BACKGROUND Chemotherapy-induced nuclear factor kappaB (NFκB) 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 NFκB using known NFκB 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)-α or paclitaxel. NFκB activity and the regulation of NFκB-related genes was analyzed. RESULTS Doxycycline induced sustained NFκB activation, followed by desensitization to further NFκB activation by TNF-α -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-α- and paclitaxel-mediated cytotoxicity and apoptosis. CONCLUSION These data indicate the possible clinical application of desensitization of NFκB to overcome chemoresistance by conventional chemotherapy for pancreatic cancer.