ABCB5-Mediated Doxorubicin Transport and Chemoresistance in Human Malignant Melanoma

Abstract

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 phenotypeexpressing 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 LD 50 from 4 to 2.3 Mmol/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. (Cancer Res 2005; 65(10): 4320-33)

Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma

“…21 Several mechanisms are involved in CSC chemoresistance, including the expression of the ATP-binding cassette superfamily of active drug transporters. 22 Members of this transmembrane superfamily act as unidirectional cellular pumps and have been linked with multidrug resistance. Resistance to anticancer drugs could be attributed to the reduced levels of drug accumulation within CSCs.…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…Moreover, these CD20-enriched cells could be induced to differentiate toward multiple lineages, including melanocyte, adipocyte, osteoblast, and chondrocyte, suggesting the presence of such a subpopulation with a stem cell phenotype (Fang et al 2005). Separately, Frank and colleagues identified a subpopulation of melanoma cells with expression of a drug efflux transporter ABCB5 and showed that this subpopulation was enriched for the CD133+ (stem cell marker-enhanced) fraction (Frank et al 2005). Interestingly, ABCB5 expression was associated with resistance to adriamycin treatment, and correspondingly, ABCB5 blockade resulted in adriamycin accumulation and enhanced drug sensitivity.…”

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

“…Increased cisplatin resistance in CD133 þ ovarian cancer cells Cancer stem cells, including those that are CD133 þ , may possess inherent resistance to chemotherapeutic CD133 þ cells in ovarian cancer T Baba et al agents (Frank et al, 2005;Lobo et al, 2007). Platinum drugs are commonly used as first-line therapeutic agents in treating ovarian cancer.…”