The Role of P-Glycoprotein (P-gp) in Cancer Multidrug Resistance (MDR): Challenges for Inhibiting P-gp in the Context of Overcoming MDR

Multidrug resistance (MDR), as is well known, is regarded as the primary factor in cancer therapy failure. A common mechanism of MDR in anticancer drugs is the expression of P-glycoprotein (P-gp), a class of ATP-dependent membrane transport efflux pumps called adenosine triphosphate (ATP)-binding cassette (ABC) transporters. It pumps xenobiotics outside the cell and plays part in typical physiological detoxification and host defense activities. This transporter is distributed in gastrointestinal mucosa epithelial cell surfaces, blood-tissue barriers, hepatic biliary epithelium, proximal tubules of the kidney, and the adrenal cortex. P-gp is known to be responsible for MDR because of its over-expression in malignant cells. It functions as an efflux pump lowering the concentration of drugs intracellularly, thus decreasing the effectiveness of cancer chemotherapy. Although using multiple anticancer medications is a good strategy, Cancerous cells are able to develop MDR. A number of chemically synthesized P-gp inhibitors were investigated to overcome MDR in clinical studies. Additionally, certain natural compounds have been observed to modulate P-gp. Numerous investigations on strategies to modulate MDR have been conducted as a result of the significant impact of chemotherapeutic drug resistance. This review discusses the role of P-gp in cancer MDR and challenges for inhibiting P-gp in the context of overcoming MDR mediated by P-gp. It is concluded that the discovery of selective, safe, and potent inhibitors of P-gp remains necessary.