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Multiple Flavonoids in the Treatment of Multidrug Resistance
Drug resistance is the main cause for therapeutic failure and death in breast cancer. One mechanism of multidrug resistance (MDR) which has been extensively characterized is the overexpression of the ATP binding cassette (ABC) proteins including P-glycoprotein ( P-gp ), Multidrug Resistance Associated Protein 1 (MRP1) and Breast Cancer Resistance Protein (BCRP) in cancer cells. The most widely-used combination chemotherapy regimens for breast cancer include substrates for these ABC proteins as either first-line or second-line treatments. We propose the use of a new class of drugs, the flavonoids, as MDR inhibitors. Flavonoids are present in fruits, vegetables and plant-derived beverages and present in a wide range of herbal dietary supplements. They are of particular interest due to their lack of toxicity and their cancer preventive properties. We have identified a number of flavonoids as inhibitors of all three ABC proteins and found in in vitro studies that flavonoids have additive or synergistic effects on the efflux of the chemotherapeutic agent mitoxantrone by BCRP. We will test the hypothesis that the administration of multiple flavonoids results in additive or synergistic effects on the reversal of multidrug resistance in breast cancer due to pharmacokinetic and/or pharmacodynamic interactions. The specific aims of this research are to characterize the effects of individual flavonoids and combinations of multiple flavonoids (1) on the cellular accumulation and cytotoxicity of chemotherapeutic agents (including vinblastine and mitoxantrone) in cell lines overexpressing P-gp or BCRP and (2) on the blood concentrations and efficacy of chemotherapeutic agents in animal models. Studies will determine if interactions are pharmacokinetic in mechanism by examining the concentrations and disposition of two flavonoids when administered alone or in combination in both cell and in vivo studies. The identification of potent and nontoxic MDR reversal therapies will result in decreased treatment failure and death in breast cancer patients.
Flavonoids are present in fruits, vegetables and beverages derived from plants (tea, red wine), and in many dietary supplements or herbal remedies including Ginkgo biloba, St. John’s wort, Soy isoflavones, and Milk thistle. Flavonoids have been described as health-promoting, disease-preventing dietary supplements, and have activity as cancer preventive agents. We have recently found that certain dietary flavonoids can increase the sensitivity of cells to anthracyclines such as doxorubicin (adriamycin), the most active single chemotherapeutic agent used in breast cancer treatment, as well as other anticancer drugs including vinca alkaloids, mitoxantrone and topotecan. Drug resistance, which is present at diagnosis or develops after drug treatment, is the most common cause of treatment failure and death in breast cancer. Therefore, flavonoids may represent a new class of drugs that can overcome the resistance to doxorubicin and other chemotherapeutic agents in breast cancer. We have found that flavonoids used in combination in cell studies can have additive or synergistic effects in reversing drug resistance. The overall objective of this research is to determine the effect of combinations of multiple flavonoids on the concentrations, effectiveness and toxicity of chemotherapeutic agents. Our hypothesis is that low doses of multiple flavonoids, used in combination, will provide increased efficacy in reversing drug resistance, without toxicity. These studies will provide information about a new type of therapy that may reverse the resistance to chemotherapy in breast cancer cells, resulting in decreased treatment failure and death in women with breast cancer.