Clinical Development of Histone Deacetylase Inhibitors as Anticancer Agents

Drummond, Daryl C.; Noble, Charles O.; Kirpotin, Dmitri B.; Guo, Zexiong; Scott, Gary K.; Benz, Christopher C.

doi:10.1146/annurev.pharmtox.45.120403.095825

Cited by 571 publications

(562 citation statements)

References 143 publications

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“…A recurring theme that emerged from these phylogenetic studies was the common nature of association between HDAC molecules. It is well established that class I and class II HDACs are often found as components of larger transcription factor protein complexes [De Ruijter et al, 2002;Lehrmann et al, 2002;Marks et al, 2004;Sengupta and Seto, 2004;Drummond et al, 2005]. The possible functional significance of association among HDAC molecules is further considered below in the context of studies on the effect of suberoylanilide hydroxamic acid, (SAHA) on proteins associated with the proximal promotor region of the p21 gene [Gui et al, 2004].…”

Section: Histone Deacetylases (Hdacs) and Histone Acetyltransferases mentioning

confidence: 99%

“…HDACs targets include histones and nonhistone proteins which regulate gene expression and proteins involved in regulation of cell cycle progression, and cell death [Lehrmann et al, 2002;Johnstone and Licht, 2003;Warrener et al, 2003;Di Gennaro et al, 2004;Marks et al, 2004;Rosato and Grant, 2004;Drummond et al, 2005]. In addition, acetylation/deacetylation of histone and nonhistone proteins plays an important role in DNA replication and mitosis which does not involve directly altering gene expression.…”

Section: Histone Deacetylases (Hdacs) and Histone Acetyltransferases mentioning

confidence: 99%

“…Some examples of the different functions of the various HDACs include (see reviews Sengupta and Seto, 2004;Drummond et al, 2005]); HDAC1 complexed with myoD serves as a repressor of proliferating myoblasts. The expression of different HDACs through embryonic development changes with different stages of embryogenesis.…”

Section: Histone Deacetylases (Hdacs) and Histone Acetyltransferases mentioning

confidence: 99%

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Prospects: Histone deacetylase inhibitors

Dokmanovic

Marks

2005

J of Cellular Biochemistry

440

363

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Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti-cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non-histone proteins are also substrates for HDACs and HATs. The structure and activity of these non-histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi.

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Section: Histone Deacetylases (Hdacs) and Histone Acetyltransferases mentioning

confidence: 99%

Section: Histone Deacetylases (Hdacs) and Histone Acetyltransferases mentioning

confidence: 99%

Section: Histone Deacetylases (Hdacs) and Histone Acetyltransferases mentioning

confidence: 99%

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Prospects: Histone deacetylase inhibitors

Dokmanovic

Marks

2005

J of Cellular Biochemistry

440

363

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“…Under normal conditions, these modifications are balanced and reversible, but they may be altered in disease states. Epigenetic modifications have been shown to play a role in the pathogenesis of cancer as well as autoimmune and inflammatory disorders (1,2). Several recent publications have reported epigenetic modifications in gene transcription in SSc (3)(4)(5)(6).…”

mentioning

confidence: 99%

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Hemmatazad¹,

Rodrigues²,

Maurer³

et al. 2009

Arthritis & Rheumatism

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Objective. We have recently shown a significant reduction in cytokine-induced transcription of type I collagen and fibronectin in systemic sclerosis (SSc) skin fibroblasts upon treatment with trichostatin A (TSA). Moreover, in a mouse model of fibrosis, TSA prevented the dermal accumulation of extracellular matrix. The purpose of this study was to analyze the silencing of histone deacetylase 7 (HDAC-7) as a possible mechanism by which TSA exerts its antifibrotic function.Methods. Skin fibroblasts from patients with SSc were treated with TSA and/or transforming growth factor ␤. Expression of HDACs 1-11, extracellular matrix proteins, connective tissue growth factor (CTGF), and intercellular adhesion molecule 1 (ICAM-1) was analyzed by real-time polymerase chain reaction, Western blotting, and the Sircol collagen assay. HDAC-7 was silenced using small interfering RNA.Results. SSc fibroblasts did not show a specific pattern of expression of HDACs. TSA significantly inhibited the expression of HDAC-7, whereas HDAC-3 was up-regulated. Silencing of HDAC-7 decreased the constitutive and cytokine-induced production of type I and type III collagen, but not fibronectin, as TSA had done. Most interestingly, TSA induced the expression of CTGF and ICAM-1, while silencing of HDAC-7 had no effect on their expression.Conclusion. Silencing of HDAC-7 appears to be not only as effective as TSA, but also a more specific target for the treatment of SSc, because it does not up-regulate the expression of profibrotic molecules such as ICAM-1 and CTGF. This observation may lead to the development of more specific and less toxic targeted therapies for SSc.

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“…Inhibitors of DNA methylation (cytosine analogs; 5-azacytidine and 5-aza-2 0 -deoxycytidine) are currently used for the treatment of myelodysplastic syndrome and the first two HDAC inhibitors, vorinostat and romidepsin, have been approved by the FDA for the treatment of cutaneous T-cell lymphoma (http://clinicaltrials.gov) (Drummond et al, 2005;Grant et al, 2007;Xu et al, 2007). With the identification of large families of histone methyltransferases and demethylases The use of epi-drugs for therapy has both advantages and drawbacks.…”

Section: Current Therapeutic Paradigms To Treat Cancermentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Clinical Development of Histone Deacetylase Inhibitors as Anticancer Agents

Cited by 571 publications

References 143 publications

Prospects: Histone deacetylase inhibitors

Prospects: Histone deacetylase inhibitors

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Towards novel paradigms for cancer therapy

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