Low Doses of a Combination of Curcumin with Ouabain or Gramicidin Selectively Kill Cancer Cells that Express the Multidrug Resistance-Linked ABCG2 Transporter

Abstract

The work presented here introduces a strategy to kill selectively multidrug resistant (MDR) cancer cells that express the ABCG2 transporter (also called breast cancer resistance protein, BCRP). The approach is based on specific stimulation of ATP hydrolysis by ABCG2 transporters with sub-toxic doses of curcumin combined with stimulation of ATP hydrolysis by the Na+ K+ ATPase with sub-toxic doses of ouabain or gramicidin A. The resulting over-consumption of ATP by both pathways inhibits the efflux activity of ABCG2 transporters and leads to depletion of intracellular ATP levels below the viability threshold. In contrast, cells without the ABCG2 transporter lack one pathway and maintain viability at basal ATP levels. Similar results were obtained with a clinically relevant human breast adenocarcinoma cell line that expresses ABCG2 transporters (MCF-7/FLV1) and its parental cell line (MCF-7). This strategy, which is based on compounds that are currently in clinical use, exploits the overexpression of ABCG2 transporters in cancer cells by accelerating their ATP hydrolysis rate to kill selectively those cells which are particularly resistant to conventional chemotherapy. This work introduces a novel strategy to exploit collateral sensitivity (CS) with a combination of two compounds that, individually, do not exert CS. It also demostrates that the mechanism for CS is necrotic cell death induced by depletion of ATP below 50% of basal intracellular levels. Since ABCG2 transporters are a putative marker for cancer stem cells (CSCs), this approach may allow targeting CSCs.