The application of BH3 mimetics in myeloid leukemias.
Animals
Antineoplastic Agents
/ adverse effects
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Apoptosis
/ drug effects
Bridged Bicyclo Compounds, Heterocyclic
/ adverse effects
Drug Design
Humans
Leukemia, Myeloid
/ drug therapy
Molecular Mimicry
Molecular Targeted Therapy
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Signal Transduction
Sulfonamides
/ adverse effects
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
26 02 2021
26 02 2021
Historique:
received:
29
09
2020
accepted:
01
02
2021
revised:
29
01
2021
entrez:
27
2
2021
pubmed:
28
2
2021
medline:
14
9
2021
Statut:
epublish
Résumé
Execution of the intrinsic apoptotic pathway is controlled by the BCL-2 proteins at the level of the mitochondrial outer membrane (MOM). This family of proteins consists of prosurvival (e.g., BCL-2, MCL-1) and proapoptotic (e.g., BIM, BAD, HRK) members, the functional balance of which dictates the activation of BAX and BAK. Once activated, BAX/BAK form pores in the MOM, resulting in cytochrome c release from the mitochondrial intermembrane space, leading to apoptosome formation, caspase activation, and cleavage of intracellular targets. This pathway is induced by cellular stress including DNA damage, cytokine and growth factor withdrawal, and chemotherapy/drug treatment. A well-documented defense of leukemia cells is to shift the balance of the BCL-2 family in favor of the prosurvival proteins to protect against such intra- and extracellular stimuli. Small molecule inhibitors targeting the prosurvival proteins, named 'BH3 mimetics', have come to the fore in recent years to treat hematological malignancies, both as single agents and in combination with standard-of-care therapies. The most significant example of these is the BCL-2-specific inhibitor venetoclax, given in combination with standard-of-care therapies with great success in AML in clinical trials. As the number and variety of available BH3 mimetics increases, and investigations into applying these novel inhibitors to treat myeloid leukemias continue apace the need to evaluate where we currently stand in this rapidly expanding field is clear.
Identifiants
pubmed: 33637708
doi: 10.1038/s41419-021-03500-6
pii: 10.1038/s41419-021-03500-6
pmc: PMC7908010
doi:
Substances chimiques
Antineoplastic Agents
0
BCL2 protein, human
0
Bridged Bicyclo Compounds, Heterocyclic
0
Proto-Oncogene Proteins c-bcl-2
0
Sulfonamides
0
venetoclax
N54AIC43PW
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
222Subventions
Organisme : Wellcome Trust
ID : 204820/Z/16/Z
Pays : United Kingdom
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