Gemcitabine potentiates anti-tumor effect of resveratrol on pancreatic cancer via down-regulation of VEGF-B
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ORIGINAL ARTICLE – CANCER RESEARCH
Gemcitabine potentiates anti‑tumor effect of resveratrol on pancreatic cancer via down‑regulation of VEGF‑B Yinan Yang1,2 · Wencong Tian1 · Lei Yang1 · Qiong Zhang3 · Mengmeng Zhu1 · Yuansheng Liu1 · Jing Li1 · Liang Yang1 · Jie Liu1 · Yanna Shen3 · Zhi Qi1,4 Received: 12 May 2020 / Accepted: 2 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose In our previous study, we discovered that resveratrol (RSV) had potential tumor-promoting effect on pancreatic cancer (PaCa) via up-regulation of VEGF-B. Therefore, we assumed that a pharmacological inhibitor of VEGF-B should potentiate the anti-tumor effect of RSV on PaCa. Methods Real-time PCR and western blotting were used to examine VEGF-B mRNA and protein levels. Cell viability and cell apoptosis were assessed by CCK-8 assay and flow cytometry analysis, respectively. PaCa cell-bearing nude mice were used to evaluate the anti-cancer effects of single treatment or co-administration of RSV and gemcitabine (GEM). Results We found that treatment with GEM alone dramatically decreased VEGF-B expression in comparison with control group, indicating that GEM is a potential pharmacological inhibitor of VEGF-B in PaCa. The co-administration of RSV and GEM significantly lowered expression of VEGF-B and increased phosphorylation level of GSK3β at Ser9 when compared to RSV alone treatment either in vitro or in vivo. Combination of RSV and GEM significantly increased cell death and apoptosis of PaCa cells in vitro and inhibited tumor growth in vivo in comparison with RSV or GEM alone treatment. Furthermore, we found that the anti-tumor effect in combination group was dramatically weakened after VEGF-B overexpressed in PaCa cells. Conclusion These results suggest that VEGF-B signaling pathway plays an important role in the development of PaCa and combination of GEM and RSV would be a promising modality for clinical PaCa therapy. Keywords Resveratrol · Gemcitabine · VEGF-B · Pancreatic cancer
Introduction
Yinan Yang and Wencong Tian contributed equally to this work. * Yanna Shen [email protected] * Zhi Qi [email protected] 1
Department of Histology and Embryology, School of Medicine, Nankai University, 94 Weijin Road, Nankai District, Tianjin 300071, China
2
Tianjin Central Hospital of Gynecology Obstetrics, Tianjin 300100, China
3
Department of Microbiology, School of Laboratory Medicine, Tianjin Medical University, 1 Guangdong Road, Hexi District, Tianjin 300203, China
4
National Clinical Research Center of Kidney Diseases, Beijing 100853, China
The prevalence of pancreatic cancer (PaCa) is increasing worldwide and its mortality is predicted to be the second in the near future (Kleeff et al. 2016). Despite that great efforts have been made in the treatment of PaCa, the 5-year survival rate of PaCa patients remains less than 10% (Neoptolemos et al. 2004); (Oettle et al. 2013). In view of this severe situation, exploring new effective treatments and strategies is urgent in clinic
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