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Research Articles: Therapeutics, Targets, and Development

Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance–linked ABCG2 transporter

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Suresh V. Ambudkar, National Cancer Institute Building 37, Room 2120, MSC 4256, 37 Convent Drive, Bethesda, MD 20892-4256. Phone: 301-402-4178; Fax: 301-435-8188. E-mail: ambudkar{at}helix.nih.gov

Abstract

Multidrug resistance due to reduced drug accumulation is a phenomenon predominantly caused by the overexpression of members of the ATP-binding cassette (ABC) transporters, including ABCB1 (P-glycoprotein), ABCG2, and several ABCC family members [multidrug resistance–associated protein (MRP)]. We previously reported that a thiosemicarbazone derivative, NSC73306, is cytotoxic to carcinoma cells that overexpress functional P-glycoprotein, and it resensitizes these cells to chemotherapeutics. In this study, we investigated the effect of NSC73306 on cells overexpressing other ABC drug transporters, including ABCG2, MRP1, MRP4, and MRP5. Our findings showed that NSC73306 is not more toxic to cells that overexpress these transporters compared with their respective parental cells, and these transporters do not confer resistance to NSC73306 either. In spite of this, we observed that NSC73306 is a transport substrate for ABCG2 that can effectively inhibit ABCG2-mediated drug transport and reverse resistance to both mitoxantrone and topotecan in ABCG2-expressing cells. Interactions between NSC73306 and the ABCG2 drug-binding site(s) were confirmed by its stimulatory effect on ATPase activity (140–150 nmol/L concentration required for 50% stimulation) and by inhibition of [¹²⁵I]iodoarylazidoprazosin photolabeling (50% inhibition at 250–400 nmol/L) of the substrate-binding site(s). Overall, NSC73306 seems to be a potent modulator of ABCG2 that does not interact with MRP1, MRP4, or MRP5. Collectively, these data suggest that NSC73306 can potentially be used, due to its dual mode of action, as an effective agent to overcome drug resistance by eliminating P-glycoprotein–overexpressing cells and by acting as a potent modulator that resensitizes ABCG2-expressing cancer cells to chemotherapeutics. [Mol Cancer Ther 2007;6(12):3287–96]

Grant support: Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research and National Institute of General Medical Sciences Pharmacology Research Associate Program (A.M. Calcagno).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 8/28/07; accepted 10/23/07.