Chemotherapy remains the principal mode of cancer treatment. Unfortunately, the """"""""intrinsic"""""""" and """"""""acquired"""""""" multidrug resistance (MDR) of cancer cells limits the success of chemotherapeutic treatment of cancers. """"""""Acquired"""""""" MDR indicates the fact that some cancers, such as breast, ovarian cancer, non-Hodgkin's lymphoma, adult acute leukemias and numerous childhood cancers, initially respond well to the chemotherapeutic treatment, but eventually become MDR during the treatment, reflecting different mechanisms from that of the """"""""intrinsic"""""""" MDR. Over-expression of P-glycoprotein, breast cancer resistant protein and/or multidrug resistance-associated protein (MRP1) confers """"""""acquired"""""""" MDR. Although all these ATP binding cassette (ABC) transporters transport anticancer drugs in an ATP dependent manner, different underlying mechanisms are involved. In addition, over-expression of these ABC transporters may not be the only reason to cause the """"""""acquired"""""""" MDR. For example, over-expression of MRP1 decreases drug accumulation inside a cancer cell and results in MDR, whereas over-expression of Bcl-2 alters apoptosis pathways and results in decreased sensitivity to anticancer drugs. Thus, there might not be a simple solution to solve the """"""""acquired"""""""" MDR caused by different mechanisms. A plausible strategy to reverse MDR is to understand the mechanism of each MDR, to treat each MDR individually and then to deal with MDR caused by multiple mechanisms globally. The objective proposed in this project is to elucidate the mechanism of ATP dependent solute transport by MRP1.
Specific aims i nvolved in this project are: 1. To test our hypothesis that ATP hydrolysis at NBD1 may not be essential for the ATP-dependent solute transport by MRP1; 2. To test whether or not the conformational changes induced by nucleotide binding at NBD1 and NBD2 are sufficient to transport the solute across the plasma membrane; 3. To test our hypothesis that nucleotide release from both NBDs facilitates the MRP1 protein to start a new cycle of ATP-dependent solute transport; 4. To determine the relationship between Km (ATP), Vmax (LTC4) and the drug resistance. New insights gained from these aims may provide the basis for novel means of combating MDR associated with over-expression of MRP1. ? ? ?
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