Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

Abstract

Most chemotherapeutic drugs can induce tumor cell death by apoptosis. Analysis of the molecular mechanisms that regulate apoptosis has indicated that anticancer agents simultaneously activate several pathways that either positively or negatively regulate the death process. The main pathway from specific damage induced by the drug to apoptosis involves activation of caspases in the cytosol by pro-apoptotic molecules such as cytochrome c released from the mitochondrial intermembrane space. At least in some cell types, anticancer drugs also upregulate the expression of death receptors and sensitize tumor cells to their cognate ligands. The Fas-mediated pathway could contribute to the early steps of drug-induced apoptosis while sensitization to the cytokine TRAIL could be used to amplify the response to cytotoxic drugs. The Bcl-2 family of proteins, that includes anti-and pro-apoptotic molecules, regulates cell sensitivity mainly at the mitochondrial level. Anticancer drugs modulate their expression (eg through p53-dependent gene transcription), their activity (eg by phosphorylating Bcl-2) and their subcellular localization (eg by inducing the translocation of specific BH3-only pro-apoptotic proteins). Very early after interacting with tumor cells, anticancer drugs also activate lipid-dependent signaling pathways that either increase or decrease cell ability to die by apoptosis. In addition, cytotoxic agents can activate protective pathways that involve activation of NF B transcription factor, accumulation of heat shock proteins such as Hsp27 and activation of proteins involved in cell cycle regulation. This review discusses 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.

Analysis of p53/BAX in primary colorectal carcinoma: Low BAX protein expression is a negative prognostic factor in UICC stage III tumors

“…5,39 Cytochrome c forms an active complex with APAF-1, which recruits procaspase-9 and thereby leads to the final execution of the cell death by activating the downstream caspase cascade. 3,[7][8][9][10][11][12] The BAX/APAF-1/Caspase pathway of apoptosis may also be functional in death receptor triggered apoptotic cell death. This process presumably involves a Bid-dependent pathway leading to a conformational change in BAX.…”

“…5 Cytochrome c forms an active complex with APAF-1 that recruits procaspase-9 and thereby leads to the final execution of the cell death by activating the downstream caspase cascade. 3,[7][8][9][10][11][12] We have shown previously that loss of BAX expression correlates with a poor prognosis in patients with hepatic metastases of colorectal cancer undergoing surgical resection of liver metastases. 13 Similar data were obtained in diffuse aggressive nonHodgkin-lymphoma, 14 ovarian, 15 pancreatic 16 and esophageal cancer 17 where reduced BAX expression was also observed to be a negative prognostic factor.…”

In vitro susceptibility to TRAIL-induced apoptosis of acute leukemia cells in the context of TRAIL receptor gene expression and constitutive NF-κB activity

“…Our findings support the assumption that TRAIL-mediated apoptosis could amplify the response to cytotoxic drugs in tumor cells. 1 Further studies on TRAIL toxicity on normal human cells will show whether TRAIL has the potential as a cotherapeutic in cancer therapy or whether it will share the fate of TNF␣ and CD95L which cannot be used in systemic anticancer therapy because of severe toxic side-effects. 1 To our knowledge, this series is so far the largest study on the in vitro TRAIL susceptibility of primary acute leukemia cells.…”

“…[1][2][3] TRAIL, a member of the TNF family, was initially shown to induce surface receptor-mediated apoptosis in tumor cells but not in normal cells. 4,5 In several mouse models, in vivo administration of TRAIL induced apoptosis in a variety of human malignant cells.…”

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

“…This striking interaction between drug-and death receptorinduced apoptosis led to the hypothesis that these receptors may be directly involved in drug-induced apoptosis. [146][147][148] Death ligands and receptors may be induced during drugtriggered apoptosis (see above).…”