Prolonged inhibition of P-glycoprotein after exposure to chemotherapeutics increases cell mortality in multidrug resistant cultured cancer cells.

Abstract

One common reason for cancer chemotherapy failure is increased drug efflux catalyzed by membrane transporters with broad pump substrate specificities, which leads to resistances to a wide range of chemically unrelated drugs. This multidrug resistance (MDR) phenomenon results in failed therapies and poor patient prognoses. A common cause of MDR is over-expression of the P-glycoprotein (ABCB1/P-gp) transporter. We report here on an MDR modulator that is a small molecule inhibitor of P-glycoprotein, but is not a pump substrate for P-gp and we show for the first time that extended exposure of an MDR prostate cancer cell line to the inhibitor following treatment with chemotherapeutics and inhibitor resulted in trapping of the chemotherapeutics within the cancerous cells. This trapping led to decreased cell viability, survival, and motility, and increased indicators of apoptosis in the cancerous cells. In contrast, extended exposure of non-Pgp-overexpressing cells to the inhibitor during and after similar chemotherapy treatments did not lead to decreased cell viability and survival, indicating that toxicity of the chemotherapeutic was not increased by the inhibitor. Increases in efficacy in treating MDR cancer cells without increasing toxicity to normal cells by such extended inhibitor treatment might translate to increased clinical efficacy of chemotherapies if suitable inhibitors can be developed.