Control of Inducible Chemoresistance: Enhanced Anti-Tumor Therapy Through Increased Apoptosis by Inhibition of NF-kappaB

Nat Med. 1999 Apr;5(4):412-7. doi: 10.1038/7410.

Abstract

Programmed cell death (apoptosis) seems to be the principal mechanism whereby anti-oncogenic therapies such as chemotherapy and radiation effect their responses. Resistance to apoptosis, therefore, is probably a principal mechanism whereby tumors are able to overcome these cancer therapies. The transcription factor NF-kappaB is activated by chemotherapy and by irradiation in some cancer cell lines. Furthermore, inhibition of NF-kappaB in vitro leads to enhanced apoptosis in response to a variety of different stimuli. We show here that inhibition of NF-kappaB through the adenoviral delivery of a modified form of IkappaBalpha, the inhibitor of NF-kappaB, sensitizes chemoresistant tumors to the apoptotic potential of TNFalpha and of the chemotherapeutic compound CPT-11, resulting in tumor regression. These results demonstrate that the activation of NF-kappaB in response to chemotherapy is a principal mechanism of inducible tumor chemoresistance, and establish the inhibition of NF-kappaB as a new approach to adjuvant therapy in cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Apoptosis*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Drug Resistance
  • Female
  • Genetic Therapy / methods
  • I-kappa B Proteins*
  • Irinotecan
  • Mice
  • Mice, Nude
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • Neoplasms, Experimental / therapy*
  • Recombinant Proteins / biosynthesis
  • Tumor Necrosis Factor-alpha / therapeutic use*

Substances

  • Antineoplastic Agents, Phytogenic
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • Nfkbia protein, mouse
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Irinotecan
  • Camptothecin