title: Metformin potentiates anti-tumor effect of resveratrol on pancreatic cancer by down-regulation of VEGF-B signaling pathway.
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.
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, School of Laboratory Medicine, Tianjin Medical University, Tianjin, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Licheng
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Tianjin Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Tianjin, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenviroment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zu
authors.affiliation: Department of Microbiology, School of Laboratory Medicine, Tianjin Medical University, Tianjin, China.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Qi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007004:Hypoglycemic Agents; D013267:Stilbenes; D042561:Vascular Endothelial Growth Factor B; D008687:Metformin; D000077185:Resveratrol
keywords: VEGF-B; apoptosis; metformin; pancreatic cancer; resveratrol