Cell death and the mitochondria: therapeutic targeting of the BCL‐2 family‐driven pathway

Abstract

The principal biological role of mitochondria is to supply energy to cells; although intriguingly, evolution has bestowed another essential function upon these cellular organelles: under physiological stress, mitochondria become the cornerstone of apoptotic cell death. Specifically, mitochondrial outer membrane permeabilization (MOMP) allows cell death factors such as cytochrome c to be released into the cytoplasm, thus inducing caspase activation and the eventual destruction of essential cellular components. Proteins of the B‐cell lymphoma 2 (BCL‐2) family control the tightly regulated pathway that causes MOMP. The equilibrium between pro‐survival and pro‐apoptotic members of the BCL‐2 family dictates the fate of cells, the homeostasis of organs and, by extension, the health of whole organisms. Dysregulation of this equilibrium is involved in a large number of diseases such as cancer, autoimmunity and neurodegenerative conditions. Modulating the activity of the BCL‐2 family of proteins with small molecules or peptides is an attractive but challenging therapeutic goal. This review highlights the latest developments in this field and provides evidence that this strategy is likely to have a positive effect on the treatment of still poorly addressed medical conditions. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8

Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma

“…On the basis of this fact, programmed cell death inhibits tumor growth and constitutes potential target for cancer therapy. Of the three common types of programmed cell death, including apoptosis, autophagy and necrosis, apoptosis is the most extensively studied and well-defined one (35)(36)(37)(38). We have found that lycorine initiates apoptotic cell death in HCC cells, which is supported by the results of DAPI staining and V-FITC/PI double staining.…”

“…Caspases that belong to the family of cysteine proteases are integral components of the apoptotic pathway. Recently, many studies have shown that a variety of chemotherapeutic agents promote apoptosis through the activation of caspases (38)(39)(40). In this study, we have found that lycorine treatment markedly augments caspase activity, and upregulates cleaved caspase-3 and PARP.…”

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

“…A number of drugs directed at inhibiting anti-apoptotic BCL-2 family proteins have been developed, with some showing great promise in clinical settings (Weyhenmeyer et al, 2012;Roy et al, 2014). Two strategies are recommended to block Bcl-2 and Bcl-xL, including I) application of Bcl-2 antisense, and II) application of small molecule inhibitors of the Bcl-2 family of proteins.…”

Apoptosis as a Therapeutic Target in Chronic Lymphocytic Leukemia

“…7 The BH3-mimetic concept has prompted the design of numerous small BH3 peptides or organic molecules. 8,9 However, many of the generated compounds turned out to act through off-target mechanisms. Only a few of them were found to behave as authentic BH3 mimetics with the ability to bind prosurvival proteins with high affinity and to induce BAX/BAK-dependent apoptosis in malignant cells.…”

“…Only a few of them were found to behave as authentic BH3 mimetics with the ability to bind prosurvival proteins with high affinity and to induce BAX/BAK-dependent apoptosis in malignant cells. 8,9 The prototype ABT-737 and its orally bioavailable derivative navitoclax (formerly, ABT-263) bind and antagonize BCL-2, BCL-XL, and BCL-W (so they are referred to as BAD-like BH3 mimetics). 10,11 Navitoclax has shown significant therapeutic activity in cancer patients but with a doselimiting thrombocytopenia because of inhibition of BCL-XL (that is a prosurvival factor for platelets).…”