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    Awarded Grants
    Interactions of Black Cohosh Extracts with Doxorubicin: Possible Mechanisms

    Scientific Abstract:
    Background: Black Cohosh (BC), an herbal medicine often used by breast cancer patients, was shown in our recent studies to produce a dramatic increase in the cytotoxicity of doxorubicin to breast cancer cells in vitro. Objective/hypothesis: Our objective is to determine the mechanism by which BC sensitizes cells to the cytotoxic effects of doxorubicin. Our hypothesis is that this reflects increased drug uptake or decreased drug efflux. Specific Aims: 1. To test whether the sensitization produced by BC reflects increased uptake or decreased efflux of doxorubicin. 2. If it does, to study the molecular mechanism underlying the change in uptake/efflux and to compare the effect of BC in drug sensitive and drug resistant breast cancer cells and in cell lines derived from critical normal tissues. 3. If sensitization does not reflect a change in uptake or efflux, to examine other possible mechanisms. Study design: Breast cancer cells in culture will be used to examine possible mechanisms by which BC could increase the cytotoxicity of doxorubicin. Our current data suggest that the effect is independent of the estrogenic/antiestrogenic effects of BC and does not reflect altered cell proliferation. We hypothesize that sensitization reflects an alteration of drug uptake or efflux; we will test this using standard techniques. If changes in uptake or efflux are found, we will examine the molecular mechanisms underlying the changes and will study the therapeutic implications of the changes using drug-sensitive and drug-resistant breast cancer cells and cells derived from heart and marrow. If sensitization does not reflect a change in uptake or efflux, we will examine other possible mechanisms, including alterations of drug metabolism or subcellular localization and changes in the repair of drug-induced damage. Potential Outcomes and Benefits of the Research: BC contains a component(s) that increases the cytotoxicity of doxorubicin. Understanding the mechanism for this interaction will increase our understanding of the clinical implications of BC use by cancer patients during therapy and will lead to studies that identify the active component(s) and assess whether it has potential value in cancer therapy.

    Lay Abstract:
    Background: Black Cohosh (BC) is an herbal medicine often used by breast cancer patients to treat menopausal symptoms, including those caused by therapy. Our recent studies showed that BC dramatically increased the ability of doxorubicin (Adriamycin) to kill breast cancer cells and slightly increased cell killing by docetaxel (Taxotere). Objective/hypothesis: Our objective is to determine the mechanism by which BC increases killing of breast cancer cells by doxorubicin. We hypothesize that BC increases drug uptake or decreases drug efflux. Specific Aims: 1. To test whether the sensitization produced by BC reflects a change in transport of drug into or out of the cell. 2. If it does, we will study the molecular mechanism by which this change occurs and will compare the effect in drug sensitive and drug resistant breast cancer cells and in cells derived from normal tissues which limit doxorubicin treatment. 3. If sensitization does not reflect a change in drug transport, we will examine other possible mechanisms of action. Study design: Breast cancer cells in culture will be used to examine possible mechanisms by which BC could increase cell killing by doxorubicin. The effect appears to be independent of the hormonal effects of BC and does not reflect changes in cell growth. We think it most likely reflects a change in the way cells take up or expel doxorubicin; we will test this. If drug transport is altered, we will study the molecular mechanisms by which this occurs. If not, we will examine other possible mechanisms, including changes in drug metabolism, localization of drug within cells, or repair of injury produced by the drug. We will examine the therapeutic implications of the changes using cancer cells and cells derived from the normal tissues that limit the intensity of treatment with doxorubicin. Potential Outcomes and Benefits: We will learn how BC increases the ability of doxorubicin to kill breast cancer cells. We will also better understand the implications of the use of BC extracts by patients with breast cancer: that is, whether BC or its active component(s) might be used in beneficial ways or whether they increase the toxicity of doxorubicin and are dangerous.