Sulfur containing tyrosine analogs can cause selective melanocytotoxicity involving tyrosinase-mediated apoptosis.
Sulfur-containing tyrosine analogs such as 4-S-cysteaminylphenol (4-S-CAP) and its N-acetyl derivative, N-acetyl-4-S-CAP, are tyrosinase substrates and can cause selective cytotoxicity or cell death of melanocytes and melanoma cells. It is not clear, however, if the cytotoxicity derives from a cytostatic or cytocidal effect. The latter can also be either apoptotic or necrotic. This paper summarizes our attempt to clarify the nature of melanocytotoxicity and cell death by using a new derivative of 4-S-CAP, N-propionyl-4-S-CAP (NPr-CAP). The i.p. administration of NPr-CAP caused marked depigmentation of black hair follicles in C57 mice. At 12 h postadministration of NPr-CAP, follicular melanocytes showed histochemical and morphologic features indicative of apoptosis by TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining and electron microscopy. The agarose gel electrophoresis of DNA from drug-treated melan a2 cells, an immortal melanocyte line of C57 black mice, showed the nucleosomal DNA ladder pattern. NPr-CAP caused irreversible cytotoxicity in melan a2 and the effect was inhibited by a tyrosinase inhibitor, phenylthiocarbamide. The tyrosinase-mediated cytotoxicity of NPr-CAP was further confirmed by the decreased viability of COS 7 monkey-kidney cells, which expressed a level of high tyrosinase activity through transfection of human tyrosinase cDNA. NPr-CAP, however, also transiently inhibited the proliferation of melan c cells, a control tyrosinase-negative albino melanocyte line, and vector-transfected COS 7 cells. Thus, the major process of NPr-CAP-mediated melanocytotoxicity involves cytocidal apoptosis associated with active tyrosinase. In addition, there is transient, nontyrosinase-mediated cytostatic cytotoxicity.
Minamitsuji
Y
Y
Department of Dermatology, School of Medicine, Sapporo Medical University, Japan. jimbow@sapmed.ac.jp
Toyofuku
K
K
Sugiyama
S
S
Yamada
K
K
Jimbow
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D019556:COS Cells; D002460:Cell Line; D003538:Cystamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006200:Hair Color / Q000187:drug effects; D018859:Hair Follicle / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008544:Melanocytes / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D018384:Oxidative Stress; D010636:Phenols / Q000494:pharmacology*; D011247:Pregnancy; D014162:Transfection
D000970:Antineoplastic Agents; C114098:N-propionyl-4-S-cysteaminylphenol; D010636:Phenols; D003543:Cysteamine; C066420:N-acetyl-4-S-cysteaminylphenol; D014442:Monophenol Monooxygenase; D003538:Cystamine