Nitric oxide affects cisplatin cytotoxicity oppositely in A2780 and A2780‐CDDP cells via the connexin32/gap junction

Abstract

Chemoresistance is a main obstacle in ovarian cancer therapy and new treatment strategies and further information regarding the mechanism of cisplatin are urgently needed. Nitric oxide has a critical role in modulating the activity of chemotherapeutic drugs and our previous work shows that Connexin32 contributes to cisplatin resistance. However, whether Nitric oxide is involved in Connexin32‐mediated cisplatin resistance remains unknown. In this study, with A2780 and A2780 cisplatin‐resistant cells, we found S‐nitroso‐N‐acetyl‐penicillamine, a nitric oxide donor attenuated cisplatin toxicity by decreasing gap junction in A2780 cells. Enhancement of gap junction using retinoic acid reversed the effects of S‐nitroso‐N‐acetyl‐penicillamine on cisplatin toxicity. However, S‐nitroso‐N‐acetyl‐penicillamine enhanced cisplatin toxicity by decreasing Connexin32 expression in A2780 cisplatin‐resistant cells. Downregulation of Connexin32 expression by small interfering RNA reversed the effects of S‐nitroso‐N‐acetyl‐penicillamine on cisplatin cytotoxicity and upregulation of Connexin32 expression by pcDNA transfection exacerbated the effects of S‐nitroso‐N‐acetyl‐penicillamine on cisplatin cytotoxicity. Our study suggests for the first time that combining cisplatin with nitric oxide in clinical therapies should be avoided before cisplatin resistance emerges in ovarian cancer. The present study provides a productive area of further study for increasing the efficacy of cisplatin by combination cisplatin with the specific inhibitors or enhancers of nitric oxide in the clinical treatment.