A Combination of Curcumin with either Gramicidin or Ouabain Selectively Kills Cells that Express the Multidrug Resistance-linked ABCG2 Transporter [Membrane Biology]
September 24th, 2014 by Rao, D. K., Liu, H., Ambudkar, S. V., Mayer, M.
This paper introduces a strategy to kill selectively multidrug resistant 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 gramicidin A or ouabain. After 72 h of incubation with the drug combinations, the resulting overconsumption of ATP by both pathways inhibits the efflux activity of ABCG2 transporters, leads to depletion of intracellular ATP levels below the viability threshold, and kills resistant cells selectively over cells that lack ABCG2 transporters. This strategy, which was also tested on a clinically relevant human breast adenocarcinoma cell line (MCF-7/FLV1), exploits the overexpression of ABCG2 transporters and induces caspase-dependent apoptotic cell death selectively in resistant cells. This work thus introduces a novel strategy to exploit collateral sensitivity (CS) with a combination of two clinically used compounds that, individually, do not exert CS. Collectively, this work expands current knowledge on ABCG2-mediated CS and provides a potential strategy for discovery of CS drugs against drug-resistant cancer cells.