COMBINED EFFECTS OF BUTHIONINE SULFOXIMINE AND CEPHARANTHINE ON CYTOTOXIC ACTIVITY OF DOXORUBICIN TO MULTIDRUG-RESISTANT CELLS

We studied the potentiation of doxorubicin (DOX) activity in multidrug -resistant (MDR) cells by buthionine sulfoximine (BSO), a specific inh ibitor of gamma-glutamylcysteine synthetase, and by cepharanthine (CE) , which interacts with P-glycopratein. The glutathione (GSH) of MDR ce lls was approximately 1.5-fold greater than that of the parental cell line. BSO reduced GSH content of MDR cells compared to that of the sen sitive ones. The BSO treatment (50 mu M) enhanced the effect of DOX by 1.8-fold, while CE caused a greater reversal of drug resistance. The combination of BSO with CE produced further potentiation of DOX activi ty in an antiproliferative effect. Pretreatment of cells with BSO did not alter the cellular accumulation of DOX in the absence or presence of CE. The addition of BSO (30 mM) to the drinking water of mice reduc ed the tissue levels of GSH in tumor cells, suggesting that the marked decrease in GSH might diminish the ability of that tumor to resist DO X. Combined administration of CE and DOX resulted in enhancement of DO X antitumor activity and prolongation of survival time. The survival o f mice treated with BSO and CE as a supplement to DOX treatment was su perior that of mice receiving DOX alone. These studies demonstrated th at the combinations of BSO with CE may be useful for killing drug-resi stant tumor cells.