Histone Deacetylase Inhibitors: Development as Anticancer Agents

Marks, Paul A.

doi:10.1002/9783527619665.ch40

Cited by 2 publications

(1 citation statement)

References 67 publications

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“…Clinical trial data demonstrate that HDACI as single agents have clinical activity with objective tumor regression, are in principle well tolerated and inhibit HDAC activity in target tumor cells as well as in peripheral blood mononuclear cells [63][64][65]100]. Various HDACI are already in clinical trials in combination with other cytotoxic principles [66][67][68][69].…”

Section: Future Perspectivesmentioning

confidence: 99%

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Fulda

2008

CCDT

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Triggering apoptosis, the cell's intrinsic death program, is a promising approach for cancer therapy. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of death inducing ligands, is of special interest for cancer therapy, since TRAIL has been shown to predominantly kill cancer cells, while sparing normal cells. However, since many cancers fail to undergo apoptosis in response to TRAIL treatment, TRAIL-based combination therapies have been developed for cancer-cell specific sensitization towards TRAIL. Chromatin remodelling plays an important role in gene regulation and aberrant architecture of the chromatin has been implicated in tumor formation and progression. In recent years, HDAC inhibitors (HDACI) that reverse aberrant epigenetic changes have emerged as a potential strategy to sensitize cancer cells for TRAIL-induced apoptosis. Synergistic tumor cell death has been reported in a variety of human cancers using different HDACI together with TRAIL. Here, recent advances in the understanding of the molecular events that underlie the synergistic interaction of HDACI and TRAIL are discussed as well as how this knowledge can be translated into the design of cancer-selective novel therapeutics.

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Section: Future Perspectivesmentioning

confidence: 99%

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Fulda

2008

CCDT

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Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

117

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The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

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Histone Deacetylase Inhibitors: Development as Anticancer Agents

Cited by 2 publications

References 67 publications

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

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