Chemotherapy is an essential part of anticancer treatment. However, the overexpression of P-glycoprotein (P-gp) and the subsequent emergence of multidrug resistance (MDR) hampers successful treatment clinically. P-gp is a multidrug efflux transporter that functions to protect cells from xenobiotics by exporting them out from the plasma membrane to the extracellular space. P-gp inhibitors have been developed in an attempt to overcome P-gp-mediated MDR; however, lack of specificity and dose limiting toxicity have limited their effectiveness clinically. Recent studies report on accessory proteins that either directly or indirectly regulate P-gp expression and function and which are necessary for the establishment of the functional phenotype in cancer cells. This review discusses the role of these proteins, some of which have been recently proposed to comprise an interactive complex, and discusses their contribution towards MDR. We also discuss the role of other pathways and proteins in regulating P-gp expression in cells. The potential for these proteins as novel therapeutic targets provides new opportunities to circumvent MDR clinically.
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