Histone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapy
Abstract
Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression by catalyzing the removal of acetyl groups, stimulating chromatin condensation and promoting transcriptional repression. Since aberrant epigenetic changes are a hallmark of cancer, HDACs are a promising target for pharmacological inhibition. HDAC inhibitors can induce cell-cycle arrest, promote differentiation, and stimulate tumor cell death. These properties have prompted numerous preclinical and clinical investigations evaluating the potential efficacy of HDAC inhibitors for a variety of malignancies. The preferential toxicity of HDAC inhibitors in transformed cells and their ability to synergistically enhance the anticancer activity of many chemotherapeutic agents has further generated interest in this novel class of drugs. Here we summarize the different mechanisms of HDAC inhibitor-induced apoptosis and discuss their use in combination with other anticancer agents.
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Enhanced histone acetylation induced by HDACi allows overexpression of genes involved in cell cycle arrest, such as cyclin-dependent kinase inhibitors or the GADD45 gene family.
“Previous studies showed that enhanced histone acetylation induced by HDACi allowed the overexpression of genes involved in cell cycle arrest such as cyclin-dependent kinase inhibitors or the growth arrest and DNA damage-inducible protein GADD45 gene family (11, 28, 40, 45-49).”
From Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability (2013) · cites this paper as [48]
Cites
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- Authors
- Carew, J. S., Giles, F. J., & Nawrocki, S. T.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Nawrocki, Steffan T.
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 269
- Issue
- 1
- Pages
- 7-17
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2021172314
- Cited by
- 421
- References
- 2
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 10 · 2020: 21 · 2019: 15 · 2018: 13 · 2017: 14 · 2016: 21 · 2015: 34 · 2014: 27 · 2013: 39 · 2012: 41
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- histone deacetylase inhibitors, histone deacetylase, epigenetic regulation, apoptosis mechanism, combination cancer therapy, synergistic anticancer activity, cell cycle arrest, differentiation therapy, chromatin condensation, transcriptional repression, cancer cell death
- MeSH terms
- Bortezomib, Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Autophagy, Boronic Acids, Clinical Trials as Topic, Drug Synergism, Enzyme Inhibitors, Humans, Mitochondria, Neoplasms, Pyrazines, Apoptosis, Reactive Oxygen Species, Angiogenesis Inhibitors, TNF-Related Apoptosis-Inducing Ligand, Histone Deacetylase Inhibitors
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