title: A combination of curcumin with either gramicidin or ouabain selectively kills cells that express the multidrug resistance-linked ABCG2 transporter.
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.
authors.affiliation: From the Departments of Biomedical Engineering and.
authors.forename: Divya K
authors.initials: DK
authors.lastname: Rao
authors.affiliation: From the Departments of Biomedical Engineering and.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: the Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.affiliation: From the Departments of Biomedical Engineering and Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109 and mimayer@umich.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Mayer
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry*; D000968:Antimycin A / Q000737:chemistry; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D003474:Curcumin / Q000737:chemistry*; D004338:Drug Combinations; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D006096:Gramicidin / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D061986:MCF-7 Cells; D008564:Membrane Potentials; D009336:Necrosis; D009363:Neoplasm Proteins / Q000737:chemistry*; D010042:Ouabain / Q000737:chemistry*; D018408:Patch-Clamp Techniques; D012402:Rotenone / Q000737:chemistry
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D004338:Drug Combinations; D009363:Neoplasm Proteins; D012402:Rotenone; D006096:Gramicidin; D010042:Ouabain; D000968:Antimycin A; D000255:Adenosine Triphosphate; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D003474:Curcumin
keywords: ABC Transporter; ABCG2 Transporter; ATPase; Collateral Sensitivity; Curcumin; Drug Resistance; Drug Transport; Gramicidin A; Na+,K+-ATPase; Ouabain