Modulation of resistance to alkylating agents in cancer cell by gossypol enantiomers.
Several cell lines resistant to alkylating agents possess increased activity of glutathione-S-transferase (GST) drug detoxifying enzymes. Inhibition of certain enzymes of the glutathione 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 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.
Ford
J M
JM
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.
Hait
W N
WN
Matlin
S A
SA
Benz
C C
CC
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D019328:Buthionine Sulfoximine; D002279:Carcinoma 256, Walker / Q000188:drug therapy*; D002330:Carmustine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002699:Chlorambucil / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004336:Drug Antagonism; D004351:Drug Resistance; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007536:Isomerism; D008558:Melphalan / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats
D000477:Alkylating Agents; D002699:Chlorambucil; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005982:Glutathione Transferase; D006072:Gossypol; D002945:Cisplatin; D008558:Melphalan; D002330:Carmustine