Abstract
Multidrug resistance (MDR) is the main obstacle to current chemotherapy and it is mainly due to the overexpression of some efflux transporters such as MRP1. One of the most studied strategies to overcome MDR has been the inhibition of MDR pumps through small molecules, but its translation into the clinic unfortunately failed. Recently, a phenomenon called collateral sensitivity (CS) emerged as a new strategy to hamper MDR acting as a synthetic lethality, where the genetic changes developed upon the acquisition of resistance towards a specific agent are followed by the development of hypersensitivity towards a second agent. Among our library of sigma ligands acting as MDR modulators, we identified three compounds, F397, F400, and F421, acting as CS-promoting agents. We deepened their CS mechanisms in the “pure” model of MRP1-expressing cells (MDCK-MRP1) and in MRP1-expressing/drug resistant non-small cell lung cancer cells (A549/DX). The in vitro results demonstrated that (i) the three ligands are highly cytotoxic for MRP1-expressing cells; (ii) their effect is MRP1-mediated; (iii) they increase the cytotoxicity induced by cis-Pt, the therapeutic agent commonly used in the treatment of lung tumors; and (iv) their effect is ROS-mediated. Moreover, a preclinical in vivo study performed in lung tumor xenografts confirms the in vitro findings, making the three CS-promoting agents candidates for a novel therapeutic approach in lung resistant tumors.
Highlights
Drug resistance, either acquired or intrinsic, is the major hurdle in treating cancer by chemotherapy
collateral sensitivity (CS), that is, a sort of synthetic lethality according to which resistant tumor cells are selectively killed, appears as a promising therapeutic approach for the treatment of resistant tumors
Multidrug resistance (MDR) pump modulators may be endowed with CS properties
Summary
Either acquired or intrinsic, is the major hurdle in treating cancer by chemotherapy. Due to the impact of MRP1 overexpression in cancer development and drug resistance, and the increasing evidence of its role in CS [19,22,31,32], the aim of the study is the identification of new CS-promoting agents having as the target the MDR protein MRP1. With this in mind, we had to identify proper MRP1 inhibitors, first. The SR was measured as the EC50 of the MDCK cells/EC50 of the MDCK-MRP1 cells
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