Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks.
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.
Pommier
Yves
Y
Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, DHHS, Bethesda, MD 20892, USA. pommiery@pasteur.fr
Sordet
Olivier
O
Antony
Smitha
S
Hayward
Richard L
RL
Kohn
Kurt W
KW
D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D016328:NF-kappa B; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt