Date of Award

5-6-2009

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Sara Rockwell

Abstract

Black cohosh (Cimicifuga racemosa), a shrub-like plant native to North America, is frequently used to mitigate the climacteric symptoms of menopause. The prevalent use of black cohosh by women with breast cancer, both during and after treatment, has raised concerns about the potential effects on breast cancer growth and interactions with anticancer therapies. Recent studies have also found that black cohosh may actually inhibit human breast cancer cell growth and sensitize cancer cells to commonly utilized chemotherapeutic agents. This study aims to investigate the effect of a commercially available black cohosh extract on the growth and viability of MCF-7 human breast cancer cells and on their response to the chemotherapeutic agents docorubicin and docetaxel. MCF-7 cells, a well characterized estrogen sensitive human breast cancer cell line, were exposed to a commercially available black cohosh extract (GAIA herbs) standardized by the manufacturer to contain 3% triterpene glycosides) at doses calculated to be 1x, 10x, and 100x the recommended human dose. Control cells were treated with the vehicle used to prepare the extract. The effect of black cohosh alone on cell proliferation and viability was determined both by cell growth assays, in which cell counts were obtained each day for 1 to 5 days after addition of the extract to MCF7 cultures, as well as by colony formation assays for clonogenicity. To determine the possible effects of the black cohosh extract on the response of MCF7 cells to chemotherapy, clonogenicity assays were performed to assay the survival of cells that were pretreated with either black cohosh or a vehicle control prior to exposure to doxorubicin or docetaxel. To study the effects on drug transport, efflux studies in MCF-7 cells treated with either black cohosh or vehicle prior to, during, and after exposure to doxorubicin were also performed. Black cohosh extract at 100x the human dose resulted in a significant decrease in the growth and viability of MCF-7 human breast cancer cells. Lower doses of the extract had no significant effects on cell growth. The highest dose of black cohosh extract also reduced the clonogenicity of the MCF7 cells, suggesting a cytotoxic effect as well as an inhibition of cell proliferation. Interestingly, this study found no significant effect of black cohosh on the dose-response curves for MCF-7 cells exposed to graded doses of the chemotherapeutic agents doxorubicin and docetaxel. This study did not show inhibition of drug efflux by black cohosh. The results from this study are in contrast to those found previously in the estrogen independent mouse mammary cancer cell line EMT6. The reason why the extract modulates the response to doxorubicin and docetaxel in EMT6 cells but not MCF7 cells is currently under investigation. We hypothesize that it may reflect differences in efflux mechanisms in the two cell lines or effects on proliferationdependent DNA repair pathways.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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