MODULATION OF RESISTANCE TO ALKYLATING-AGENTS IN CANCER CELL BY GOSSYPOL ENANTIOMERS

Several cell lines resistant to alkylating agents possess increased activity of gluthathione-S-transferase (GST) drug detoxifying enzymes. Inhibition of certain enzymes of the gluthathione redox system may affect cellular sensitivity to alkylators. We report that the (-)enantiomer of gossypol is a potent and selective inhibitor of GST-alpha and GST-pi isozymes, and that in combination with buthionine sulfoximine (BSO), causes the enhanced modulation of alkylator resistance in two drug resistant cell lines with increased GST activity. The use of (-)gossypol alone had no effect on the 2-5-fold resistance of MCF-7 Adr(R) and Walker resistant cells to chlorambucil, melphalan and BCNU. Cellular depletion of glutathione with BSO resulted in a 2-4-fold modulation of cell sensitivity to these alkylators. However, the combination of (-)gossypol with BSO resulted in a markedly greater modulation of alkylator sensitivity than with either inhibitor alone. Therefore, the complementary inhibition of glutathione and GST by BSO and (-)gossypol, respectively, produced a synergistic modulation of alkylator cytotoxicity in these drug resistant cell lines. The favorable clinical pharmacokinetics of (-)gossypol suggest its further evaluation for use in combination with BSO and alkylating agents in clinical trials.