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.
Finn
Gregory J
GJ
Department of Applied Science, School of Science, Institute of Technology, National Centre for Sensor Research, Tallaght, Dublin 24, Ireland.
Creaven
Bernadette S
BS
Egan
Denise A
DA
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