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MRP1-dependent Collateral Sensitivity of Multidrug-resistant Cancer Cells: Identifying Selective Modulators Inducing
Doriane Lorendeau1, Lauriane Dury1, Rachad Nasr1
1Drug Resistance and Membrane Proteins, UMR 5086 CNRS/Université Lyon 1, Molecular Microbiology and Structural Biochemistry, IBCP, 7 passage du Vercors, 69367 Lyon. France.
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.
Insights
Cancer cells develop multidrug resistance (MDR) via drug efflux pumps. Targeting these pumps, particularly multidrug resistance protein 1 (MRP1), with collateral sensitivity (CS) agents offers a new strategy against resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cancer cells develop multidrug resistance (MDR) by overexpressing ATP-binding cassette (ABC) drug efflux pumps, hindering chemotherapy efficacy.
- Traditional strategies to overcome MDR by inhibiting ABC transporters have yielded limited success due to a lack of specificity.
- A novel approach, collateral sensitivity (CS), exploits the hypersensitivity of drug-resistant cancer cells to specific compounds.
Purpose of the Study:
- To review inhibitors and modulators of multidrug resistance protein 1 (MRP1).
- To focus on collateral sensitivity (CS) agents that specifically target MRP1 in resistant cancer cells.
- To explore the role of glutathione translocation and cellular redox balance in CS.
Main Methods:
- Review of existing literature on MRP1 inhibitors and CS agents.
- Analysis of the chemical classes of CS compounds targeting MRP1.
- Discussion of the link between glutathione transport, redox balance, and CS.
Main Results:
- Multidrug resistance protein 1 (MRP1) overexpression can be exploited as an "Achilles' heel" in resistant cancer cells.
- Certain chemical compounds induce collateral sensitivity (CS) in MRP1-overexpressing cells.
- Glutathione translocation and cellular redox state are implicated in the mechanism of CS.
Conclusions:
- Collateral sensitivity (CS) agents targeting MRP1 represent a promising therapeutic strategy for overcoming multidrug resistance (MDR) in cancer.
- Understanding the role of glutathione and redox balance is crucial for developing effective CS-based therapies.
- Further development of CS agents holds potential for eradicating resistant tumors.
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