Research Papers:

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

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

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Oncotarget. 2016; 7:84190-84200. https://doi.org/10.18632/oncotarget.12391

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Mengmeng Zhu1,*, Qiong Zhang2,*, Xiaoling Wang1, Licheng Kang1, Yinan Yang1, Yuansheng Liu1, Lei Yang3, Jing Li1, Liang Yang1, Jie Liu1, Yin Li4, Lingling Zu5, Yanna Shen2, Zhi Qi1

1Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China

2Department of Microbiology, School of Laboratory Medicine, Tianjin Medical University, Tianjin, China

3Tianjin Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Tianjin, China

4Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, China

5Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenviroment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

*These authors contributed equally to this work

Correspondence to:

Yanna Shen, email: shenyanna@sina.com

Zhi Qi, email: qizhi@nankai.edu.cn

Keywords: pancreatic cancer, metformin, resveratrol, VEGF-B, apoptosis

Received: February 28, 2016     Accepted: September 25, 2016     Published: October 01, 2016


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.

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