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

Amila K Nanayakkara,Pia D Vogel,John G Wise,Jed N Lampe

doi:10.1371/journal.pone.0217940

Amila K Nanayakkara, Pia D Vogel + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0217940

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Journal: PloS one	Publication Date: Jun 7, 2019
Citations: 15	License type: CC BY 4.0

Affiliation: Southern Methodist University

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.

Highlights

Chemotherapy treatments are often part of cancer therapies, either before surgery to decrease the size of existing tumors, or after surgery to target metastatic cells that may have migrated out of the primary site of the disease
We show here in a multidrug resistant cancer cell line that over-expresses P-gp, that the continued presence of an inhibitor of P-glycoprotein after a short exposure of the cells to chemotherapeutic in the presence of the inhibitor, and the subsequent removal of the chemotherapeutic from the medium in the presence of the inhibitor, significantly increases the effectiveness of the therapy
In experiments aimed at investigating whether the rate of release of chemotherapeutic drugs from multidrug resistant human prostate cancer cells was affected by the continued presence

Summary

Introduction

Chemotherapy treatments are often part of cancer therapies, either before surgery to decrease the size of existing tumors, or after surgery to target metastatic cells that may have migrated out of the primary site of the disease. For cancers that are not surgically accessible, chemotherapy is often the only treatment option. Some of these therapies can be remarkably effective, but many cancers recur after initial, seemingly successful treatments and still others do not respond well to chemotherapies [1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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