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Antimicrobial Agents and Chemotherapy, August 2009, p. 3256-3265, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01497-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Curcumin Modulates Efflux Mediated by Yeast ABC Multidrug Transporters and Is Synergistic with Antifungals{triangledown}

Monika Sharma,1 Raman Manoharlal,1 Suneet Shukla,2 Nidhi Puri,1 Tulika Prasad,1,3 Suresh V. Ambudkar,2 and Rajendra Prasad1*

Membrane Biology Laboratory, School of Life Sciences,1 Advanced Instrumentation Facility, University Science Instrumentation Centre, Jawaharlal Nehru University, New Delhi 110 067, India,3 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 9 November 2008/ Returned for modification 12 February 2009/ Accepted 11 May 2009

Curcumin (CUR), a natural product of turmeric, from rhizomes of Curcuma longa, is a known agent of reversal of drug resistance phenotypes in cancer cells overexpressing ATP-binding cassette (ABC) transporters, viz., ABCB1, ABCG2, and ABCC1. In the present study, we evaluated whether CUR could also modulate multidrug transporters of yeasts that belong either to the ABC family or to the major facilitator superfamily (MFS). The effect of CUR on multidrug transporter proteins was demonstrated by examining rhodamine 6G (R6G) efflux in Saccharomyces cerevisiae cells overexpressing the Candida albicans ABC transporters Cdr1p and Cdr2p (CaCdr1p and CaCdr2p, respectively) and the MFS transporters CaMdr1p and S. cerevisiae Pdr5p. CUR decreased the extracellular concentration of R6G in ABC transporter-expressing cells but had no effect on methotrexate efflux mediated through the MFS transporter CaMdr1p. CUR competitively inhibited R6G efflux and the photolabeling of CaCdr1p by [125I]iodoarylazidoprazosin, a drug analogue of the substrate prazosin (50% inhibitory concentration, 14.2 µM). Notably, the mutant variants of CaCdr1p that displayed abrogated efflux of R6G also showed reduced modulation by CUR. Drug susceptibility testing of ABC protein-expressing cells by spot assays and checkerboard tests revealed that CUR was selectively synergistic with drug substrates such as R6G, ketoconazole, itraconazole, and miconazole but not with fluconazole, voriconazole, anisomycin, cycloheximide, or FK520. Taken together, our results provide the first evidence that CUR modulates only ABC multidrug transporters and could be exploited in combination with certain conventional antifungal drugs to reverse multidrug resistance in Candida cells.

* Corresponding author. Mailing address: Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110 067, India. Phone: 91-11-26704509. Fax: 91-11-26741081. E-mail: rp47{at}mail.jnu.ac.in

{triangledown} Published ahead of print on 26 May 2009.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3256-3265, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01497-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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