Positive and negative regulation of apoptotic pathways by cytotoxic agentsin hematological malignancies

Most chemotherapeutic drugs can induce tumor cell death by apoptosis. Analy sis of the molecular mechanisms that regulate apoptosis has indicated that anticancer agents simultaneously activate several pathways that either posi tively or negatively regulate the death process. The main pathway from spec ific damage induced by the drug to apoptosis involves activation of caspase s in the cytosol by pro-apoptotic molecules such as cytochrome c released f rom the mitochondrial intermembrane space. At least in some cell types, ant icancer drugs also upregulate the expression of death receptors and sensiti ze tumor cells to their cognate ligands. The Fas-mediated pathway could con tribute to the early steps of drug-induced apoptosis while sensitization to the cytokine TRAIL could be used to amplify the response to cytotoxic drug s. The Bcl-2 family of proteins, that includes anti- and pro-apoptotic mole cules, regulates cell sensitivity mainly at the mitochondrial level. Antica ncer drugs modulate their expression leg through p53-dependent gene transcr iption), their activity leg by phosphorylating Bcl-2) and their subcellular localization leg by inducing the translocation of specific BH3-only pro-ap optotic proteins). Very early after interacting with tumor cells, anticance r drugs also activate lipid-dependent signaling pathways that either increa se or decrease cell ability to die by apoptosis. In addition, cytotoxic age nts can activate protective pathways that involve activation of NF kappa B transcription factor, accumulation of heat shock proteins such as Hsp27 and activation of proteins involved in cell cycle regulation. This review disc usses how modulation of the balance between noxious and protective signals that regulate drug-induced apoptosis could be used to improve the efficacy of current therapeutic regimens in hematological malignancies.