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-jB) involved in multidrug resistance. We will present our molecular interaction mapping conventions to summarize the AKT and IjB/NF-jB 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.

Histone deacetylase inhibitors: molecular mechanisms of action

“…The basis of resistance to HDACi is not well understood. High levels of Bcl-2 (Pommier et al, 2004), Trx (Powis et al, 2000) and peroxiredoxins (Chung et al, 2001) have been associated with resistance of transformed cells to chemotherapy, and may play a role in the resistance to HDACi. Upregulation of Trx protects normal cells against HDACi-induced cell death (Ungerstedt et al, 2005).…”

Epigenetics as a mechanism driving polygenic clinical drug resistance

“…This can be reduced by grouping genes into predefined groups according to a biological hypothesis such as grouping those with similar biological roles or within the same pathway, on the assumption that disruption of any one gene within a pathway or group will disrupt the functioning of that cellular response. This is undoubtedly an oversimplification and the approach will need to be refined as more sophisticated molecular interaction maps and networks are developed (Pommier et al, 2004). An alternative approach will be to use supervised search algorithms that efficiently search array data to identify clusters that associate with clinical outcome (for instance, see Bair and Tibshirani, 2004).…”

The role of histone acetylation versus DNA damage in drug-induced senescence and apoptosis

“…During the last decade, the major focus of basic research was directed towards defining the molecular pathways of apoptosis and determination of their role in chemotherapy outcome, particularly since this form of cellular demise was believed to be a key factor in the development of drug resistance. 1 However, recent evidence indicates that the inhibition of apoptosis alone may not be sufficient for acquisition of the drug resistance phenotype [2][3][4] and that cancer cells not only have to be viable, but must be able to proliferate in order for the tumor to progress and develop a drug-resistant phenotype. Considering that cancer cell lines with deficiencies in the apoptotic pathway can still undergo proliferation arrest as a generalized response to drugs, achieving irreversible growth arrest would be sufficient for the control of cancer progression and the prevention of drug resistance.…”