A2780 Cisplatin-resistant Cells Research Articles

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.

Cisplatin, glutathione and the third wheel: a copper-(1,10-phenanthroline) complex modulates cisplatin-GSH interactions from antagonism to synergism in cancer cells resistant to cisplatin.

The antagonistic effect of glutathione (GSH) against the cytotoxicity of cisplatin was observed in both wild type and cisplatin-resistant human leukaemia and ovarian carcinoma cell lines. The simultaneous presence of the cytotoxic copper complex [Cu(phen)2(OH2)](ClO4)2 (C0) restored the sensitivity of the cells to cisplatin, and, at selected concentrations, led to strong synergistic effects. The C0–cisplatin–glutathione system showed a synergistic toxic effect even in the presence of 1000 μM GSH. The three-drug cocktail exerted a higher potency against leukemic cells than against freshly isolated lymphocytes from healthy donors. Compared to actively proliferating normal lymphocytes, leukaemia cells were much more susceptible to the cytocide effect of the three-drug combination and underwent the dying process(es) much faster. When the ovarian carcinoma cells were treated with cisplatin, alone or in combination with C0, late apoptotic effects were mainly observed, suggesting that DNA interactions with the C0–cisplatin complex trigger a process of programmed cell death. In contrast, the ternary combination induced apoptotic effects similar to that shown by C0 in single treatment, that is, early apoptosis. One possible explanation is that C0 and cisplatin compete for GSH-binding in the culture medium. GSH in combination with C0 and cisplatin caused a significant induction of the apoptotic process(es), through a pathway which does not compromise the integrity of the plasma membrane of cells.