A Combination of Curcumin with Either Gramicidin or Ouabain Selectively Kills Cells That Express the Multidrug Resistance-linked ABCG2 Transporter |
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Authors: | Divya K. Rao Haiyan Liu Suresh V. Ambudkar Michael Mayer |
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Affiliation: | From the Departments of ‡Biomedical Engineering and ;¶Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109 and ;the §Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 |
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Abstract: | This paper introduces a strategy to kill selectively multidrug-resistant cells that express the ABCG2 transporter (also called breast cancer resistance protein, or BCRP). The approach is based on specific stimulation of ATP hydrolysis by ABCG2 transporters with subtoxic doses of curcumin combined with stimulation of ATP hydrolysis by Na+,K+-ATPase with subtoxic 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 the current knowledge on ABCG2-mediated CS and provides a potential strategy for discovery of CS drugs against drug-resistant cancer cells. |
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Keywords: | ABC Transporter ATPase Drug Resistance Drug Transport Na+ K+-ATPase ABCG2 Transporter Collateral Sensitivity Curcumin Gramicidin A Ouabain |
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