Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer.
Int J Cancer. 2009 Nov 11. PMID: 19908231
Gemcitabine, while a standard treatment of advanced pancreatic cancer (PaCa), alone is not very effective. New agents that are safe and effective are highly needed. Resveratrol is one such agent which is safe and multi-targeted; and has been linked with suppression of survival, proliferation, invasion, and angiogenesis of cancer. Whether resveratrol can sensitize PaCa to gemcitabine in vitro and in vivo was investigated. We established PaCa xenografts in nude mice, randomized into four groups, and treated with vehicle, gemcitabine, resveratrol and with combination. Modulation of NF-kappaB and markers of proliferation, angiogenesis, and invasion were ascertained using electrophoretic mobility shift assay (EMSA), immuno histochemistry and western blot analysis. Resveratrol inhibited the proliferation of four different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expressions of bcl-2, bcl-xL, COX-2, cyclin D1, MMP-9 and VEGF. In an orthotopic model of human PaCa, we found that resveratrol significantly suppressed the growth of the tumor (p<0.001) and this effect was further enhanced by gemcitabine (p<0.001). Both the markers of proliferation index Ki-67 and the micro vessel density CD31 were significantly down regulated in tumor tissue by the combination of gemcitabine and resveratrol (p<0.001vs control; p<0.01 vs gemcitabine). As compared to vehicle control, resveratrol also suppressed the NF-kappaB activation and expression of cyclin D1, COX-2, ICAM-1, MMP-9, and survivin. Overall our results demonstrate that resveratrol can synergies the effects of gemcitabine through suppression of markers of proliferation, invasion, angiogenesis and metastasis. (c) 2009 UICC.