Desensitization of NFkB for overcoming chemoresistance of pancreatic cancer cells to TNF-alpha or paclitaxel

Background: Chemotherapy-induced nuclear factor kappaB (NF?B) activation is thought to play a key role in acquisition of chemoresistance by cancer cells. We focused on blockade of this activation by using the observation so-called 'desensitization' of NF(Kappa)B using known NF(Kappa)B activator, doxycycline. Materials and Methods: The human pancreatic cancer cell line PANC-1 was incubated with doxycycline, followed by treatment with tumor necrosis factor (TNF)-alpha or paclitaxel. NF(Kappa)B activity and the regulation of NF(Kappa)B-related genes was analyzed. Results: Doxycycline induced sustained NF(Kappa)B activation, followed by desensitization to further NF(Kappa)B activation by TNF-alpha -or paclitaxel, which was accompanied by decreased expression of TNF receptor p55, p75, and epidermal growth factor receptor. Consistent with these observations, doxycycline-pre-treatment resulted in an augmentation of TNF-alpha- and paclitaxel-mediated cytotoxicity and apoptosis. Conclusion: These data indicate the possible clinical application of desensitization of NF(Kappa)B to overcome chemoresistance by conventional chemotherapy for pancreatic cancer.