Chen Kevin G, Valencia Julio C, Lai Barry, Zhang Guofeng, Paterson Jill K, Rouzaud François, Berens Werner, Wincovitch Stephen M, Garfield Susan H, Leapman Richard D, Hearing Vincent J, Gottesman Michael M
Laboratories of Cell Biology and Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9903-7. doi: 10.1073/pnas.0600213103. Epub 2006 Jun 15.
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 approximately 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.
恶性黑色素瘤难以治疗背后的多药耐药机制在很大程度上仍不清楚。在本研究中，我们证明黑色素瘤中多药耐药的发展涉及细胞内细胞毒性药物如顺二氯二氨铂（顺铂；CDDP）的亚细胞隔离。CDDP最初被隔离在诸如黑素小体等亚细胞细胞器中，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在黑素小体中的积累通过酪氨酸酶活性的显著增加显著调节黑色素生成。改变的黑色素生成表现为细胞内色素沉着以及含有CDDP的黑素小体的细胞外转运均增加了约8倍。因此，我们的实验提供了证据，表明黑素小体通过隔离细胞毒性药物和增加黑素小体介导的药物输出，对黑色素瘤细胞的难治性特性有贡献。通过抑制黑素小体的功能来防止细胞毒性药物在黑素小体中的隔离，作为一种提高黑色素瘤细胞化学敏感性的方法可能具有巨大潜力。
