Action of cysteaminylphenols on human melanoma cells in vivo and in vitro: 4-S-cysteaminylphenol binds protein disulphide isomerase.
Systemically administered 4-S-cysteaminylphenol (4-S-CAP) and N-acetyl-4-S-CAP inhibited the growth of xenografts of a human melanoma cell line but not of an ovarian tumour cell line. No selective cytotoxicity for melanoma cells was observed in culture, however. Further study of the in vitro mechanism of 4-S-CAP toxicity showed minimal inhibition of tyrosinase activity or DNA, RNA and protein synthesis, and there was no phase-specific arrest of the cell cycle. However, expression of an 80 kD melanosomal antigen was decreased. Cytotoxicity of 4-S-CAP in culture was decreased by simultaneous treatment with a monoamine oxidase inhibitor. An affinity column prepared from 4-S-CAP retained several proteins from a melanoma cell lysate. One protein, found also in HeLa cells, was identified by N-terminal sequencing as protein disulphide isomerase, a molecule which has multiple roles in the modification of secretory proteins. These results identify a protein target for 4-S-CAP as one possible mechanism of cytotoxicity.
Parsons
P G
PG
Queensland Institute of Medical Research, Brisbane, Australia.
Favier
D
D
McEwan
M
M
Takahashi
H
H
Jimbow
K
K
Ito
S
S
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D005260:Female; D006367:HeLa Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007535:Isomerases / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008969:Molecular Sequence Data; D008995:Monoamine Oxidase / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000473:pathology; D010636:Phenols / Q000494:pharmacology* / Q000627:therapeutic use; D019704:Protein Disulfide-Isomerases; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010636:Phenols; D003543:Cysteamine; D004295:Dihydroxyphenylalanine; C066420:N-acetyl-4-S-cysteaminylphenol; D008995:Monoamine Oxidase; D007535:Isomerases; D019704:Protein Disulfide-Isomerases; C043037:4-S-cysteaminylphenol