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Research Articles: Therapeutics

Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway

¹ Department of Radiation Oncology, Dana-Farber Cancer Institute; ² Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute/Boston Children's Hospital, Harvard Medical School; ³ Division of Gynecologic Oncology, Massachusetts General Hospital Cancer Center; and ⁴ Division of Hematology Oncology, Massachusetts General Hospital, Boston, Massachusetts

Requests for reprints: Alan D. D'Andrea, Dana-Farber Cancer Institute, Department of Radiation Oncology, Harvard Medical School, 44 Binney Street, Boston, MA 02115. Phone: 617-632-2112; Fax: 617-632-5757. E-mail: alan_dandrea{at}dfci.harvard.edu

Abstract

Cisplatin resistance occurs, at least in part, through the function of the Fanconi anemia (FA)/BRCA pathway, a DNA-damage response pathway required for repair of cisplatin cross-links. In the current study, we designed a cell-based screening strategy to identify small-molecule inhibitors of the FA/BRCA pathway with the hypothesis that such molecules could restore sensitivity to platinum agents. We identified four inhibitors, including three protein kinase inhibitors (wortmannin, H-9, and alsterpaullone) and one natural compound (curcumin) that inhibit the FA/BRCA pathway. We show that curcumin, a compound that is generally regarded as safe, inhibits the monoubiquitination of the FANCD2 protein as predicted by the screen and consequently sensitizes ovarian and breast tumor cell lines to cisplatin through apoptotic cell death. We believe that this study shows an efficient, high-throughput method for identifying new compounds that may sensitize cancer cells to DNA-damaging chemotherapy. [Mol Cancer Ther 2006;5(4):952–61]

Grant support: NIH grants RO1HL52725, RO1 DK43889, P0150654, P50 CA105009-01, and PO1HL54785 (A.D. D'Andrea); Dana Farber/Harvard Cancer Center Ovarian Specialized Programs of Research Excellence (M.V. Seiden); Doris Duke Charitable Foundation (A.D. D'Andrea and M.V. Seiden); and Susan G. Komen Breast Cancer Foundation (R. Kennedy).

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.

Note: The current address for T. Taniguchi is Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024.

⁵ http://iccb.med.harvard.edu.

Received 11/28/05; revised 1/31/06; accepted 2/21/06.