Potentiation of cisplatin cytotoxicity in human ovarian carcinoma cell lines by trifluoperazine, a calmodulin inhibitor

Abstract

Abstract Chemotherapy for ovarian cancer is frequently limited by cisplatin (CDDP) resistance. Enhanced DNA repair is one of several mechanisms which may cooperate to produce resistance in human ovarian carcinoma cell lines. Published reports suggest that calmodulin inhibitors, such as trifluoperazine (TFP), may inhibit one or more steps in DNA repair. The effects of TFP alone or in combination with CDDP were determined by clonogenic assay of six human ovarian carcinoma cell lines, derived from untreated patients (some of which were selected for cisplatin resistance in vitro ) and from patients clinically refractory to cisplatin-based chemotherapy. TFP produced dose-dependent cytotoxicity in all cell lines. In addition, TFP (10 μM ) produced approximately two-fold enhancement of CDDP cytotoxicity in three of the six cell lines (A2780, 2780-CP8, and 2780-C30). TFP and CDDP had additive or synergistic cytotoxicity in four of the six cell lines by median effects analysis, while clear antagonism was apparent in the remaining cell lines. These results suggest that TFP may enhance CDDP cytotoxicity in some, but not all, human ovarian carcinoma cell lines. The potential utility of trifluoperazine in ovarian cancer, either alone or in combination with cisplatin, remains to be defined in xenograft models and in clinical trials.