title: Desensitization of NFκB for overcoming chemoresistance of pancreatic cancer cells to TNF-α or paclitaxel.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  These data indicate the possible clinical application of desensitization of NFκB to overcome chemoresistance by conventional chemotherapy for pancreatic cancer.
authors.affiliation: Department of Surgery, Jikei University Hospital, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. sfujioka@jikei.ac.jp
authors.forename: Shuichi
authors.initials: S
authors.lastname: Fujioka
authors.forename: Kyonsu
authors.initials: K
authors.lastname: Son
authors.forename: Shinji
authors.initials: S
authors.lastname: Onda
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt
authors.forename: Guido M
authors.initials: GM
authors.lastname: Scrabas
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Okamoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Fujita
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D017239:Paclitaxel / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004318:Doxycycline; D017239:Paclitaxel