Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies
Abstract
The 'hallmarks of cancer' are generally accepted as a set of genetic and epigenetic alterations that a normal cell must accrue to transform into a fully malignant cancer. It follows that therapies designed to counter these alterations might be effective as anti-cancer strategies. Over the past 30 years, research on the BCL-2-regulated apoptotic pathway has led to the development of small-molecule compounds, known as 'BH3-mimetics', that bind to pro-survival BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and, specifically, its roles in cancer development and therapy.
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In response to apoptotic stimuli, MOMP is mediated by BAX and/or BAK.
“In response to apoptotic stimuli, MOMP is mediated by BCL2 associated X, apoptosis regulator (BAX), and/or BCL2 antagonist/killer 1 (BAK1; best known as BAK), both of which contain four BH domains and a conserved transmembrane domain [44–46].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [44]
MOMP directly promotes the cytosolic release of apoptogenic factors that normally reside in the mitochondrial intermembrane space, including cytochrome c (CYCS) and SMAC.
“MOMP directly promotes the cytosolic release of apoptogenic factors that normally reside in the mitochondrial intermembrane space [40, 44, 156]. These mitochondrial proteins include (but are not limited to) cytochrome c, somatic (CYCS), which usually operates as an electron shuttle in the mitochondrial respiratory chain [157–160], and diablo IAP-binding mitochondrial protein (DIABLO; also known as”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [44]
Overexpression of drug resistance-associated genes, such as P-gp and Bcl-2, is one of the most consistent alterations in multidrug resistant cells.
“Overexpression of drug resistance-associated genes, such as P-gp and Bcl-2, is one of the most consistent alterations in multidrug resistant cells [131–134].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [134]
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Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak
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- Authors
- Delbridge, A. R. D., Grabow, S., Strasser, A., & Vaux, D. L.
- Affiliations
- The University of Melbourne (AU)
- Corresponding author
- Strasser, Andreas
- Vaux, David L.
- Venue
- Nature Reviews Cancer
- Published
- 2016-01-29
- Volume
- 16
- Issue
- 2
- Pages
- 99-109
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2252711380
- Cited by
- 752
- References
- 196
- Citations by year
- 2026: 36 · 2025: 42 · 2024: 65 · 2023: 75 · 2022: 75 · 2021: 100 · 2020: 91 · 2019: 70 · 2018: 78 · 2017: 92 · 2016: 27
- FWCI
- 8.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Clusterin in disease pathology
- Keywords
- Bcl-2, Bcl-2 family proteins, apoptosis, BH3 mimetics, cancer therapy, cancer hallmarks
- MeSH terms
- Animals, Biphenyl Compounds, Multigene Family, Humans, Neoplasms, Nitrophenols, Piperazines, Sulfonamides, Gene Expression Regulation, Neoplastic, Cell Death, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Genes, bcl-2, Mitochondrial Membrane Transport Proteins, bcl-2-Associated X Protein, Mice, Molecular Targeted Therapy
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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