A study of the role of cell cycle events mediating the action of coumarin derivatives in human malignant melanoma cells.
6-Nitro-7-hydroxycoumarin (6-NO2-7-OHC) and 3,6,8-trinitro-7-hydroxycoumarin (3,6,8-NO2-7-OHC) have previously been shown to be potent and selective anti-proliferative agents to the human skin cell line, SK-MEL-31. Here, we investigate the reversibility of their cytotoxicity, along with their effects on DNA synthesis and cell cycle events. Comparative studies were carried out using the main metabolite of coumarin in man, 7-hydroxycoumarin (7-OHC). 6-NO2-7-OHC and 3,6,8-NO2-7-OHC, were found to be irreversible cytotoxic agents, unlike 7-OHC. All three derivatives inhibited DNA synthesis, but 7-OHC was only nitro-derivatives which acted in an irreversible manner. Flow cytometric studies demonstrated that both nitro-derivatives caused a dose- and time-dependant S phase accumulation. 7-OHC exerted a similar effect, but appeared to be less potent. Finally, the two nitro-derivatives caused a dose-dependant inhibition of the S phase regulatory protein, cyclin A. Consequently, these and other nitro-derivatives of 7-OHC may represent novel therapeutic agents for the treatment of malignant melanoma as they are capable of selective and irreversible cytotoxicity.
Department of Applied Science, School of Science, Institute of Technology, National Centre for Sensor Research, Tallaght, Dublin 24, Ireland.
Gregory J
GJ
Finn
Bernadette S
BS
Creaven
Denise A
DA
Egan
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D019925:Cyclin A / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D009574:Nitro Compounds / Q000494:pharmacology* / Q000633:toxicity*; D012878:Skin Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014468:Umbelliferones / Q000494:pharmacology* / Q000633:toxicity*
C492875:3,6,8-trinitro-7-hydroxycoumarin; C492874:6-nitro-7-hydroxycoumarin; D000970:Antineoplastic Agents; D019925:Cyclin A; D009574:Nitro Compounds; D014468:Umbelliferones; D004247:DNA