MRP1-dependent Collateral Sensitivity of Multidrug-resistant Cancer Cells: Identifying Selective Modulators Inducing Cellular Glutathione Depletion

Title:MRP1-dependent Collateral Sensitivity of Multidrug-resistant Cancer Cells: Identifying Selective Modulators Inducing Cellular Glutathione Depletion

Volume: 24 Issue: 12

Author(s): Doriane Lorendeau, Lauriane Dury, Rachad Nasr, Ahcene Boumendjel, Elisabetta Teodori, Michael Gutschow, Pierre Falson, Attilio Di Pietro and Helene Baubichon-Cortay*

Affiliation:

• Drug Resistance and Membrane Proteins, UMR 5086 CNRS/Université Lyon 1, Molecular Microbiology and Structural Biochemistry, IBCP, 7 passage du Vercors, 69367 Lyon,France

Keywords: ABCC1/MRP1, multidrug resistance protein 1, glutathione, collateral sensitivity, drug design, flavonoids, molecular models, multidrug resistance, Quantitative Structure-Activity Relationships.

Abstract: Cancer cells are permanently being selected for survival and proliferation. During this process, tumor cells often co-opt basic physiological mechanisms to protect themselves from toxic chemotherapy. One of these mechanisms is the overexpression of ATP-binding cassette (ABC) drug efflux pumps leading to multidrug resistance (MDR) of cancer cells through an increase of drug efflux. In the past 20 years, many efforts were done to circumvent MDR through the inhibition of ABC transporters. A number of inhibitors of these transporters were found but are rarely specific or rationally developed. Beside this approach, a new therapeutic strategy towards eradicating drug resistant tumor cells has recently emerged from the observation that cancer cells expressing a high level of these pumps show an unexpected hypersensitivity, called collateral sensitivity (CS) to a selected subset of chemical compounds. In this review, we target the multidrug resistance protein 1 (MRP1) and after a non-exhaustively highlighting of some of the most exemplary inhibitors of MRP1 and modulators of its expression, we focus on CS agents specifically targeting MRP1 which becomes, when overexpressed, the so called "Achilles' heel" of multidrug resistant cancer cells. We discuss the link between the prominent role of glutathione translocation and related redox balance of the cell and the CS induced by certain types of compounds. The latter are discussed according to their chemical class, and perspectives in their development for successful eradication of resistant cancer are proposed.

Cite this article as:

Lorendeau Doriane, Dury Lauriane, Nasr Rachad, Boumendjel Ahcene, Teodori Elisabetta, Gutschow Michael, Falson Pierre, Di Pietro Attilio and Baubichon-Cortay Helene*, MRP1-dependent Collateral Sensitivity of Multidrug-resistant Cancer Cells: Identifying Selective Modulators Inducing Cellular Glutathione Depletion, Current Medicinal Chemistry 2017; 24 (12) . https://dx.doi.org/10.2174/0929867324666161118130238