Cytotoxic effect of 1-methyl-4-phenylpyridinium ion on human melanoma cell lines, HMV-II and SK-MEL-44, is dependent on the melanin contents and caused by inhibition of mitochondrial electron transport.
MPP+, an oxidative metabolite of a neurotoxin, MPTP, was found to be cytotoxic to human melanoma cell lines, HMV-II and SK-MEL-44. After 3 days of culture in the presence of MPP+, a larger amount of MPP+ was accumulated in HMV-II cells than in SK-MEL-44 cells, which correlated well with the melanin contents; HMV-II cells contain larger amounts of melanin than SK-MEL-44 cells. After 6 days of culture in the presence of MPP+, the cytotoxicity of MPP+ on these cell types was evaluated by counting cell numbers with the dye exclusion test and double-layer soft agar clonogenic assay. It was found that exposure to MPP+ reduced the survival of HMV-II cells more significantly than that of SK-MEL-44 cells. In HMV-II cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to elucidate the mechanism of MPP+ lethality. The formazan formation was reduced markedly by the presence of MPP+ at concentrations much lower than those required for cell death. These results suggest that cytotoxicity of MPP+ may be ascribed to its accumulation due to high affinity for melanin, and to inhibition of the enzymes utilizing ubiquinone in the mitochondrial respiratory chain.
Umemura
T
T
Department of Dermatology, Nagoya University School of Medicine, Japan.
Naoi
M
M
Takahashi
T
T
Fukui
Y
Y
Yasue
T
T
Ohashi
M
M
Nagatsu
T
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D004579:Electron Transport / Q000187:drug effects*; D005562:Formazans / Q000378:metabolism; D006801:Humans; D020267:MPTP Poisoning; D008543:Melanins / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D005562:Formazans; D008543:Melanins; D011726:Pyridinium Compounds; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; C026560:1-(4-methoxyphenyl)pyridinium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine