Cytotoxicity of gossypol enantiomers and its quinone metabolite gossypolone in melanoma cell lines.
The cytotoxicity of the (-)- and (+)-isomers and the quinone metabolite gossypolone prepared from the naturally occurring polyphenolic dialdehyde gossypol were compared using two human melanoma cell lines (SK-mel-19 and SK-mel-28) with a similar growth rate, one melanotic (melanin content of 69 pg/cell) and one amelanotic (melanin content of 10 pg/cell). Results from two viability assays (MTT and flow cytometry) showed that the cytotoxicity of racemic gossypol was identical for both cell lines (50% inhibition of cell growth IC50 = 22 microM). Gossypolone at equimolar concentrations was inactive in the amelanotic cell line and as potent as racemic gossypol in the melanotic cell line. (-)-Gossypol was significantly more active in both cell lines compared with the (+)-isomer. The cytotoxic effect of (-)-gossypol was both concentration and time dependent. Under serum-free conditions, the cytotoxicity of both enantiomers was increased, suggesting that serum protein binding may play a role in the differential toxicity of these isomers in vitro. Morphological changes after exposure to (-)-gossypol included shrinkage and loss of adherence. Cell sensitivity to the (-)-isomer was five-fold greater (IC50 = 4 microM) using a clonogenic assay. At equimolar concentrations, (-)-gossypol was more cytotoxic to both cell lines than the clinically used drugs cisplatin, dacarbazine and melphalan. The results of this study suggest that (-)-gossypol may be of potential therapeutic benefit in melanoma patients.
Blackstaffe
L
L
Cancer Biology and Pharmacology Group, Velindre NHS Trust Hospital, Cardiff, UK.
Shelley
M D
MD
Fish
R G
RG
D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006072:Gossypol / Q000031:analogs & derivatives* / Q000633:toxicity*; D006801:Humans; D008545:Melanoma / Q000473:pathology* / Q000648:ultrastructure; D008855:Microscopy, Electron, Scanning; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
C043259:gossypolone; D006072:Gossypol