Combination therapy with interleukin-15 and metformin as a synergistic treatment for pancreatic cancer.

OBJECTIVE: To investigate the efficacies and mechanisms of combination therapy with interleukin-15 (IL-15) and metformin (Met) on suppressing pancreatic cell proliferation and protecting Panc02-bearing mice. MATERIALS AND METHODS: MTT assays were applied to assess the inhibitory effects of IL-15 combined Met or Met and IL-15 alone on proliferation of normal HPDE6-C7 and Panc02 cells. After tumor grew up to 150 mm3, the Panc02-bearing xenograft model mice were randomly divided into saline group, IL-15 and Met alone group and combined treatment group (n=8) with the administration of each agent every other day for three weeks, and survival rates were recorded. The changes in tumor size, expression levels of the apoptosis, autophagy as well as Akt/mTOR/STAT3-related factors in tumor tissues were all measured. RESULTS: MTT assays demonstrated significantly inhibiting efficacy of combination therapy with IL-15 and Met on Panc02 cell proliferation compared to other groups (all p<0.05) with combination index<1 showing evident synergistic effect. Moreover, the apoptosis rate of Panc02 cell under combined treatment were 95.5±3.2% and significantly higher than those of others (all p<0.01). In addition, combined administration remarkably inhibited the growth of pancreatic carcinoma, and improved survival rate of Panc02-bearing model with less body weight loss. Furthermore, combined treatment significantly downregulated anti-apoptotic proteins as well as Akt/mTOR/STAT3 signaling pathway and upregulated autophagy related factors, respectively, compared with those of monotherapy groups in both Panc02 cells and tumor tissues. CONCLUSIONS: Combined treatment of IL-15 with Met showed synergistic anti-tumor efficacies on Panc02 cells attributing to promotion on apoptosis, autophagy and inhibition on Akt/mTOR/STAT3 signaling-transduction in Panc02-bearing model mice. [ABSTRACT FROM AUTHOR]