Escin augments the efficacy of gemcitabine through down-regulation of nuclear factor-κB and nuclear factor-κB-regulated gene products in pancreatic cancer both in vitro and in vivo

Pancreatic cancer is an aggressive malignancy, which generally develops resistance to chemotherapy. Agents that are safe and can sensitize cancer to chemotherapy are urgently needed. Escin, a natural mixture of triterpene saponins isolated from Aesculus wilsonii Rehd, has been demonstrated to possess anti-cancer activity both in vitro and in vivo. The anti-cancer activity of escin could be, in part, due to the inactivation of nuclear factor-kappa B (NF-kappa B). In contrast, chemotherapy including gemcitabine could activate NF-kappa B and lead to chemoresistance. Here, for the first time, we investigated whether escin, via the inactivation of NF-kappa B, would potentiate the antitumor activity of gemcitabine in pancreatic cancer. Cell viability and proliferation, apoptosis, NF-kappa B activity and the expression of NF-kappa B-linked genes were all examined in vitro. The antitumor effect of escin with or without gemcitabine in pancreatic cancer was also assessed using BxPC-3 xenografts subcutaneously established in BALB/c nude mice. Escin not only potentiated the proliferation-inhibiting and apoptosis-inducing effect of gemcitabine in both BxPC-3 and PANC-1 cell lines in vitro, but also dramatically enhanced its suppressive effect on tumor growth in nude mice. The mechanism is at least partially due to the inhibition of NF-kappa B activity and consequent inhibition of c-Myc, COX-2, Cyclin D1, Survivin, Bcl-2 and Bcl-xL, and the activation of caspase-3. These data suggest that escin, via inactivation of NF-kappa B, could potentiate the efficacy of gemcitabine in combating pancreatic cancer, which could be a novel and potentially important therapeutic approach for the treatment for pancreatic cancer.