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    Anticancer and Chemopreventive Potential of Constituents of Black Cohosh on Breast Cancer

    Scientific Abstract:
    Anticancer and Chemopreventive Potential of Constituents of Black Cohosh on Breast Cancer Background: Black cohosh, Actaea racemosa L. (= Cimicifuga racemosa), is a North American perennial in the buttercup family (Ranunculaceae) used for various women's health conditions. The rhizome contains triterpene glycosides and aromatic acids. Crude extracts of the rhizome and triterpene glycosides, isolated from the rhizome, have been reported to have anticancer effects in vitro. These studies have, however, been very limited in scope and have not addressed issues of specificity and mechanism of action. Objective/Hypothesis: The overall objective of this project is to determine whether black cohosh contains components that may eventually be useful in the prevention or treatment of breast cancer. Indeed, our preliminary experiments indicate that an ethyl acetate extract of black cohosh inhibits the growth of human breast cancer cells. The extract induces cell cycle arrest at G1 at low concentrations and at G2/M at high concentrations, suggesting that it contains a mixture of active components. We found that the triterpene glycoside fraction of black cohosh, isolated by polyamide chromatography, and purified triterpene glycosides inhibit the growth of breast cancer cells and induce cell cycle arrest at G1. This project will clarify the nature of the active components in black cohosh, which we hypothesize to be triterpene glycosides, and their modes of action, in order to develop novel drugs for cancer chemoprevention and therapy. Specific Aims: 1) Determine whether black cohosh extracts and isolated components alone and in combination with chemotherapy agents inhibit the growth of Her-2 overexpressing human breast cancer cell lines and normal human mammary epithelial cells 2) Analyze black cohosh extracts and isolated compounds for their effects on cell cycle progression and induction of apoptosis, and determine the specific signaling pathways and cellular targets involved in the mechanisms of action of these compounds. 3) Examine the effects of purified compounds from black cohosh on gene expresssion profiles. 4) Isolate and characterize the structures of the specific chemicals that mediate the effects of these extracts on breast cancer cells and examine structure-function relationships. Study Design: Extracts of black cohosh and isolated compounds will be studied in the human breast cancer cell line MDA-MB-453 (ER negative, Her2 overexpressing) and in the normal mammary epithelial cell line MCF-10F. Assays will be performed for cell proliferation, cell cycle kinetics and apoptosis. Western blot analysis will be done to examine possible effects on the expression of cyclin D1; CDK4, 6; CDIs p27, p21, p16, inos, cox-2, NF-kB and on MAP kinase pathways. Luciferase reporter assays will be done to monitor effects on the transcription of cyclin D1, NF-kB, fos, myc, and jun. Complementary DNA microarrays will be used to determine effects on gene expression patterns. Analytic chemical techniques will be used to identify novel compounds in these extracts that might mediate these effects. Potential Outcomes and Benefits of the Research: Women are increasingly turning to black cohosh as a 'more natural' alternative to estrogen, in the belief that it has the benefits, without the risks of estrogen therapy. Research is needed to clarify whether black cohosh stimulates or inhibits breast cancer cells. This research could identify a safe choice for women who have had or are at risk of developing breast cancer. In addition, this research project could reveal novel compounds that might be useful for the prevention and/or treatment of breast cancer. In future studies, these compounds could be tested alone or in combination with chemotherapy agents in collaboration with clinicians.

    Lay Abstract:
    Anticancer and Chemopreventive Potential of Constituents of Black Cohosh on Breast Cancer Black cohosh, Actaea racemosa L. (= Cimicifuga racemosa), is a North American perrenial in the buttercup family (Ranunculaceae) used for various women’s health conditions. Black cohosh, also known as baneberry, black snakeroot, squaw root, bugbane, rattleweed and rattleroot, grows in Eastern North America, from southern Maine to Georgia. The roots and rhizomes were used by Native Americans for a variety of purposes that include inflammatory conditions, stimulation of menstrual flow, dysmenorrhea, suppression of cough, treatment of diarrhea, and rheumatism. The part of the plant used is the rhizome and root. The rhizome contains a complex mixture of chemicals including triterpene glycosides, aromatic acids, cinnamic acid esters, sugars, tannins and long-chain fatty acids. Knowledge about black cohosh reached Europe, where it has been prescribed by physicians, and also examined in clinical studies for menopausal symptoms for more than 50 years. Currently, black cohosh is in a clinical trial for the treatment of menopausal hot flashes, as well as assessment of cognitive function and bone metabolism. American women are increasingly turning to black cohosh as a ‘more natural’ alternative to estrogen, in the belief that it has the benefits, without the risks of estrogen therapy. There is, however, no definitive information on whether black cohosh inhibits or enhances breast cancer. Therefore, research is needed to clarify whether black cohosh extract stimulates or inhibits breast cancer cells. Women with breast cancer require answers to these questions as they seek safe treatments for disturbing symptoms. In preliminary studies we found that crude extracts of black cohosh inhibit, rather than stimulate, the growth of both estrogen receptor (ER) positive and ER-negative/Her-2 positive human breast cancer cell lines. These promising results suggest that black cohosh may contain specific components that might be effective in the prevention and/or treatment of breast cancer. The overall objective of this project is to identify these specific chemicals and also the mechanisms by which they inhibit breast cancer cells. Partially purified extracts and specific chemicals including triterpene glycosides will be examined for their abilities alone and in combination with chemotherapy agents to inhibit growth, arrest the cell cycle and cause apoptosis (programmed cell death) in Her-2 overexpressing human breast cancer cell lines. The most active components will then be studied for their effects on the function of specific molecules that control cell growth, the cell cycle, apoptosis and the function of the ER and Her-2 receptor. Since preliminary results indicate that black cohosh constituents induce changes at the transcriptional level, the effects of components from black cohosh on gene expression profiles will be determined using complementary DNA microarrays. We are hopeful that this research project will identify novel naturally occurring compounds that might be effective, alone or in combination with other medicines, in breast cancer prevention and treatment. Future studies could involve clinical trials on women who are at high risk of developing breast cancer and also on women who have already developed breast cancer, in collaboration with clinicians.