Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks

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.