ABSTRACT
P-glycoprotein (P-gp; also known as MDR1 and ABCB1) being the first identified ABC (ATP [adenosine triphosphate]-binding cassette) transporter utilizes the energy of ATP hydrolysis to transport a broad range of substrates, including anticancer agents, across biological membranes against concentration gradients. It has the ability to confer multidrug resistance (MDR) in various types of cancer cells. Its expression is often associated with adverse prognosis of patients and is supposed to be a major obstacle limiting the therapeutic efficacy of cancer chemotherapy. Hence, intensive efforts have been made to search for specific and high-affinity inhibitors that could antagonize their action and overcome MDR in the clinic. Development of the first-generation (G1) P-gp inhibitors (e.g., verapamil, cyclosporine A etc.), second-generation (G2) P-gp inhibitors (e.g., Valspodar and Biricodar etc.), and third-generation (G3) P-gp inhibitors (e.g., Tariquidar and CBT-1 etc.) have been limelighted as cancer chemotherapeutics at clinic outset. This chapter provides a better understanding and advances in the development of P-gp inhibitors to reverse MDR. The problems highlighted by off-site effects, the inhibition of the normal function of ABCB1 transporters in healthy tissue, and the need for combinatorial therapies, have prompted the development of nanotechnology-based targeting strategies.
