title: Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas.
abstract: 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.
authors.affiliation: Laboratories of Cell Biology and Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Chen
authors.forename: Julio C
authors.initials: JC
authors.lastname: Valencia
authors.forename: Barry
authors.initials: B
authors.lastname: Lai
authors.forename: Guofeng
authors.initials: G
authors.lastname: Zhang
authors.forename: Jill K
authors.initials: JK
authors.lastname: Paterson
authors.forename: François
authors.initials: F
authors.lastname: Rouzaud
authors.forename: Werner
authors.initials: W
authors.lastname: Berens
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Wincovitch
authors.forename: Susan H
authors.initials: SH
authors.lastname: Garfield
authors.forename: Richard D
authors.initials: RD
authors.lastname: Leapman
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hearing
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D000970:Antineoplastic Agents / Q000032:analysis / Q000378:metabolism*; D001692:Biological Transport; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000032:analysis / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000648:ultrastructure; D020460:Melanosomes / Q000737:chemistry / Q000201:enzymology*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C009904:melanogen; D002945:Cisplatin