A role for P-glycoprotein in regulating cell growth and survival

Abstract

Multidrug resistance (MDR) mediated by the adenosine triphosphate (ATP)-dependent drug efflux protein P-glycoprotein (P-gp), is a major obstacle to the successful treatment of cancer. P-gp is expressed in many types of cancers and the clinical success of chemotherapeutic treatment often correlates inversely with the level of P-gp expression. P-gp is a 170–180 kD cell-surface transporter protein and has historically been thought to confer resistance to chemotoxins by actively effluxing them from the cell. While there is little doubt that P-gp plays an important role as an efflux pump in conferring multidrug resistance, new evidence is mounting to suggest that in addition, P-gp may act as a general anti-apoptotic protein to increase the threshold for cell death. Effectively, P-gp may protect cells at two levels, firstly by decreasing the amount of toxins that accumulate in the cell, and secondly by blocking apoptotic pathways induced by toxins and cellular stress. Understanding how P-gp can regulate cell death could lead to novel therapies for the treatment of MDR tumors.