Targeting the apoptosis pathway in hematologic malignancies

Abstract

Apoptosis is a cell death program that is well-orchestrated for normal tissue homeostasis and for removal of damaged, old, or infected cells. It is regulated by intrinsic and extrinsic pathways. The intrinsic pathway responds to signals such as ultraviolet radiation or DNA damage and activates “executioner” caspases through a mitochondria-dependent pathway. The extrinsic pathway is activated by death signals induced, for example, by an infection that activates the immune system or receptor-mediated pathways. The extrinsic pathway signals also cascade down to executioner caspases that cleave target proteins and lead to cell death. Strict control of cellular apoptosis is important for the hematopoietic system as it has a high turnover rate. However, the apoptosis program is often deregulated in hematologic malignancies leading to the accumulation of malignant cells. Therefore, apoptosis pathways have been identified for development of anticancer therapeutics. We review here the proteins that have been targeted for anticancer drug development in hematologic malignancies. These include BCL-2 family proteins, death ligands and receptors, inhibitor of apoptosis family proteins, and caspases. Except for caspase activators, drugs that target each of these classes of proteins have advanced into clinical trials.

Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells

“…Dysregulation of the apoptotic pathways may not only promote tumorigenesis, but also render the cancer cells resistant to treatment. Therefore, it's very important to control cellular apoptosis strictly for the organisms, especially hematopoietic system as it has a high turnover rate [36]. In this study, we found celastrol could cause apoptosis of APL cells both in vitro and in vivo , indicating celastrol has anti-leukemia effect through inducing apoptosis.…”

A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy

“…DISC activates caspase 8, which then activates downstream caspases to initiate apoptotic cell death [19,73]. In the intrinsic pathway stress signals including DNA damage and loss of survival factors lead to the permeabilization of the OMM, which leads to loss of membrane potential and release of apoptogenic proteins such as cytochrome c from the IMS.…”

A novel synthetic compound exerts effective anti-tumour activity in vivo via the inhibition of tubulin polymerisation in A549 cells

“…4). In addition of mitochondria-mediated apoptosis pathway, membrane death receptor-mediated apoptosis and endoplasmic reticulum stress-mediated apoptosis are other important signaling pathway of apoptosis [53]. Further investigations that revealed whether compound 12P also activate other signaling pathway of apoptosis are under performed.…”