Targeting Bcl-2 Family Proteins: What, Where, When?
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REVIEW
Targeting BCL2 Family Proteins: What, Where, When? V. V. Senichkin1, N. V. Pervushin1, A. P. Zuev1, B. Zhivotovsky1,2, and G. S. Kopeina1,a* 1
Faculty of Basic Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia 2 Institute of Environmental Medicine, Karolinska Institute, 171 77 Stockholm, Sweden a email: [email protected] Received July 15, 2020 Revised July 15, 2020 Accepted August 8, 2020
Abstract—Proteins of the Bcl2 family are known as regulators of apoptosis, one of the most studied forms of programmed cell death. The Bcl2 protein family is represented by both pro and antiapoptotic members. Antiapoptotic proteins are often exploited by tumor cells to avoid their death, thus playing an important role in carcinogenesis and in acquisition of resistance to various therapeutic agents. Therefore, antiapoptotic proteins represent attractive targets for cancer therapy. A detailed investigation of interactions between Bcl2 family proteins resulted in the development of highly selective inhibitors of individual antiapoptotic members. These agents are currently being actively studied at the preclinical and clinical stages and represent a promising therapeutic strategy, which is highlighted by approval of venetoclax, a selective inhibitor of Bcl 2, for medical use. Meanwhile, inhibition of antiapoptotic Bcl2 family proteins has significant therapeutic potential that is yet to be revealed. In the coming era of precision medicine, a detailed study of the mechanisms responsible for the sensitiv ity or resistance of tumor cells to various therapeutic agents, as well as the search for the most effective combinations, is of great importance. Here, we discuss mechanisms of how the Bcl2 family proteins function, principles of their inhibition by small molecules, success of this approach in cancer therapy, and, eventually, biochemical features that can be exploited to improve the use of Bcl2 family inhibitors as anticancer drugs. DOI: 10.1134/S0006297920100090 Keywords: apoptosis, Bcl2 family, cancer therapy, BH3mimetics
INTRODUCTION The search for new anticancer therapeutic strategies is one of the major challenges of modern medicine. The main principle of tumor cell biology is selection of the cells that are best adapted for survival. As a result, these cells are characterized by a number of acquired adaptive mechanisms, including resistance to programmed cell death (PCD) [1]. Apoptosis, which is one of the most studied forms of PCD, plays an important role in tumor suppression [1]. There are two main pathways of apoptosis induction: the intrinsic (mitochondrial) and the extrinsic (death receptor) pathways. The latter is initiated, in particular, via binding of the corresponding ligands (e.g., tumor Abbreviations: AML, acute myeloid leukemia; BHdomain, Bcl2 homology domain; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; MOMP, mitochondrial outer mem brane permeabilization; NSCLC, nonsmall cell lung carcino ma; OMM, outer mitochondrial membrane; PCD, pro grammed cell death;
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