Selective potentiation of platinum drug cytotoxicity in cisplatin-sensitive and-resistant human ovarian carcinoma cell lines by amphotericin B

Abstract

Resistance to the clinically used platinum-based drugs cisplatin and carboplatin represents a major limitation to their clinical effectiveness. Using cisplatin-sensitive and-resistant human ovarian carcinoma cell lines previously characterized in terms of their major underlying mechanisms of resistance, we attempted to potentiate the cytotoxic effects of cisplatin and carboplatin using the clinically used antifungal agent amphotericin B (AmB). Using nontoxic concentrations of AmB (up to 15 μg/ml) and continuous exposure to cisplatin, a concentration-dependent selective potentiation (maximum of 3.2-fold) of cisplatin cytotoxicity was observed in two cisplatin-resistant cell lines (41 McisR6, acquired resistant, and HX/62, intrinsically resistant). In both these cisplatin-resistant cell lines, previous studies have shown resistance to be due primarily to reduced platinum uptake. Notably, no significant potentiation was observed in the parent 41M cell line, in the intrinsically resistant SKOV-3 cell line (where reduced drug accumulation plays only a partial role in determining resistance) or in a pair of cell lines (CH1 and its acquired-resistant variant CH1cisR6) where reduced drug uptake does not play any role in determining resistance. The potentiating effect of AmB was lower with carboplatin and not significant in all cell lines. Platinum uptake following a 2-h exposure of cells to cisplatin was enhanced 3.5-fold in 41McisR6 cells (producing platinum levels similar to those obtained in the parental line) and 1.7-fold in 41M cells by the concomitant exposure to AmB. These data indicate that the potentiation of cisplatin (and carboplatin) cytotoxicity by AmB is not due to a generalized membrane disruption, as effects were observed only in resistant lines where reduced drug transport was apparent. Moreover, AmB did not increase the cytotoxicity of JM216 [bis-acetatoammine(cyclohexylamine)dichloroplatinum (II)], a recently developed, more lipophilic orally active platinum drug, in the 41M/41McisR6 lines. JM216 has previously been shown to circumvent acquired cisplatin resistance due to decreased drug uptake. In vivo, however, using the HX/62 xenograft, AmB (at its maximum tolerated dose of 20 mg/kg; q7d×4 schedule) did not enhance the antitumour effect of carboplatin (at its maximum tolerated dose of 80 mg/kg; q7d×4 schedule).