ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma
ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma
复制标题
DOI：
10.1158/0008-5472.can-04-3327
复制
发表时间：
2005-05-15
期刊：
影响因子：
11.2
通讯作者：
Frank, MH
中科院分区：
文献类型：
--
作者：
Frank, NY;Margaryan, A;Frank, MH
由ABCB1 P -糖蛋白及相关ATP结合盒转运体介导的药物外排增强是多药耐药的几种机制之一，这种耐药机制被认为会影响人类癌症化疗的成功。在恶性黑色素瘤中，其对化疗耐药的潜在作用尚不明确。在此，我们发现ABCB5在生理性皮肤祖细胞中作为膜电位的决定因素和细胞融合的调节因子发挥作用，它在临床恶性黑色素瘤肿瘤中表达，并在恶性黑色素瘤培养物和临床黑色素瘤中优先标记出一部分超极化的、表达CD133(+)干细胞表型的肿瘤细胞。我们发现ABCB5阻断显著逆转了G3361黑色素瘤细胞对阿霉素的耐药性，临床发现黑色素瘤对阿霉素具有耐药性，ABCB5阻断使阿霉素的半数致死量（LD50）从4 μmol/L降低到2.3 μmol/L，降低了43%（P < 0.05）。我们的研究结果确定ABCB5介导的阿霉素外排转运是耐药的潜在机制，因为ABCB5阻断显著增加了细胞内药物的积累。与ABCB5在阿霉素耐药中的这种新功能和机制相一致，美国国家癌症研究所用于药物筛选的一组人类癌细胞系中该转运体的基因表达水平与肿瘤对阿霉素的耐药性显著相关（r = 0.44；P = 0.016）。我们的研究结果确定ABCB5是人类恶性黑色素瘤中一种新的药物转运体和化疗耐药介导因子。此外，我们的研究结果表明，ABCB5是黑色素瘤群体中一部分具有化疗耐药性、表达干细胞表型的肿瘤细胞的一种新型分子标记，并且表明可以通过ABCB5特异性地靶向这些化疗耐药细胞以提高细胞毒效应。
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 mu mol/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.