<br>一氧化氮通过 connexin32/间隙连接对 A2780 和 A2780-CDDP 细胞中的顺铂细胞毒性产生相反的影响。,Cancer Science

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一氧化氮通过 connexin32/间隙连接对 A2780 和 A2780-CDDP 细胞中的顺铂细胞毒性产生相反的影响。
Cancer Science ( IF 4.5 ) Pub Date : 2020-04-27 , DOI: 10.1111/cas.14436
Lixia Fan _{1,

2} , Ningze Zheng ₁ , Fuhua Peng ₁ , Ziyu Zhao ₁ , Di Fan ₁ , Shaoyi Cai ₁ , Liang Tao ₁ , Qin Wang ₁

Affiliation

化学耐药性是卵巢癌治疗的主要障碍，迫切需要新的治疗策略和有关顺铂药物机制的进一步信息。一氧化氮在调节化疗药物的活性方面具有关键作用。我们之前的工作表明 connexin32 导致顺铂耐药。然而，一氧化氮是否参与连接蛋白32介导的顺铂耐药仍不清楚。在这项研究中，使用 A2780 和 A2780 顺铂耐药细胞，我们发现一氧化氮供体S-亚硝基-N-乙酰基青霉胺通过减少 A2780 细胞中的间隙连接来减轻顺铂毒性。使用视黄酸增强间隙连接逆转了S-亚硝基-N-乙酰基-青霉胺对顺铂毒性的影响。然而，在 A2780 顺铂耐药细胞中， S-亚硝基-N-乙酰基-青霉胺通过降低 connexin32 表达来增强顺铂毒性。小干扰RNA下调connexin32表达加剧了S-亚硝基-N-乙酰青霉胺对顺铂细胞毒性的影响，而pcDNA转染上调connexin32表达则逆转了S-亚硝基-N-乙酰青霉胺对顺铂细胞毒性的影响。我们的研究首次表明，在出现顺铂耐药性之前，应避免在卵巢癌的临床治疗中将顺铂与一氧化氮联合使用。本研究为进一步研究通过在临床治疗中将顺铂与一氧化氮的特异性抑制剂或增强剂相结合来提高顺铂的疗效提供了一个富有成效的领域。

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

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.

更新日期：2020-04-27

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