Metformin potentiates anti-tumor effect of resveratrol on pancreatic cancer by down-regulation of VEGF-B signaling pathway
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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
Yanna Shen, email: [email protected]
Zhi Qi, email: [email protected]
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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