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Research Articles: Therapeutics

Modulation of the function of the multidrug resistance–linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin

¹ Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland and ² Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

Requests for reprints: Suresh V. Ambudkar, Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute/NIH, Department of Health and Human Services, Bethesda, MD 20892. Phone: 301-402-4178; Fax: 301-435-8188. E-mail: ambudkar{at}helix.nih.gov or Pornngarm Limtrakul, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Phone: 66-53-945-323; Fax: 66-53-894-031. E-mail: plimtrak{at}mail.med.cmu.ac.th

Curcumin (curcumin I), demethoxycurcumin (curcumin II), and bisdemethoxycurcumin (curcumin III) are the major forms of curcuminoids found in the turmeric powder, which exhibit anticancer, antioxidant, and anti-inflammatory activities. In this study, we evaluated the ability of purified curcuminoids to modulate the function of either the wild-type 482R or the mutant 482T ABCG2 transporter stably expressed in HEK293 cells and drug-selected MCF-7 FLV1000 and MCF-7 AdVp3000 cells. Curcuminoids inhibited the transport of mitoxantrone and pheophorbide a from ABCG2-expressing cells. However, both cytotoxicity and [³H]curcumin I accumulation assays showed that curcuminoids are not transported by ABCG2. Nontoxic concentration of curcumin I, II, and III sensitized the ABCG2-expressing cells to mitoxantrone, topotecan, SN-38, and doxorubicin. This reversal was not due to reduced expression because ABCG2 protein levels were unaltered by treatment with 10 µmol/L curcuminoids for 72 hours. Curcumin I, II, and III stimulated (2.4- to 3.3-fold) ABCG2-mediated ATP hydrolysis and the IC₅₀s were in the range of 7.5 to 18 nmol/L, suggesting a high affinity of curcuminoids for ABCG2. Curcuminoids also inhibited the photolabeling of ABCG2 with [¹²⁵I]iodoarylazidoprazosin and [³H]azidopine as well as the transport of these two substrates in ABCG2-expressing cells. Curcuminoids did not inhibit the binding of [-³²P]8-azidoATP to ABCG2, suggesting that they do not interact with the ATP-binding site of the transporter. Collectively, these data show that, among curcuminoids, curcumin I is the most potent modulator of ABCG2 and thus should be considered as a treatment to increase the efficacy of conventional chemotherapeutic drugs. [Mol Cancer Ther 2006;5(8):1995–2006]

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Note: W. Chearwae and S. Shukla contributed equally to this work.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁴ S. Shukla, W. Chearwae, and S.V. Ambudkar, unpublished data.

Received 2/16/06; revised 5/ 5/06; accepted 6/14/06.

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