Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas
Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas
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DOI：
10.1073/pnas.0600213103
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发表时间：
2006-06-27
影响因子：
11.1
通讯作者：
Gottesman, Michael M.
中科院分区：
文献类型：
--
作者：
Chen, Kevin G.;Valencia, Julio C.;Gottesman, Michael M.
恶性黑色素瘤难治性的多药耐药机制在很大程度上仍然未知。在这项研究中，我们表明，黑色素瘤的多药耐药的发展涉及细胞内的细胞毒性药物，如顺二氨二氯铂II（顺铂，CDDP）的亚细胞隔离。CDDP最初被隔离在亚细胞细胞器如黑素体中，与非黑色素瘤/KB-3-1表皮样癌细胞相比，这显著降低了其核定位。CDDP的黑素体积累通过酪氨酸酶活性的显著增加显著调节黑素生成。改变的黑素生成表现出细胞内色素沉着和含CDDP的黑素体的细胞外转运增加约8倍。因此，我们的实验提供的证据表明，黑素体有助于通过螯合细胞毒性药物和增加黑素体介导的药物输出的黑色素瘤细胞的难治性。通过抑制黑素体的功能来防止细胞毒性药物的黑素体隔离可能具有很大的潜力，作为改善黑色素瘤细胞的化学敏感性的方法。
Multidrug resistance mechanisms underlying the intractability of malignant melanomas remain largely unknown. In this study, we demonstrate that the development of multidrug resistance in melanomas involves subcellular sequestration of intracellular cytotoxic drugs such as cis-diaminedichloroplatinum II (cisplatin; CDDP). CDDP is initially sequestered in subcellular organelles such as melanosomes, which significantly reduces its nuclear localization when compared with nonmelanoma/KB-3-1 epidermoid carcinoma cells. The melanosomal accumulation of CDDP remarkably modulates melanogenesis through a pronounced increase in tyrosinase activity. The altered melanogenesis manifested an approximate to 8-fold increase in both intracellular pigmentation and extracellular transport of melanosomes containing CDDP. Thus, our experiments provide evidence that melanosomes contribute to the refractory properties of melanoma cells by sequestering cytotoxic drugs and increasing melanosome-mediated drug export. Preventing melanosomal sequestration of cytotoxic drugs by inhibiting the functions of melanosomes may have great potential as an approach to improving the chemosensitivity of melanoma cells.