CYTOTOXICITY OF GOSSYPOL ENANTIOMERS AND ITS QUINONE METABOLITE GOSSYPOLONE IN MELANOMA CELL-LINES

The cytotoxicity of the (-)- and (+)-isomers and the quinone metabolit e gossypolone prepared from the naturally occurring polyphenolic diald ehyde gossypol were compared using two human melanoma cell lines (SK-m el-19 and SK-mel-28) with a similar growth rate, one melanotic (melani n content of 69 pg/cell) and one amelanotic (melanin content of 10 pg/ cell). Results from two viability assays (MTT and flow cytometry) show ed that the cytotoxicity of racemic gossypol was identical for both ce ll lines (50% inhibition of cell growth IC50 = 22 mu M). Gossypolone a t equimolar concentrations was inactive In the amelanotic cell line an d as potent as racemic gossypol in the melanotic cell line. (-)-Gossyp ol was significantly more active in both cell lines compared with the (+)-isomer. The cytotoxic effect of (-)-gossypol was both concentratio n 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 vitr o. Morphological changes after exposure to (-)-gossypol included shrin kage and loss of adherence. Cell sensitivity to the (-)-isomer was fiv e-fold greater (IC50 = 4 mu M) using a clonogenic assay. At equimolar concentrations, (-)-gossypol was more cytotoxic to both cell lines tha n the clinically used drugs cisplatin, dacarbazine and melphalan. The results of this study suggest that (-)-gossypol may be of potential th erapeutic benefit in melanoma patients.