Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin

Oncogene. 2001 Feb 15;20(7):859-68. doi: 10.1038/sj.onc.1204168.


The transcription factor NF-kappaB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that differ in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 microM) and doxorubicin (0.3 microM): Highly sensitive T3M4 [corrected] and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistant to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-kappaB activity in all cell lines, whereas basal NF-kappaB binding was nearly undetectable in T3M4 [corrected] and PT45-P1 cells, but rather high in Capan-1 and A818-4 cells, as demonstrated by gel-shift and luciferase assays. Treatment with various NF-kappaB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IkappaBalpha super-repressor, strongly enhanced the apoptotic effects of VP16 or doxorubicin on resistant Capan-1 and 818-4 cells. Our results indicate that under certain conditions the resistance of pancreatic carcinoma cells to chemotherapy is due to their constitutive NF-kappaB activity rather than the transient induction of NF-kappaB by some anti-cancer drugs. Blockade of basal NF-kappaB activity by well established drugs efficiently reduces chemoresistance of pancreatic cancer cells and offers the potential for improved therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Carcinoma / drug therapy*
  • DNA-Binding Proteins / biosynthesis
  • Doxorubicin / pharmacology*
  • Drug Resistance
  • Etoposide / pharmacology*
  • Gliotoxin / pharmacology
  • Humans
  • I-kappa B Proteins*
  • Leupeptins / pharmacology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • Pancreatic Neoplasms / drug therapy*
  • Sulfasalazine / pharmacology


  • Antineoplastic Agents
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Leupeptins
  • NF-kappa B
  • NFKBIA protein, human
  • NF-KappaB Inhibitor alpha
  • Sulfasalazine
  • Gliotoxin
  • Etoposide
  • Doxorubicin
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde