Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks

Oncogene. 2004 Apr 12;23(16):2934-49. doi: 10.1038/sj.onc.1207515.

Abstract

Intrinsic (innate) and acquired (adaptive) resistance to chemotherapy critically limits the outcome of cancer treatments. For many years, it was assumed that the interaction of a drug with its molecular target would yield a lethal lesion, and that determinants of intrinsic drug resistance should therefore be sought either at the target level (quantitative changes or/and mutations) or upstream of this interaction, in drug metabolism or drug transport mechanisms. It is now apparent that independent of the factors above, cellular responses to a molecular lesion can determine the outcome of therapy. This review will focus on programmed cell death (apoptosis) and on survival pathways (Bcl-2, Apaf-1, AKT, NF-kappaB) involved in multidrug resistance. We will present our molecular interaction mapping conventions to summarize the AKT and IkappaB/NF-kappaB networks. They complement the p53, Chk2 and c-Abl maps published recently. We will also introduce the 'permissive apoptosis-resistance' model for the selection of multidrug-resistant cells.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis*
  • Apoptotic Protease-Activating Factor 1
  • Drug Resistance, Neoplasm*
  • Humans
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / pathology*
  • Protein-Serine-Threonine Kinases*
  • Proteins / physiology
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / physiology

Substances

  • APAF1 protein, human
  • Apoptotic Protease-Activating Factor 1
  • NF-kappa B
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt