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ABCB5-Mediated Doxorubicin Transport and Chemoresistance in Human Malignant Melanoma

¹ Department of Genetics, Children's Hospital Boston and ² Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts; ³ Program in Pharmacogenomics, Department of Pharmacology, The Ohio State University, Columbus, Ohio; and ⁴ Department of Surgery, University of Würzburg Medical School, Würzburg, Germany

Requests for reprints: Markus H. Frank, Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, 75 Francis Street, Boston, MA 02115. Phone: 617-919-2993; Fax: 617-730-0129; E-mail: mfrank{at}rics.bwh.harvard.edu.

Enhanced drug efflux mediated by ABCB1 P-glycoprotein and related ATP-binding cassette transporters is one of several mechanisms of multidrug resistance thought to impair chemotherapeutic success in human cancers. In malignant melanoma, its potential contribution to chemoresistance is uncertain. Here, we show that ABCB5, which functions as a determinant of membrane potential and regulator of cell fusion in physiologic skin progenitor cells, is expressed in clinical malignant melanoma tumors and preferentially marks a subset of hyperpolarized, CD133⁺ stem cell phenotype-expressing tumor cells in malignant melanoma cultures and clinical melanomas. We found that ABCB5 blockade significantly reversed resistance of G3361 melanoma cells to doxorubicin, an agent to which clinical melanomas have been found refractory, resulting in a 43% reduction in the LD₅₀ from 4 to 2.3 µmol/L doxorubicin (P < 0.05). Our results identified ABCB5-mediated doxorubicin efflux transport as the underlying mechanism of resistance, because ABCB5 blockade significantly enhanced intracellular drug accumulation. Consistent with this novel ABCB5 function and mechanism in doxorubicin resistance, gene expression levels of the transporter across a panel of human cancer cell lines used by the National Cancer Institute for drug screening correlated significantly with tumor resistance to doxorubicin (r = 0.44; P = 0.016). Our results identify ABCB5 as a novel drug transporter and chemoresistance mediator in human malignant melanoma. Moreover, our findings show that ABCB5 is a novel molecular marker for a distinct subset of chemoresistant, stem cell phenotype-expressing tumor cells among melanoma bulk populations and indicate that these chemoresistant cells can be specifically targeted via ABCB5 to enhance cytotoxic efficacy.

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