Metformin potentiates anti-tumor effect of resveratrol on pancreatic cancer by down-regulation of VEGF-B signaling pathway.

Mengmeng Zhu,Jing Li,Yanna Shen,Lei Yang,Zhi Qi,Licheng Kang,Xiaoling Wang,Lingling Zu,Yinan Yang,Yuansheng Liu,Jie Liu,Liang Yang,Yin Li,Qiong Zhang

doi:10.18632/oncotarget.12391

Abstract

Our previous study showed that resveratrol (RSV) exhibited not only anti-tumor effect, but also had potential tumor promotion effect on pancreatic cancer (Paca) cells through up-regulation of VEGF-B. We determined whether metformin (MET) could potentiate the anti-tumor effect of RSV on PaCa in this study. Combination of RSV (100 μmol/l) and MET (20 mmol/l) significantly inhibited tumor growth and increased apoptosis of human PaCa in comparison with RSV or MET alone treatment in PaCa cell lines (Miapaca-2, Panc-1 and Capan-2). Combination of RSV (60 mg/kg, gavage) and MET (250 mg/kg, i.p.) significantly inhibited tumor growth in PaCa bearing nude mice (subcutaneous injection of 5 × 106 Miapaca-2 cells) in comparison with RSV or MET alone treatment on day 40. Combination treatment significantly decreased VEGF-B expression and inhibited activity of GSK-3β when compared to the RSV alone treatment. Up-regulated expressions of Bax, cleaved caspase-3 and down-regulated expression of Bcl-2 were observed in RSV+ MET group in comparison with RSV group either in vitro or in vivo. Inhibition of VEGF-B by VEGF-B small interfering RNA (siRNA) mimicked the effects of MET on PaCa cells. These results suggested that MET, a potential pharmacological inhibitor of VEGF-B signaling pathway, potentiated the anti-tumor effect of RSV on PaCa, and combination of MET and RSV would be a promising modality for clinical PaCa therapy.

Highlights

Pancreatic cancer (PaCa) is one of the most lethal human cancers with the lowest five-year relative survival rate of only 7% from 2004 to 2010 [1]
We assumed that combination of RSV with pharmacological inhibitor of Vascular endothelial growth factor b (VEGF-B) signaling pathway could potentiate the anti-tumor effect of RSV, and would be a promising modality for clinical PaCa therapy
Previous study showed that RSV inhibited apoptosis of PaCa cells via up-regulating expression of VEGF-B [21]

Summary

Introduction

Pancreatic cancer (PaCa) is one of the most lethal human cancers with the lowest five-year relative survival rate of only 7% from 2004 to 2010 [1]. Despite major progress in the treatment of PaCa during the last few decades, the survival rate of patients has not significantly improved. Gemcitabine administration is the standard clinical therapy for the patients with PaCa; the therapeutic effect was unsatisfactory. The median overall survival time was 5–8 months and oneyear survival rate was only 17–25% after gemcitabine alone treatment [2]. Yang et al reported that VEGF-B promoted pulmonary metastasis of human melanomas which lead to the poor survival rate of human cancer patients [8]. VEGF-B overexpression predicted for increased distant metastasis and shorter survival in bladder cancer patients [9]. Albrecht et al suggested that over expression of VEGF-B could inhibit pancreatic neuroendocrine tumorigenesis [10]

Objectives

Methods

Results

Conclusion