Open AccessNitric oxide affects cisplatin cytotoxicity oppositely in A2780 and A2780‐CDDP cells via the connexin32/gap junction
Author(s) -
Fan Lixia,
Zheng Ningze,
Peng Fuhua,
Zhao Ziyu,
Fan Di,
Cai Shaoyi,
Tao Liang,
Wang Qin
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14436
Subject(s) - cisplatin , nitric oxide , cytotoxicity , chemistry , connexin 32 , toxicity , pharmacology , cancer research , penicillamine , gap junction , connexin , biochemistry , biology , in vitro , medicine , chemotherapy , intracellular , organic chemistry
Chemoresistance is a main obstacle in ovarian cancer therapy and new treatment strategies and further information regarding the mechanism of the medication cisplatin are urgently needed. Nitric oxide has a critical role in modulating the activity of chemotherapeutic drugs. Our previous work showed that connexin32 contributed to cisplatin resistance. However, whether nitric oxide is involved in connexin32‐mediated cisplatin resistance remains unknown. In this study, using A2780 and A2780 cisplatin‐resistant cells, we found that S ‐nitroso‐ N ‐acetyl‐penicillamine, a nitric oxide donor, attenuated cisplatin toxicity by decreasing gap junctions in A2780 cells. Enhancement of gap junctions using retinoic acid reversed the effects of S ‐nitroso‐ N ‐acetyl‐penicillamine on cisplatin toxicity. In A2780 cisplatin‐resistant cells, however, S ‐nitroso‐ N ‐acetyl‐penicillamine enhanced cisplatin toxicity by decreasing connexin32 expression. Downregulation of connexin32 expression by small interfering RNA exacerbated the effects of S ‐nitroso‐ N ‐acetyl‐penicillamine on cisplatin cytotoxicity and upregulation of connexin32 expression by pcDNA transfection reversed 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 for ovarian cancer should be avoided before cisplatin resistance emerges. The present study provides a productive area of further study for increasing the efficacy of cisplatin by combining cisplatin with the specific inhibitors or enhancers of nitric oxide in clinical treatment.