Insulin in combination with cisplatin induces the apoptosis of ovarian cancer cells via p53 and JNK activation.

Abstract

Drug resistance is an obstacle to effective treatment of ovarian cancer. There have been substantial evidences supporting the association between diabetes and the sensitivity to chemotherapy. Insulin (INS) is believed to be the strongest, most lasting hypoglycemic drug. Therefore, the present study aimed to elucidate whether insulin could facilitate the anti‑proliferative activities of cisplatin (cis‑diamminedichloroplatinum, DDP) in the A2780 ovarian cancer cell line. The inhibitory effects of DPP with/without INS on the growth of A2780 cells was measured by MTT assay. The cell cycle stages and levels of apoptosis were determined by flow cytometry. The amounts of signaling elements involved in the regulation of were examined using western blotting and reverse transcription‑quantitative polymerase chain reaction analysis. The results indicated that INS pre‑treatment enhanced the inhibitory effect of DDP on the proliferation of A2780 cells, and facilitated the apoptosis induced by DDP. INS‑DDP treatment led to a marked decrease in the percentage of G0/G1 phase cells, but a corresponding increase in the proportion of S phase cells. Furthermore, A2780 cells pretreated with INS followed by DDP upregulated the protein expression level of phosphorylated c‑Jun N‑terminal kinase (JNK), which resulted in a substantial increase in the expression levels of p53 mRNA and protein, compared with DDP administration alone. In conclusion, the combination of INS and DDP facilitated the apoptosis of A2780 cells, which may be associated with the activation of the JNK signaling pathway and consequently the involvement of p53 at both mRNA and protein expression levels. These results may be useful in furthering our understanding of the mechanisms involved in the chemotherapeutic treatment of ovarian cancer.