Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells
Linda Saxe Einbond,a* Ye Wen-Cai,b† Kan He,c† Hsan-au Wu,a Erica Cruz,a Marc Roller,c and Fredi Kronenberga
aDepartment of Rehabilitation Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 bInstitute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, ChinacNaturex, Hackensack, New Jersey.
Abstract The purpose of this report is to explore the growth inhibitory effect of extracts and compounds from black cohosh and related Cimicifuga species on human breast cancer cells and to determine the nature of the active components. Black cohosh fractions enriched for triterpene glycosides and purified components from black cohosh and related Asian species were tested for growth inhibition of the ER− Her2 over expressing human breast cancer cell line MDA-MB-453. Growth inhibitory activity was assayed using the Coulter Counter, MTT and colony formation assays.Results suggested that the growth inhibitory activity of black cohosh extracts appears to be related to their triterpene glycoside composition. The most potent Cimicifuga component tested was 25-acetyl-7,8-didehydrocimigenol 3-O-β-D-xylopyranoside, which has an acetyl group at position C-25. It had an IC50 of 3.2 µg/ml (5 µM) compared to7.2 µg/ml (12.1 µM) for the parent compound 7,8-didehydrocimigenol 3-O-β-D-xylopyranoside. Thus, the acetyl group at position C-25 enhances growth inhibitory activity.The purified triterpene glycoside actein (β-D-xylopyranoside), with an IC50 equal to 5.7 µg/ml (8.4 µM), exhibited activity comparable to cimigenol 3-O-β-D-xyloside. MCF7 (ER+Her2 low) cells transfected for Her2 are more sensitive than the parental MCF7 cells to the growth inhibitory effects of actein from black cohosh, indicating that Her2 plays a role in the action of actein. The effect of actein on Her2 over expressing MDA-MB-453 and MCF7 (ER+Her2 low) human breast cancer cells was examined by fluorescent microscopy. Treatment with actein altered the distribution of actin filaments and induced apoptosis in these cells.These findings, coupled with our previous evidence that treatment with the triterpene glycoside actein induced a stress response and apoptosis in human breast cancer cells, suggest that compounds from Cimicifuga species may be useful in the prevention and treatment of human breast cancer.
Black Cohosh Increases Metastatic Mammary Cancer in Transgenic Mice Expressing c-erbB2
Vicki L. Davis1, Manuel J. Jayo2, Arline Ho3, Mary P. Kotlarczyk1, Mary L. Hardy4, Warren G. Foster5 and Claude L. Hughes6
1 Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania; 2 Tengion Laboratories, Winston-Salem, North Carolina; 3 Cedars-Sinai Medical Center and 4 Simms/Mann-UCLA Center for Integrative Oncology, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; 5 Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada; and 6 Medical and Scientific Services, Quintiles, Research Triangle Park, North Carolina
Black cohosh is an herbal extract that is often used as an alternative to estrogen-based replacement therapies to treat hot flushesthat frequently accompany the transition to menopause. Althoughcancer-free women as well as breast cancer patients and survivors use black cohosh to relieve vasomotor symptoms, there is limited information on its potential to influence breast cancer developmentor progression. Therefore, in this study, the effects of blackcohosh on mammary tumorigenesis were investigated in the MMTV-neumouse model due to its similarities to HER2+ breast cancer,including stochastic development of mammary tumors, which frequently progress to metastatic disease. Using an adjusted dose for the mice to correlate to the recommended dose in women (40 mg/d),no differences were detected in the incidence or onset of mammary tumors in black cohosh–treated versus control females.The lack of effect on mammary tumor development suggests that black cohosh would not influence breast cancer risk if given to women before tumor formation. In contrast, black cohosh significantly increased the incidence of lung metastases in tumor-bearing animals compared with mice fed the isoflavone-free control diet.Additional studies will be needed to correlate these findings to women taking different black cohosh products at various times during breast cancer development; however, these results suggest caution for women using black cohosh, especially for extended periods of time. As metastatic progression is linked to patient survival, these data stress the importance of investigating how women's therapies influence all stages of mammary tumorigenesis,particularly for assessing their safety. [Cancer Res 2008;68(20):8377–83]