Gemcitabine potentiates anti-tumor effect of resveratrol on pancreatic cancer via down-regulation of VEGF-B

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. 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). 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. 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.