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Mechanisms of Mult-Drug Resistance in Breast Cancer Chemotherapy
Multi-drug resistance (MDR) is characterized in tumor cells by resistance to chemotherapeutics and cross-resistance to structurally and mechanistically unrelated drugs. This resistance may occur by a variety of mechanisms including enhanced expression of the ATP binding cassette transporter proteins (transporters) in tumor cells. To overcome MDR, new agents are being sought that can repress transporter expression. Such agents may include phytochemicals or botanicals (P/B). There has been a dramatic increase in the use of P/B by cancer patients who often combine herbal remedies with chemotherapeutics. This combination can alter the efficacy of therapeutics. Altered efficacy may result from increased or decreased expression of drug transporters. P/B that enhance expression of transporters should be avoided during chemotherapy whereas those P/B that repress expression of transporters, may be beneficial in overcoming MDR. Thus, the overall goals of this proposal are to identify commonly used P/B that can overcome or prevent MDR and those that should be avoided during chemotherapy. Studies in specific aim 1 are designed to identify P/B that induce or repress the transporters in the human breast cancer cell line, MCF7. These cells express the transporters, P-glycoprotein (Pgp), the multi-drug resistance associated protein (MRP) 1 and the BCRP (MXR) transporter. I will investigate the effects of P/B on transporter expression in both sensitive and resistant cells and in those cells developing resistance. Studies described in this aim will focus primarily on P/B often used in conjunction with anti-neoplastic agents and those found to alter transporter function. Following treatment of cells with these P/B, transporter mRNA and protein levels will be assessed by quantitative RT-PCR and immunoblot analysis, respectively. In specific aim 2, I will determine transporter activity altered by P/B and the effects of this alteration on chemotherapeutic outcome. These experiments will include measuring the accumulation of chemotherapeutic agents in MCF7 cells exhibiting MDR and those cells that are sensitive to anti-neoplastics. I will also determine if P/B can directly inhibit or stimulate transporter activity and enhance cellular accumulation of chemotherapeutics. Collectively, I will identify P/B that alter drug accumulation and determine the role of these agents in this impediment to successful chemotherapy of breast cancer.
Cancer cells are able to adapt to drug exposure. In cancer treatment, this adaptation results in tumors that are resistant to chemotherapy, a primary obstacle to successful therapy. Cancer cells often develop resistance not only to the drug that they have been exposed but also to other drugs, a phenomenon known as multidrug resistance (MDR). MDR occurs when there is an increase in export of the drug from the cell. The required pumping action out of the cell is commonly mediated through proteins called transporters. When these transporters are overactive, drug concentrations within the cancer cell are minimized. Thus, drug resistance hampers successful chemotherapy. Studies described here will focus on increased or decreased drug expulsion due to altered expression of transporters. There has been an intense search for compounds, including natural products, that can reverse resistance in several cancers including breast cancer. The use of botanicals, herbals and dietary supplements in the United States has experienced unprecedented growth over the past few years especially in patients with cancers. Such patients frequently use botanicals along with conventional therapeutics. The combination of herbals and anti-neoplastics may be beneficial or harmful. The use of certain botanicals might overcome cell resistance to chemotherapy and conceivably increase the efficacy of anti-neoplastics. Conversely, some botanicals may increase transporter activity adding to MDR caused by chemotherapeutics. Thus, I propose to identify herbals that can either enhance or repress transporter expression in a human breast tumor cell line. I hypothesize that herbals with the capacity to repress transporter expression in these cells will be beneficial for overcoming MDR during chemotherapy of breast cancer. I will also identify herbals that increase expression or stimulate activity of these transporters, fostering the development of resistance. Moreover, I will determine the effects of altered transporter activity by botanicals on the outcome of chemotherapy. The culmination of these investigations will demonstrate which herbals are beneficial in treating breast cancer by preventing resistance to chemotherapeutics. The ability to circumvent or prevent drug resistance through the use of botanicals will improve chemotherapy and increase the chances for survival.