphane and that nonisothiocyanate substances in the extract may not interfere with the anti-proliferative activity of the isothiocyanates. These data show that broccoli sprout isothiocyanate extract is a highly promising substance for cancer prevention/treatment and that its anti-proliferative activity is exclusively derived from isothiocyanates (Tang et al., 2006).

Ovarian Cancer

Sulforaphane is an extract from the mustard family recognized for its anti-oxidation abilities, phase 2 enzyme induction, and anti-tumor activity. The cell-cycle arrest in G2/M by sulforaphane and the expression of cyclin B1, Cdc2, and the cyclin B1/CDC2 complex in PA-1 cells using Western blotting and co-IP Western blotting. The anti-cancer effects of dietary isothiocyanate sulforaphane on ovarian cancer were investigated using cancer cells line PA-1.

Sulforaphane -treated cells accumulated in metaphase by CDC2 down-regulation and dissociation of the cyclin B1/CDC2 complex.

These findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may also provide anti-tumor activity in established ovarian cancer (Chang et al., 2013).

Leukemia Stem Cells

Isolated leukemia stem cells (LSCs) showed high expression of Oct4, CD133, β-catenin, and Sox2 and imatinib (IM) resistance. Differentially, CD34(+)/CD38(-) LSCs demonstrated higher BCR-ABL and β-catenin expression and IM resistance than CD34(+)/CD38(+) counterparts. IM and sulforaphane (SFN) combined treatment sensitized CD34(+)/CD38(-) LSCs and induced apoptosis, shown by increased caspase 3, PARP, and Bax while decreased Bcl-2 expression. Mechanistically, imatinib (IM) and sulforaphane (SFN) combined treatment resensitized LSCs by inducing intracellular reactive oxygen species (ROS). Importantly, β-catenin-silenced LSCs exhibited reduced glutathione S-transferase pi 1 (GSTP1) expression and intracellular GSH level, which led to increased sensitivity toward IM and sulforaphane.

It was hence demonstrated that IM and sulforaphane combined treatment effectively eliminated CD34(+)/CD38(-) LSCs. Since SFN has been shown to be well tolerated in both animals and human, this regimen could be considered for clinical trials (Lin et al., 2012).

DCIS Stem Cells

A miR-140/ALDH1/SOX9 axis has been found to be critical to basal cancer stem cell self-renewal and tumor formation in vivo, suggesting that the miR-140 pathway may be a promising target for preventive strategies in patients with basal-like Ductal Carcinoma in Situ (DCIS). The dietary compound sulforaphane has been found to decrease Transcription factor SOX-9 and Acetaldehyde dehydrogenases (ALDH1), and thereby reduced tumor growth in vivo (Li et al., 2013).

Glioma, Prostate Cancer, Colon Cancer, Breast Cancer, Liver Cancer

Phenethyl isothiocyanate (PEITC), a natural dietary isothiocyanate, inhibits angiogenesis. The effects of PEITC were examined under hypoxic conditions on the intracellular level of the hypoxia inducible factor (HIF-1α) and extracellular level of the vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Gupta et al., (2013) observed that PEITC suppressed the HIF-1α accumulation during hypoxia in human glioma U87, human prostate cancer DU145, colon cancer HCT116, liver cancer HepG2, and breast cancer SkBr3 cells. PEITC treatment also significantly reduced the hypoxia-induced secretion of VEGF.

Suppression of HIF-1α accumulation during treatment with PEITC in hypoxia was related to PI3K and MAPK pathways.

Taken together, these results suggest that PEITC inhibits the HIF-1α expression through inhibiting the PI3K and MAPK signaling pathway and provide a new insight into a potential mechanism of the anti-cancer properties of PEITC.

Breast Cancer Metastasis

Breast tumor metastasis is a leading cause of cancer-related deaths worldwide. Breast tumor cells frequently metastasize to brain and initiate severe therapeutic complications. The chances of brain metastasis are further elevated in patients with HER2 overexpression. The MDA-MB-231-BR (BR-brain seeking) breast tumor cells stably transfected with luciferase were injected into the left ventricle of mouse heart and the migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent imaging system.

Results demonstrate that the growth of metastatic brain tumors in PEITC treated mice was about 50% less than that of control. According to Kaplan Meir's curve, median survival of tumor-bearing mice treated with PEITC was prolonged by 20.5%. Furthermore, as compared to controls, we observed reduced HER2, EGFR and VEGF expression in the brain sections of PEITC treated mice. These results demonstrate the anti-metastatic effects of PEITC in vivo in a novel breast tumor metastasis model and provides the rationale for further clinical investigation (Gupta et al., 2013).

Osteosarcoma, Melanoma

Phenethyl isothiocyanate (PEITC) has been found to induce apoptosis in human osteosarcoma U-2 OS cells. The following end points were determined in regard to human malignant melanoma cancer A375.S2 cells: cell morphological changes, cell-cycle arrest, DNA damage and fragmentation assays and morphological assessment of nuclear change, reactive oxygen species (ROS) and Ca2+ generations, mitochondrial membrane potential disruption, and nitric oxide and 10-N-nonyl acridine orange productions, expression and activation of caspase-3 and -9, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, poly (adenosine diphosphate-ribose) polymerase, and cytochrome c release, apoptosis-inducing factor and endonuclease G. PEITC

It was therefore concluded that PEITC-triggered apoptotic death in A375.S2 cells occurs through ROS-mediated mitochondria-dependent pathways (Huang et al., 2013).

Prostate Cancer

The glucosinolate-derived phenethyl isothiocyanate (PEITC) has recently been demonstrated to reduce the risk of prostate cancer (PCa) and inhibit PCa cell growth. It has been shown that p300/CBP-associated factor (PCAF), a co-regulator for the androgen receptor (AR), is upregulated in PCa cells through suppression of the mir-17 gene. Using AR-responsive LNCaP cells, the inhibitory effects of PEITC were observed on the dihydrotestosterone-stimulated AR transcriptional activity and cell growth of PCa cells.

Expression of PCAF was upregulated in PCa cells through suppression of miR-17. PEITC treatment significantly decreased PCAF expression and promoted transcription of miR-17 in LNCaP cells. Functional inhibition of miR-17 attenuated the suppression of PCAF in cells treated by PEITC. Results indicate that PEITC inhibits AR-regulated transcriptional activity and cell growth of PCa cells through miR-17-mediated suppression of PCAF, suggesting a new mechanism by which PEITC modulates PCa cell growth (Yu et al., 2013).

Bladder Cancer; Adramycin (ADM) Resistance

The role of PEITC on ADM resistance reversal of human bladder carcinoma T24/ADM cells has been examined, including an increased drug sensitivity to ADM, cell apoptosis rates, intracellular accumulation of Rhodamine-123 (Rh-123), an increased expression of DNA topoisomerase II (Topo-II), and a decreased expression of multi-drug resistance gene (MDR1), multi-drug resistance-associated protein (MRP1), bcl-2 and glutathione s transferase π (GST-π). The results indicated that PEITC might be used as a potential therapeutic strategy to ADM resistance through blocking Akt and activating MAPK pathway in human bladder carcinoma (Tang et al., 2013).

Breast Cancer; Chemo-enhancing

The synergistic effect between paclitaxel (taxol) and phenethyl isothiocyanate (PEITC) on the inhibition of breast cancer cells has been examined. Two drug-resistant breast cancer cell lines, MCF7 and MDA-MB-231, were treated with PEITC and taxol. Cell growth, cell-cycle, and apoptosis were examined.

The combination of PEITC and taxol significantly decreased the IC50 of PEITC and taxol over each agent alone. The combination also increased apoptosis by more than 2-fold over each single agent in both cell lines. A significant increase of cells in the G2/M phases was detected. Taken together, these results indicated that the combination of PEITC and taxol exhibits a synergistic effect on growth inhibition in breast cancer cells. This combination deserves further study in vivo (Liu et al., 2013).

References

Chang CC, Hung CM, Yang YR, Lee MJ, Hsu YC. (2013). Sulforaphane induced cell-cycle arrest in the G2/M phase via the blockade of cyclin B1/CDC2 in human ovarian cancer cells. J Ovarian Res, 6(1):41. doi: 10.1186/1757-2215-6-41


Cornblatt BS, Ye LX, Dinkova-Kostova AT, et al. (2007). Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis, 28(7):1485-1490. doi: 10.1093/carcin/bgm049


Gupta B, Chiang L, Chae K, Lee DH. (2013). Phenethyl isothiocyanate inhibits hypoxia-induced accumulation of HIF-1 α and VEGF expression in human glioma cells. Food Chem, 141(3):1841-6. doi: 10.1016/j.foodchem.2013.05.006.


Gupta P, Adkins C, Lockman P, Srivastava SK. (2013). Metastasis of Breast Tumor Cells to Brain Is Suppressed by Phenethyl Isothiocyanate in a Novel In Vivo Metastasis Model. PLoS One, 8(6):e67278. doi:10.1371/journal.pone.0067278


Hostetler G, Riedl K, Cardenas H, et al. (2012). Flavone deglycosylation increases their anti-inflammatory activity and absorption. Molecular Nutrition & Food Research, 56(4):558-569. doi: 10.1002/mnfr.201100596


Huang SH, Hsu MH, Hsu SC, et al. (2013). Phenethyl isothiocyanate triggers apoptosis in human malignant melanoma A375.S2 cells through reactive oxygen species and the mitochondria-dependent pathways. Hum Exp Toxicol. doi: 10.1177/0960327113491508


Johnson JL, Gonzalez de Mejia E. (2013). Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem Toxicol, 60:83-91. doi: 10.1016/j.fct.2013.07.036.


Li Q, Yao Y, Eades G, Liu Z, Zhang Y, Zhou Q. (2013). Down-regulation of miR-140 promotes cancer stem cell formation in basal-like early stage breast cancer. Oncogene. doi: 10.1038/onc.2013.226.


Li Y, Zhang T. (2013). Targeting cancer stem cells with sulforaphane, a dietary component from broccoli and broccoli sprouts. Future Oncol, 9(8):1097-103. doi: 10.2217/fon.13.108.


Lin LC, Yeh CT, Kuo CC, et al. (2012). Sulforaphane potentiates the efficacy of imatinib against chronic leukemia cancer stem cells through enhanced abrogation of Wnt/ β-catenin function. J Agric Food Chem, 60(28):7031-9. doi: 10.1021/jf301981n.


Liu K, Cang S, Ma Y, Chiao JW. (2013). Synergistic effect of paclitaxel and epigenetic agent phenethyl isothiocyanate on growth inhibition, cell-cycle arrest and apoptosis in breast cancer cells. Cancer Cell Int, 13(1):10. doi: 10.1186/1475-2867-13-10.


Pratheeshkumar P, Son YO, Budhraja A, et al. (2012). Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. PLoS One, 7(12):52279. doi: 10.1371/journal.pone.0052279.


Tang K, Lin Y, Li LM. (2013). The role of phenethyl isothiocyanate on bladder cancer ADM resistance reversal and its molecular mechanism. Anat Rec (Hoboken), 296(6):899-906. doi: 10.1002/ar.22677.


Tang L, Zhang Y, Jobson HE, et al. (2006). Potent activation of mitochondria-mediated apoptosis and arrest in S and M phases of cancer cells by a broccoli sprout extract. Mol Cancer Ther, 5(4):935-44. doi: 10.1158/1535-7163.MCT-05-0476


Theodoratou E, Kyle J, Cetnarskyj R, et al. (2007). Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev,16(4):684-93.


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


Shan Y, Wu K, Wang W, et al. (2009). Sulforaphane down-regulates COX-2 expression by activating p38 and inhibiting NF-kappaB-DNA-binding activity in human bladder T24 cells. Int J Oncol, 34(4):1129-34.


Yu C, Gong AY, Chen D, et al. (2013). Phenethyl isothiocyanate inhibits androgen receptor-regulated transcriptional activity in prostate cancer cells through suppressing PCAF. Mol Nutr Food Res. doi: 10.1002/mnfr.201200810.

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.

A375, Akt, anti-proliferative, anti-proliferative effect, apoptosis, Apoptotic, Autophagy, Canavalia ensiformis, Chapter 7 Isolates and Cancer Research, Immune, Melanoma, p38, p53, ROS

Concanavalin A

Cancer: Melanoma

Action: Autophagy

Concanavalin A (ConA) is isolated from Canavalia ensiformis [(L.) DC.].

Autophagy

Plant lectins, a group of highly diverse carbohydrate-binding proteins of non-immune origin, are ubiquitously distributed through a variety of plant species, and have recently drawn rising attention due to their remarkable ability to kill tumor cells using mechanisms implicated in autophagy. Plant lectins concanavalin A, Polygonatum cyrtonema lectin and mistletoe lectins can target autophagy by modulating BNIP-3, ROS-p38-p53, Ras-Raf and PI3KCI-Akt pathways, as well as Beclin-1, in many types of cancer cells (Liu et al., 2013).

Melanoma

Con A possesses a remarkable anti-proliferative effect on human melanoma A375 cells, and there is a link between the anti-proliferative activity of Con A and its sugar-binding activity. Subsequently, Con A can induce human melanoma A375 cell apoptosis in a caspase-dependent manner. It has been demonstrated that there may be a close correlation between the anti-proliferative activity of Con A and its sugar-binding activity. More importantly, Con A can induce human melanoma A375 cell death in a caspase-dependent manner as well as via a mitochondrial apoptotic pathway (Liu et al.,2009).

References

Liu B, Min MW, Bao JK. (2009). Induction of apoptosis by Concanavalin A and its molecular mechanisms in cancer cells. Autophagy, 5(3):432-3. doi: 10.1016/j.abb.2008.12.003


Liu Z, Luo Y, Zhou TT, Zhang WZ. (2013). Could plant lectins become promising anti-tumor drugs for causing autophagic cell death? Cell Prolif, 46(5):509-15. doi: 10.1111/cpr.12054.

AKR1C1/1C2, Akt, anti-inflammatory, anti-oxidant, apoptosis, attenuation of immune suppression, Breast cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemoprevention, Colon Cancer or Colorectal cancer, Gastric cancer or Stomach cancer, HIF, hNSC, honey, HT-29, Immune, Immunomodulatory, induces apoptosis, Lung cancer, MAPK, MDR, p21, p38, Passiflora caerulea, Passiflora incarnate, Scutellaria baicalensis, SGC7901, VEGF, VEGF

Chrysin

Cancer:
Lung cancer, breast cancer, leukemia, gastric, colon

Action: Anti-inflammatory, induces apoptosis, inhibits HIF-1 α, immunomodulatory

Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound extracted from many plants (including Scutellaria baicalensis (Georgi), Passiflora caerulea (L.), Passiflora incarnate (L.))., honey, and propolis. It possesses potent anti-inflammatory, anti-oxidant properties, promotes cell death, and perturbs cell-cycle progression. Chrysin induced p38-MAPK activation, and using a specific p38-MAPK inhibitor, SB203580, attenuated chrysin-induced p21 (Waf1/Cip1) expression (Weng et al., 2005).

MDR; NSCLC

Chrysin is a major flavonoid in Scutellaria baicalensis, a widely used traditional Chinese and Japanese medicine. Novel links of pro-inflammatory signals, AKR1C1/1C2 expression and drug resistance in human non-small lung cancer have been demonstrated, and the protein kinase C pathway may play an important role in this process. It is thought that chrysin may act as a potential adjuvant therapy for drug-resistant non-small lung cancer, especially for those with AKR1C1/1C2 overexpression (Wang et al., 2007).

Gastric Cancer, Colon Cancer

Additionally, derivatives of chrysin have been shown to have strong activities against SGC-7901 human gastric cell line and HT-29 human colon cancer cell lines (Zheng et al., 2003).

Breast Cancer

While Chrysin is a potent breast cancer resistance protein inhibitor, it was found to have no significant effect on toptecan pharmacokinetics in rats (Zhang et al., 2005).

VEGF, HIF-1

Chrysin was found to inhibit hypoxia-inducible factor-1α (HIF-1α) expression through AKT signaling. Inhibition of HIF-1α by chrysin resulted in abrogation of vascular endothelial growth factor expression (Fu et al., 2007).

Leukemia

Chrysin has been shown to inhibit proliferation and induce apoptosis, and is more potent than other tested flavonoids in leukemia cells, where chrysin is likely to act via activation of caspases and inactivation of Akt signaling in the cells (Khoo et al., 2010).

Immune

The chemo-preventive action of chrysin has been found to specifically inhibit the enzymatic activity of IDO-1 but not mRNA expression in human neuronal stem cells (hNSC), confirmed by cell-based assay and qRT-PCR. These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy (Chen et al., 2012).

References

Chen SS, Corteling R, Stevanato L, Sinden J. (2012). Polyphenols Inhibit Indoleamine 3,5-Dioxygenase-1 Enzymatic Activity — A Role of Immunomodulation in Chemoprevention. Discovery Medicine.


Fu B, Xue J, Li Z, et al. (2007). Chrysin inhibits expression of hypoxia-inducible factor-1 α through reducing hypoxia-inducible factor-1 α stability and inhibiting its protein synthesis. Mol Cancer Ther, 6:220. doi: 10.1158/1535-7163.MCT-06-0526


Khoo BY, Chua SL, Balaram P. (2010). Apoptotic Effects of Chrysin in Human Cancer Cell Lines. Int. J. Mol. Sci, 11(5), 2188-2199. doi:10.3390/ijms11052188


Wang HW, Lin CP, Chiu JH, et al. (2007). Reversal of inflammation-associated dihydrodiol dehydrogenases (AKR1C1 and AKR1C2) overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin. International Journal of Cancer, 120(9), 2019-2027.


Weng MS, Ho YS, Lin JK. (2005). Chrysin induces G1 phase cell-cycle arrest in C6 glioma cells through inducing p21Waf1/Cip1 expression: involvement of p38 mitogen-activated protein kinase. Biochem Pharmacol, 69(12):1815-27.


Zhang S, Wang X, Sagawa K, Morris ME. (2005). Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (,äì/,äì) mice. Drug Metabolism and Disposition, 33(3), 341-348.


Zheng X, Meng WD, Xu YY, Cao JG, & Qing FL. (2003). Synthesis and anti-cancer effect of chrysin derivatives. Bioorganic & Medicinal Chemistry Letters, 13(5), 881-884.

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

Caffeic acid phenethyl ester (CAPE)

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

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

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

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

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

Multiple Immunomodulatory and Anti-inflammatory Activities

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

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

Breast Cancer

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

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

Prostate Cancer

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

EMT, Prostate Cancer

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

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

Cervical Cancer

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

Oral Cancer

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

Melanoma

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

References

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


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


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


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


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


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


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


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


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


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


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


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

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

Betulin and Betulinic acid

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

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

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

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

Anti-cancer, Induces Apoptosis

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

Lung Cancer

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

Esophageal Squamous Carcinoma

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

Leukemia

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

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

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

Multiple Myeloma

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

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

Anti-angiogenic Effects, Colorectal Cancer

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

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

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

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

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

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

Cervical Carcinoma

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

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

Anti-oxidant, Cytotoxic and Immunomodifying Activities

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

Pancreatic Cancer

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

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

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

Multiple Myeloma, Prostate Cancer

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

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

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

Melanoma

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

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

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

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

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

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

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

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

Glioma

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

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

Head and Neck Carcinoma

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

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

References

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.


Rieber M & Strasberg-Rieber M. (1998). Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma. DNA Cell Biol, 17(5):399–406. doi:10.1089/dna.1998.17.399.


Rzeski W, Stepulak A, Szymanski M, et al. (2009). Betulin Elicits Anti-Cancer Effects in Tumor Primary Cultures and Cell Lines In Vitro. Basic and Clinical Pharmacology and Toxicology, 105(6):425–432. doi: 10.1111/j.1742-7843.2009.00471.x


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


Sun S, Xu MZ, Poon RT, Day PJ, Luk JM. (2010). Circulating Lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients. J Proteome Res, 9(1):70-8. doi: 10.1021/pr9002118.


Tan YM, Yu R, Pezzuto JM. (2003). Betulinic Acid-induced Programmed Cell Death in Human Melanoma Cells Involves Mitogen-activated Protein Kinase Activation. Clin Cancer Res, 9:2866.


Thurnher D, Turhani D, Pelzmann M, et al. (2003). Betulinic acid: A new cytotoxic compound against malignant head and neck cancer cells. Head & Neck. 25(9):732–740. doi: 10.1002/hed.10231


Wang P, Li Q, Li K, Zhang X, et al. (2012). Betulinic acid exerts immunoregulation and anti-tumor effect on cervical carcinoma (U14) tumor-bearing mice. Pharmazie, 67(8):733-9.


Wick W, Grimmel C, Wagenknecht B, Dichgans J, Weller M. (1999). Betulinic Acid-Induced Apoptosis in Glioma Cells: A Sequential Requirement for New Protein Synthesis, Formation of Reactive Oxygen Species, and Caspase Processing. JPET, 289(3):1306-1312.


Zuco V, Supino R, Righetti SC, et al. (2002). Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Letters, 175(1): 17–25. doi:10.1016/S0304-3835(01)00718-2. PMID 11734332.

Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, Anti-tumoral, Anti-tumoral., AP-1, Apoptotic, Breast cancer, c-Jun, Chapter 8 Injectables and Cancer Research, chemo-preventive, Chemoprevention, Colon Cancer or Colorectal cancer, COX-2, ERK1, inflammation, Melanoma, p38, PKC, Prostate cancer, Skin cancer

Carnosol

Cancer: Breast, prostate, skin, colon, leukemia, stomach

Action: Anti-inflammatrory, anti-angiogenic

Carnosol is found in certain Mediterranean meats, fruits, vegetables, and olive oil. In particular, it is sourced from rosemary (Rosmarinus officinalis (L.)) and desert sage (Salvia pachyphylla (Epling ex Munz)).

Prostate Cancer, Breast Cancer, Skin Cancer, Colon Cancer, Leukemia

One agent, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals.

This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent (Johnson, 2011).

Literature evidence from animal and cell culture studies demonstrates the anti-cancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells (Ngo et al., 2011).

Anti-inflammatory

Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anti-cancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity.

Carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms (Subbaramaiah, 2002).

Breast Cancer

Two rosemary components, carnosol and ursolic acid, appear to be partly responsible for the anti-tumorigenic activity of rosemary. Supplementation of diets for 2 weeks with rosemary extract (0.5% by wt) but not carnosol (1.0%) or ursolic acid (0.5%) resulted in a significant decrease in the in vivo formation of rat mammary DMBA-DNA adducts, compared to controls. When injected intraperitoneally (i.p.) for 5 days at 200 mg/kg body wt, rosemary and carnosol, but not ursolic acid, significantly inhibited mammary adduct formation by 44% and 40%, respectively, compared to controls. Injection of this dose of rosemary and carnosol was associated with a significant 74% and 65% decrease, respectively, in the number of DMBA-induced mammary adenocarcinomas per rat, compared to controls. Ursolic acid injection had no effect on mammary tumorigenesis.

Therefore, carnosol is one rosemary constituent that can prevent DMBA-induced DNA damage and tumor formation in the rat mammary gland, and, thus, has potential for use as a breast cancer chemopreventative agent (Singletary et al., 1996).

Anti-angiogenic

The anti-angiogenic activity of carnosol and carnosic acid could contribute to the chemo-preventive, anti-tumoral and anti-metastatic activities of rosemary extracts and suggests that there is potential in the treatment of other angiogenesis-related malignancies (L-pez-JimŽnez et al., 2013).

References:

Johnson JJ. (2011). Carnosol: A promising anti-cancer and anti-inflammatory agent. Cancer Letters, 305(1):1-7. doi:10.1016/j.canlet.2011.02.005.


L-pez-JimŽnez A, Garc'a-Caballero M, Medina Mç, Quesada AR. (2013). Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary. Eur J Nutr, 52(1):85-95. doi: 10.1007/s00394-011-0289-x.


Ngo SN, Williams DB, Head RJ. (2011). Rosemary and cancer prevention: preclinical perspectives. Crit Rev Food Sci Nutr, 51(10):946-54. doi: 10.1080/10408398.2010.490883.


Singletary K, MacDonald C & Wallig M. (1996). Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation. Cancer Letters, 104(1):43-8. doi: 10.1016/0304-3835(96)04227-9


Subbaramaiah K, Cole PA, Dannenberg AJ. (2002). Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription by CREB-binding Protein/p300-dependent and -independent Mechanisms. Cancer Res, 62:2522

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.

Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, Anti-tumoral, Anti-tumoral., AP-1, Apoptotic, Breast cancer, c-Jun, Chapter 7 Isolates and Cancer Research, chemo-prevention, chemo-preventive, Chemo-preventive agent, Colon Cancer or Colorectal cancer, COX-2, COX-2 inhibitor, ERK1, inflammation, Lung cancer, Melanoma, p38, PKC

Carnosol

Cancer: Breast, prostate, skin, colon, leukemia, stomach

Action: Anti-inflammatrory, anti-angiogenic

Carnosol is found in certain Mediterranean meats, fruits, vegetables, and olive oil. In particular, it is sourced from rosemary (Rosmarinus officinalis (L.)) and desert sage (Salvia pachyphylla (Epling ex Munz)).

Prostate Cancer, Breast Cancer, Skin Cancer, Colon Cancer, Leukemia

One agent, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals.

This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent (Johnson, 2011).

Literature evidence from animal and cell culture studies demonstrates the anti-cancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells (Ngo et al., 2011).

Anti-inflammatory

Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anti-cancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity.

Carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms (Subbaramaiah, 2002).

Breast Cancer

Two rosemary components, carnosol and ursolic acid, appear to be partly responsible for the anti-tumorigenic activity of rosemary. Supplementation of diets for 2 weeks with rosemary extract (0.5% by wt) but not carnosol (1.0%) or ursolic acid (0.5%) resulted in a significant decrease in the in vivo formation of rat mammary DMBA-DNA adducts, compared to controls. When injected intraperitoneally (i.p.) for 5 days at 200 mg/kg body wt, rosemary and carnosol, but not ursolic acid, significantly inhibited mammary adduct formation by 44% and 40%, respectively, compared to controls. Injection of this dose of rosemary and carnosol was associated with a significant 74% and 65% decrease, respectively, in the number of DMBA-induced mammary adenocarcinomas per rat, compared to controls. Ursolic acid injection had no effect on mammary tumorigenesis.

Therefore, carnosol is one rosemary constituent that can prevent DMBA-induced DNA damage and tumor formation in the rat mammary gland, and, thus, has potential for use as a breast cancer chemopreventative agent (Singletary et al., 1996).

Anti-angiogenic

The anti-angiogenic activity of carnosol and carnosic acid could contribute to the chemo-preventive, anti-tumoral and anti-metastatic activities of rosemary extracts and suggests that there is potential in the treatment of other angiogenesis-related malignancies (L-pez-JimŽnez et al., 2013).

References:

Johnson JJ. (2011). Carnosol: A promising anti-cancer and anti-inflammatory agent. Cancer Letters, 305(1):1-7. doi:10.1016/j.canlet.2011.02.005.


L-pez-JimŽnez A, Garc'a-Caballero M, Medina Mç, Quesada AR. (2013). Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary. Eur J Nutr, 52(1):85-95. doi: 10.1007/s00394-011-0289-x.


Ngo SN, Williams DB, Head RJ. (2011). Rosemary and cancer prevention: preclinical perspectives. Crit Rev Food Sci Nutr, 51(10):946-54. doi: 10.1080/10408398.2010.490883.


Singletary K, MacDonald C & Wallig M. (1996). Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation. Cancer Letters, 104(1):43-8. doi: 10.1016/0304-3835(96)04227-9


Subbaramaiah K, Cole PA, Dannenberg AJ. (2002). Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription by CREB-binding Protein/p300-dependent and -independent Mechanisms. Cancer Res, 62:2522

AMPK, Anti-cancer, anti-inflammatory, blocks neurotoxicity, Breast cancer, cAMP, Chapter 7 Isolates and Cancer Research, COX-2, CYP1A1, CYP1A2, HER2, inflammation, MAPK, MDR, neuro-protective, Nitric Oxide, Ovarian cancer, P-gp, p38, Rubia cordifolia, SK-BR-3, SKOV-3

Mollugin

Cancer: Breast, ovarian

Action: Multi-drug resistance, anti-inflammatory, blocks neurotoxicity

Mollugin originally isolated from Rubia cordifolia (L.) is a pharmacological compound for its anti-inflammation, anti-cancer, and anti-viral activity. Mollugin-caused inhibition of phenacetin O-deethylation was concentration-dependent in hierarchical linear models (HLMs), but not time-dependent. In addition, the Lineweaver-Burk plot indicated a typical competitive inhibition. Inhibitory effects of mollugin on human recombinant cDNA-expressed CYP1A1 and 1A2 were comparable. Taken together, the results suggested that mollugin might cause herb-drug interaction through selective inhibition of CYP1A2 in humans receiving herbal medications, including R. cordifolia (Kim et al., 2013).

MDR, Anti-inflammatory

Mollugin treatment significantly inhibited MDR1 expression by blocking MDR1 transcription. P-glycoprotein (P-gp), an important efflux transporter, is encoded by the MDR1 class of genes and is a central element of the multi-drug resistance (MDR) phenomenon in cancer cells. The suppression of MDR1 promoter activity and protein expression was mediated through mollugin-induced activation of AMP-activated protein kinase (AMPK). Furthermore, mollugin inhibited MDR1 expression through the suppression of NF-κB and cAMP-response element binding protein (CREB) activation. These results suggest that mollugin treatment enhanced suppression of P-gp expression by inhibiting the NF-κB signaling pathway and COX-2 expression, as well as attenuating cAMP-response element (CRE) transcriptional activity through AMPK activation (Tran et al., 2013).

Breast Cancer; Ovarian Cancer

Mollugin exhibited potent inhibitory effects on cancer cell proliferation, especially in HER2-overexpressing SK-BR-3 human breast cancer cells and SK-OV-3 human ovarian cancer cells in a dose- and time-dependent manner without affecting immortalized normal mammary epithelial cell line MCF-10A. Mollugin treatment caused a dose-dependent inhibition of HER2 gene expression at the transcriptional level, potentially in part through suppression of NF-κB activation. The combination of mollugin with a MEK1/2 inhibitor may be required in order to achieve optimal efficacy in HER2-overexpressing cancers.

These findings suggest that mollugin is a novel modulator of the HER2 pathway in HER2-overexpressing cancer cells with a potential role in the treatment and prevention of human breast and ovarian cancer with HER2 overexpression (Do et al., 2013).

Blocks Neurotoxicity, Anti-inflammatory

Mollugin also has effects as a neuro-protective agent in glutamate-induced neurotoxicity in the mouse hippocampal HT22 cell line and as an anti-inflammatory agent in lipopolysaccharide-induced microglial activation in BV2 cells. Mollugin showed potent neuro-protective effects against glutamate-induced neuro-toxicity and reactive oxygen species generation in mouse hippocampal HT22 cells.

In addition, the anti-inflammatory effects of mollugin were demonstrated by the suppression of pro-inflammatory mediators, including pro-inflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) and cytokines (tumor necrosis factor-α and interleukin-6). Furthermore, mollugin also activated the p38 mitogen-activated protein kinase (MAPK) pathway both in HT22 and BV2 cells. These results suggest that mollugin may be a promising candidate for the treatment of neurodegenerative diseases related to neuroinflammation (Jeong et al., 2011).

References

Do MT, Hwang YP, Kim HG, et al. (2013). Mollugin inhibits proliferation and induces apoptosis by suppressing fatty acid synthase in HER2-overexpressing cancer cells. Journal of Cellular Physiology, 228(5):1087–1097. doi: 10.1002/jcp.24258.


Jeong GS, Lee DS, Kim DC, et al. (2011). Neuroprotective and anti-inflammatory effects of mollugin via up-regulation of heme oxygenase-1 in mouse hippocampal and microglial cells. Eur J Pharmacol, 654(3):226-34. doi: 10.1016/j.ejphar.2010.12.027.


Kim H, Choi HK, Jeong TC, et al. (2013). Selective inhibitory effects of mollugin on CYP1A2 in human liver microsomes. Food Chem Toxicol, 51:33-7. doi: 10.1016/j.fct.2012.09.013.


Tran TP, Kim HG, Choi JH, et al. (2013). Reversal of P-glycoprotein-mediated Multi-drug resistance is induced by mollugin in MCF-7/adriamycin cells. Phytomedicine. doi:10.1016/j.phymed.2013.01.014.

ABC, Anti-cancer, anti-inflammatory, anti-metastasis, Anti-metastatic, anti-oxidant, anti-proliferative, apoptosis, apoptosis induction, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Bladder cancer, Breast cancer, c-Fos, c-Jun, CDC2, CDC25A, CDC25C, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, ER, ERK1, G1, G2/M, hTERT, JNK, Lung cancer, lymphangiogenesis inhibitor, lymphangiogenesis inhibitors, MCF-7, MCF-7, MDA-MB-231, MDA-MB-231, MDR, metastasis, MPSC1 (PT), A2780 (PT) and SKOV3 (PT), Nausea and Vomiting, NFATc1, Ovarian cancer, p21, p38, p53, PARP, Pro-apoptotic, pro-oxidative, Prostate cancer, ROS, S, Sarcoma, T24, TIMP-2, TNF

Costunolide and Dehydrocostus Lactone

Cancers:
Breast, cervical., lung, ovarian, bladder, leukemia, prostate, gastric

Action: Anti-inflammatory, pro-oxidative, MDR, lymphangiogenesis inhibitor, anti-metastasis, mediates apoptosis, anti-metastatic

Components of Saussurea lappa Clarke, Vladimiria souliei (Franchet) Lingelsheim (Compositae)

Breast cancer; Anti-metastatic

It was found that costunolide inhibited the growth and telomerase activity of MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner. The expression of hTERT mRNA was also inhibited but hTR mRNA was not. In addition, the bindings of transcription factors in hTERT promoters were significantly decreased in both cells by the treatment of costunolide. These results suggest that costunolide inhibited the growth of both MCF-7 and MDA-MB-231 cells and this effect was mediated at least in part by a significant reduction in telomerase activity (Choi et al., 2005).

Breast Cancer

Costunolide has been demonstrated to suppress tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNF-α induced NF-kB activation. Costunolide also inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in the in vivo mouse orthotopic tumor growth assays.

In addition, costunolide inhibited in vitro TNF-α induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNF-α induced NF-kB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-kB-dependent gene to mediate breast cancer cell growth and metastases. Taken together, these results suggest that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNF-α induced NF-k B activation, suggesting that costunolide as well as SLC may be promising anti-cancer drugs, especially for metastatic breast cancer (Choi et al., 2013).

Several Chinese herbs, namely, Herba Taraxaci Mongolici (Pu Gong Ying), Radix Glycyrrhizae Uralensis (Gan Cao), Radix Bupleuri (Chai Hu), Radix Aucklandiae Lappae/ Radix Aucklandiae Lappae (Mu Xiang), Fructus Trichosanthis (Gua Lou) and Rhizoma Dioscoreae Bulbiferae (Huang Yao Zi) are frequently used in complex traditional Chinese medicine formulas for breast hyperplasia and breast tumor therapy.

The pharmacological effects of these Chinese herbs are all described as 'clearing heat-toxin and resolving masses' in traditional use. A bioactivity-oriented screening platform, which was based on a human breast cancer MCF-7 cellular model was developed to rapidly screen the 6 Chinese herbs. Two potential anti-breast cancer compounds, which were costunolide (Cos) and dehydrocostus lactone (Dehy), were identified in Radix Aucklandiae Lappae.

Combination of the two compounds showed a synergism on inhibiting the proliferation of MCF-7 cells in vitro, which exhibits a potential application prospect for breast cancer therapy. This bioactivity-oriented screening strategy is rapid, economical., reliable and specific for screening potential anti-breast cancer compounds in traditional Chinese medicines (Peng et al., 2013).

Dehydrocostuslactone (DHE) suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G(0)/G(1)-S phase arrest in MCF-7 cells. In contrast, DHE caused S-G(2)/M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell-cycle progression and cell death through SOCS-1 and SOCS-3.

Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer (Kuo et al., 2009).

ER- Breast Cancer

Costunolide induced apoptosis through the extrinsic pathway, including the activation of Fas, caspase-8, caspase-3, and degradation of PARP. However, it did not have the same effect on the intrinsic pathway as revealed by analysis of mitochondrial membrane potential (Δψ m) with JC-1 dye and expression of Bcl2 and Bax proteins level.

Furthermore, costunolide induced cell-cycle arrest in the G2/M phase via decrease in Cdc2, cyclin B1 and increase in p21WAF1 expression, independent of p53 pathway in p53-mutant MDA-MB-231 cells, and increases Cdc2-p21WAF1 binding/

Through this study it was confirmed that costunolide induces G2/M cell-cycle arrest and apoptotic cell death via extrinsic pathway in MDA-MB-231 cells, suggesting that it could be a promising anti-cancer drug especially for ER negative breast cancer (Choi et al., 2012).

Bladder Cancer

Costunolide, a member of sesquiterpene lactone family, possesses potent anti-cancer properties. The effects of costunolide were investigated on the cell viability and apoptosis in human bladder cancer T24 cells. Treatment of T24 cells with costunolide resulted in a dose-dependent inhibition of cell viability and induction of apoptosis, which was associated with the generation of ROS and disruption of mitochondrial membrane potential (Δψm).

These effects were significantly blocked when the cells were pre-treated with N-acetyl- cysteine (NAC), a specific ROS inhibitor. Exposure of T24 cells to costunolide was also associated with increased expression of Bax, down-regulation of Bcl-2, and of   survivin and significant activation of caspase-3, and its downstream target PARP. These findings provide the rationale for further in vivo and clinical investigation of costunolide against human bladder cancer (Rasul et al., 2013).

Sarcomas; MDR

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 on cell proliferation, cell-cycle distribution, apoptosis induction, and ABC transporter expression were analyzed. 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. Moreover, it led to enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP indicating apoptosis induction.

These data demonstrate 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., 2013).

Leukemia, Lung Cancer

Costunolide, an active compound isolated from the stem bark of Magnolia sieboldii, has been found to induce apoptosis via reactive oxygen species (ROS) and Bcl-2-dependent mitochondrial permeability transition in human leukemia cells. Mitogen-activated protein kinases (MAPKs) were investigated for their involvement in the costunolide-induced apoptosis in human promonocytic leukemia U937 cells.

Treatment with costunolide resulted in the significant activation of c-Jun N-terminal kinase (JNK), but not of extracellular-signal-related kinase (ERK1/2) or p38. In vitro kinase assays showed that JNK activity was low in untreated cells but increased dramatically after 30 minutes of costunolide treatment. U937 cells co-treated with costunolide and sorbitol, a JNK activator, exhibited higher levels of cell death. In addition, inhibition of the JNK pathway using a dominant-negative mutation of c-jun and JNK inhibitor SP600125, significantly prevented costunolide-induced apoptosis.

Furthermore, pre-treatment with the anti-oxidant NAC (N-acetyl-L-cysteine) blocked the costunolide-stimulated activation of JNK while the overexpression of Bcl-2 failed to reverse JNK activation. These results indicate that costunolide-induced JNK activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis. Moreover, the administration of costunolide (intraperitoneally once a day for 7 days) significantly suppressed tumor growth and increased survival in 3LL Lewis lung carcinoma-bearing model (Choi et al., 2009).

Prostate Cancer

Several pharmacological and biochemical assays were used to characterize the apoptotic-signaling pathways of costunolide in prostate cancer cells. Costunolide showed effective anti-proliferative activity against hormone dependent (LNCaP) and independent (PC-3 and DU-145) prostate cancer cells (ATCC¨) by sulforhodamine B assay, clonogenic test and flow cytometric analysis of carboxyfluorescein succinimidyl ester labeling. In PC-3 cells data showed that costunolide induced a rapid overload of nuclear Ca(2+), DNA damage response and ATR phosphorylation.

This indicated the crucial role of intracellular Ca(2+) mobilization and thiol depletion but not of reactive oxygen species production in apoptotic signaling. Data suggest that costunolide induces the depletion of intracellular thiols and overload of nuclear Ca(2+) that cause DNA damage and p21 up-regulation. The association of p21 with the cyclin dependent kinase 2/cyclin E complex blocks cyclin dependent kinase 2 activity and inhibits Rb phosphorylation, leading to G1 arrest of the cell-cycle and subsequent apoptotic cell death in human prostate cancer cells (Hsu et al., 2011).

Gastric Cancer, Prostate Cancer

Radix Aucklandiae Lappae/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 G(2) growth arrest and apoptosis in gastric cancer cells. The effects of hexane extracts of S. lappa (HESLs) on the migration of DU145 and TRAMP-C2 prostate cancer cells were investigated.

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. These results demonstrate 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 for the treatment of prostate cancer (Kim et al., 2012).

Anti-metastatic

Lymphangiogenesis inhibitors from crude drugs used in Japan and Korea were investigated for their impact on metastasis. 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.

Among isolated compounds, several compounds; costunolide, dehydrocostus lactone, psoracorylifol D, bavachinin, bakuchiol, showed an inhibitory effect on the proliferation and the capillary-like tube formation of TR-LE cells. In addition, all compounds showed selective inhibition of the proliferation of TR-LE cells compared to Hela and Lewis lung carcinoma (LLC) cells.

These compounds might offer clinical benefits as lymphangiogenesis inhibitors and may be good candidates for novel anti-cancer and anti-metastatic agents (Jeong et al., 2013).

Ovarian Cancer, MDR

The apoptosis-inducing effect of costunolide, a natural sesquiterpene lactone, was studied in platinum-resistant human ovarian cancer cells relative to cisplatin.

The MTT assay for cell viability, PI staining for cell-cycle profiling, and annexin V assay for apoptosis analysis were performed. Costunolide induced apoptosis of platinum-resistant cells in a time and dose-dependent manner and suppressed tumor growth in the SKOV3 (PT)-bearing mouse model. In addition, costunolide triggered the activation of caspase-3, caspase-8, and caspase-9. Pre-treatment with caspase inhibitors neutralized the pro-apoptotic activity of costunolide. We further demonstrated that costunolide induced a significant increase in intracellular reactive oxygen species (ROS). Moreover, costunolide synergized with cisplatin to induce cell death in platinum-resistant ovarian cancer cells.

Data suggests that costunolide, alone or in combination with cisplatin, may be of therapeutic potential in platinum-resistant ovarian cancers (Yang, Kim, Lee, & Choi, 2011).

Anti-inflammatory, Anti-oxidant, Mediates Apoptosis

Cheon et al. (2013) found that costunolide significantly inhibited RANKL-induced BMM differentiation into osteoclasts in a dose-dependent manner without causing cytotoxicity. Costunolide did not regulate the early signaling pathways of RANKL, including the mitogen-activated protein kinase and NF-κB pathways.

However, costunolide suppressed nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression via inhibition of c-Fos transcriptional activity without affecting RANKL-induced c-Fos expression. The inhibitory effects of costunolide were rescued by overexpression of constitutively active (CA)-NFATc1. Taken together, these results suggest that costunolide inhibited RANKL-induced osteoclast differentiation by suppressing RANKL-mediated c-Fos transcriptional activity.

References

Cheon YH, Song MJ, Kim JY, Kwak SC, Park JH, Lee CH, Kim JJ, Kim JY, Choi MK, Oh J, Kim YC, Yoon KH., Kwak HB, Lee MS. (2013). Costunolide inhibits osteoclast differentiation by suppressing c-Fos transcriptional activity. Phytotherapy, July, (6). doi: 10.1002/ptr.5034.

Choi SH, Im E, Kang HK, et al. (2005). Inhibitory effects of costunolide on the telomerase activity in human breast carcinoma cells. Cancer Lett, 227(2):153-62.


Choi JH, Lee KT. (2009). Costunolide-induced apoptosis in human leukemia cells: involvement of c-jun N-terminal kinase activation. Biol Pharm Bull, 32(10):1803-8.


Choi YK, Seo HS, Choi HS, et al. (2012). Induction of Fas-mediated extrinsic apoptosis, p21WAF1-related G2/M cell-cycle arrest and ROS generation by costunolide in estrogen receptor-negative breast cancer cells, MDA-MB-231. Mol Cell Biochem, 363(1-2):119-28. doi: 10.1007/s11010-011-1164-z.


Choi YK, Cho S-G, Woo S-M, et al. (2013). Saussurea lappa Clarke-Derived Costunolide Prevents TNF α-Induced Breast Cancer Cell Migration and Invasion by Inhibiting NF-κ B Activity. Evidence-Based Complementary and Alternative Medicine. doi:10.1155/2013/936257.


Hsu JL, Pan SL, Ho YF, Het al. (2011). Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer. The Journal of Urology, 185(5):1967-74. doi: 10.1016/j.juro.2010.12.091.


Jeong D, Watari K, Shirouzu T, et al. (2013). Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs. Biol Pharm Bull, 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. J Med 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 Med, 78(16):1749-56. doi: 10.1055/s-0032-1315385.


Kuo PL, Ni WC, Tsai EM, Hsu YL. (2009). Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells. Mol Cancer Ther, 8(5):1328-39. doi: 10.1158/1535-7163.MCT-08-0914.


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. Biomed Chromatogr. doi: 10.1002/bmc.2990.


Rasul A, Bao R, Malhi M, et al. (2013). Induction of apoptosis by costunolide in bladder cancer cells is mediated through ROS generation and mitochondrial dysfunction. Molecules, 18(2):1418-33. doi: 10.3390/molecules18021418.


Yang YI, Kim JH, Lee KT, & Choi JH. (2011). Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species. Gynecologic Oncology, 123(3), 588-96. doi: 10.1016/j.ygyno.2011.08.031.

Akt, AMPK, anti-apoptotic, Anti-cancer, anti-inflammatory, Anti-oxidation, apoptosis, Apoptotic, AT6.3, autophagic cell death, Bcl-2, blood sugar regulation, cAMP, CDK1, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, ERK, ERR, estrogen receptor modulator, G2/M, JNK, K-HEP-1, Osteosarcoma, Ovarian cancer, OVCAR-3 and A2780/CP70, p38, Sarcoma, U-2, various plants, VEGF, VEGF

Kaempferol

Cancer:
Pancreatic, osteosarcoma, metastasis, ovarian cancer

Action: Anti-oxidation, anti-inflammatory, cell-cycle arrest, blood sugar regulation, estrogen receptor modulator, metastasis

Kaempferol is a flavonol compound present in various plants and Chinese medicinal herbs, including Allium cepa (L.).

Blood Sugar Regulation

It has been found that kaempferol, a flavonol compound present in various Chinese medicinal herbs, has cyto-protective effects on cultured clonal beta-cells and pancreatic human islets. Kaempferol treatment dose-dependently promoted viability, inhibited cellular apoptosis, and reduced caspase-3 activity in beta-cells and human islets exposed to chronic high glucose, with 10 µM kaempferol exerting the maximum effect. In addition, kaempferol treatment improved the expression of anti-apoptotic proteins Akt and Bcl-2, that was significantly reduced in beta-cells and human islets chronically exposed to hyperglycemia.

Furthermore, exposure of beta-cells and human islets to kaempferol restored high glucose-attenuated intracellular cAMP and ATP production. Inhibition of protein kinase A or Akt activation ablated the anti-apoptotic effect of kaempferol. These cytoprotective effects of kaempferol were associated with improved insulin secretory function and synthesis in beta-cells and human islets.

These findings provide evidence that kaempferol may be a naturally occurring anti-diabetic compound through protecting pancreatic beta-cell survival and function in a hostile environment that would otherwise lead to type 2 diabetes (Zhang et al., 2011).

Ovarian Cancer

Recent studies indicate that apigenin, genistein, kaempferol, luteolin, and quercetin potently inhibit VEGF production and suppress ovarian cancer cell metastasis in vitro. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well-documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Estrogen Receptor Modulator

Kaempferol is a dietary flavonoid that can function as a selective estrogen receptor modulator (SERM). Estrogen-related receptors alpha and gamma (ERR α and ERRγ) are orphan nuclear receptors that play important roles in mitochondrial biogenesis and cancer development. Wang, Gao, & Wang (2013) have shown that kaempferol can functionally antagonize the activities of ERRs based on both response element reporter systems and target gene analysis. Kaempferol modulation of mitochondrial function and suppression of cancer cell growth has been confirmed. These findings suggest that kaempferol may exert its anti-cancer activities through antagonizing ERRs activity.

Osteosarcoma; Metastasis

Kaempferol displayed inhibitory effects on the invasion and adhesion of U-2 osteosarcoma (OS) cells in a concentration-dependent manner and it also inhibited the migration of U-2 OS cells in a concentration-dependent manner. Kaempferol treatment reduced the enzymatic activities and protein levels of matrix metalloproteinase (MMP)-2, MMP-9 and urokinase plasminogen activator (uPA) and furthermore, kaempferol was able to reduce the protein phosphorylation of ERK, p38 and JNK. Results suggest a potential role for kaempferol in the therapy of tumor metastasis of OS (Chen et al., 2013).

Cell-cycle Arrest

Kaempferol decreased cell viability as determined by MTT assays and induced a G2/M phase cell-cycle arrest in a concentration-dependent manner. CDK1/cyclin B expression and the AMPK and AKT signaling pathways contributed to kaempferol-induced G2/M cell-cycle arrest and autophagic cell death in SK-HEP-1 human hepatic cancer cells (Huang et al., 2013).

References

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.


Chen HJ, Lin CM, Lee CY, et al. (2013). Kaempferol suppresses cell metastasis via inhibition of the ERK-p38-JNK and AP-1 signaling pathways in U-2 OS human osteosarcoma cells. Oncol Rep, 30(2):925-32. doi: 10.3892/or.2013.2490.


Huang WW, Tsai SC, Peng SF, et al. (2013). Kaempferol induces autophagy through AMPK and AKT signaling molecules and causes G2/M arrest via down-regulation of CDK1/cyclin B in SK-HEP-1 human hepatic cancer cells. Int J Oncol, 42(6):2069-77. doi: 10.3892/ijo.2013.1909.


Wang H, Gao M, Wang J. (2013). Kaempferol inhibits cancer cell growth by antagonizing estrogen-related receptor α and γ activities. Cell Biol Int. doi: 10.1002/cbin.10152.


Zhang Y, Liu D. (2011). Flavonol kaempferol improves chronic hyperglycemia-impaired pancreatic beta-cell viability and insulin secretory function. Eur J Pharmacol, 670(1):325-32. doi: 10.1016/j.ejphar.2011.08.011.

Anti-cancer, Anti-cancer effect, anti-oxidant, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BAX, Bcl-2, BGC-823, Bladder cancer, c-Jun, Chapter 7 Isolates and Cancer Research, Chemotherapy, ERK1, Gallbladder cancer, Gastric cancer or Stomach cancer, Herba epimedii, induces apoptosis, JNK, MCF-7, MDR, p38, restores T cell function, ROS, VASP

Icariin

Cancer: Breast, gastric, Leydig cell, gall bladder

Action: Potentiates chemotherapy, restores T cell function, MDR, induces apoptosis

Estrogen Agonist

Icariin is a pure extract of the traditional Chinese medicine Herba epimedii. It is a flavonoid found in several species of the genus Epimedium (L.).

The estrogenic activities of icariin (ICA) and its derivatives were investigated, and their structure-estrogenic activity relationship determined. Icaritin (ICT) and desmethylicaritin (DICT) were derived from ICA. The estrogenic activities of ICA, ICT and DICT were examined by cell proliferation and progestogen receptor mRNA expression of estrogen-receptor-positive MCF-7 cells.

These studies indicated that ICT and DICT both markedly enhanced the proliferation of MCF-7 cells; as compared to estradiol (100%); their relative proliferative effects (RPE) were 90% and 94%, respectively. Those phenomena were not observed with ICA. Results demonstrate that ICT and DICT (nonconjugated forms) possess estrogen-like activity; however, ICA appears to have no estrogenicity in the MCF-7 cell line model in vitro (Ye et al., 2005).

Gastric Cancer

In an in vitro study, the inhibitory effect and underlying molecular mechanism of icariin was investigated on the invasive and migration properties of human gastric cancer cell line BGC-823. At 50% growth-inhibiting concentration, icariin significantly suppressed tumor cells migration and invasion, which were traceable to down-regulation of Rac1 and VASP.

Together with icariin, the selected siRNA targeting Rac1 or VASP reinforced these inhibitory effects. Moreover, transfection with Rac1 plasmids pcDNA3-EGFP-Rac1-Q61L led to the enhancement in expression level of both Rac1 and VASP.

These results indicate that icariin exerts negative effects on tumor cell invasion and migration via the Rac1-dependent VASP pathway and may be a potential anti-cancer drug (Wang et al., 2010).

Gallbladder Cancer; Gemcitabine

Icariin, by suppressing NF-κB activity, exerts anti-tumor activity, and potentiates the anti-tumor activity of gemcitabine in gallbladder cancer. Combined administration of gemcitabine and icariin may offer a better therapeutic option for patients with gallbladder cancer. Icariin (40-160 µg/mL) dose-dependently suppressed cell proliferation and induced apoptosis in both GBC-SD and SGC-996 cells, with SGC-996 cells being less sensitive to the drug. Icariin (40 µg/mL) significantly enhanced the anti-tumor activity of gemcitabine (0.5 µmol/L) in both GBC-SD and SGC-996 cells (Zhang et al., 2013).

Restores T cell function

Tumor-induced myeloid-derived suppressor cells (MDSCs) are a critical barrier to effective immunotherapy of cancer. We identified that Docetaxel and a natural compound, Icariin, can target MDSCs with preferential apoptosis of M2 cells and polarization of the surviving cells towards M1 cells. Such strategic targeting of MDSCs restored T cell function accompanied by tumor retardation in vivo (Djeu & Wei, 2012).

Leydig Cell (Testicle)

Findings suggest a novel anti-cancer effect of icariin in Leydig cell tumor, derived from interstitial cells (rare neoplasm) through activation of the mitochondrial pathway and down-regulation of the expression of piwil4 (Wang et al., 2011).

Induces Apoptosis

Icariin triggered the mitochondrial/caspase apoptotic pathway indicated by enhanced Bax-to-Bcl-2 ratio, loss of mitochondrial membrane potential., cytochrome c release, and caspase cascade. Moreover, icariin induced a sustained activation of the phosphorylation of c-Jun N-terminal kinase (JNK) but not p38 and ERK1/2, and SP600125 (an inhibitor of JNK) almost reversed icariin-induced apoptosis in SMMC-7721 cells. In addition, icariin provoked the generation of reactive oxygen species (ROS) in SMMC-7721 cells, while the anti-oxidant N-acetyl cysteine almost completely blocked icariin-induced JNK activation and apoptosis. Taken together, these findings suggest that icariin induces apoptosis through a ROS/JNK-dependent mitochondrial pathway (Li et al., 2010).

References

Djeu J, Wei S. (2012). Chemoimmunomodulation of MDSCs as a novel strategy for cancer therapy. Oncoimmunology, 1(1):121-122.


Li S, Dong P, Wang J, et al. (2010). Icariin, a natural flavonol glycoside, induces apoptosis in human hepatoma SMMC-7721 cells via a ROS/JNK-dependent mitochondrial pathway. Cancer Lett, 298(2):222-30. doi: 10.1016/j.canlet.2010.07.009.


Wang Y, Dong H, Zhu M, et al. (2010). Icariin exterts negative effects on human gastric cancer cell invasion and migration by vasodilator-stimulated phosphoprotein via Rac1 pathway. Eur J Pharmacol, 635(1-3):40-8. doi: 10.1016/j.ejphar.2010.03.017.


Wang Q, Hao J, Pu J, et al. (2011). Icariin induces apoptosis in mouse MLTC-10 Leydig tumor cells through activation of the mitochondrial pathway and down-regulation of the expression of piwil4. Int J Oncol, 39(4):973-80. doi: 10.3892/ijo.2011.1086.


Ye HY, Lou YJ. (2005). Estrogenic effects of two derivatives of icariin on human breast cancer MCF-7 cells. Phytomedicine, 12(10):735-41.


Zhang DC, Liu JL, Ding YB, Xia JG, Chen GY. (2013). Icariin potentiates the anti-tumor activity of gemcitabine in gallbladder cancer by suppressing NF-κ B. Acta Pharmacol Sin, 34(2):301-8. doi: 10.1038/aps.2012.162.