Targeting histone deacetylase in cancer therapy (original) (raw)
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International journal of biological sciences, 2014
Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, studies over the past decades have demonstrated that epigenetic regulation also participates in the development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are a group of enzymes which catalyze the removal of the acetyl groups of both histones and non-histone proteins. HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors are being investigated to act as cancer chemotherapeutics. The...
Applied Microbiology and Biotechnology, 2007
Histone deacetylase inhibitors reside among the most promising targeted anticancer agents that are potent inducers of growth arrest, differentiation, and/or apoptotic cell death of transformed cells. In October 2006, the US Food and Drug Administration approved the first drug of this new class, vorinostat (1, Zolinza, Merck). Several histone deacetylase (HDAC) inhibitors more are in clinical trials. HDAC inhibitors have shown significant activity against a variety of hematological and solid tumors at doses that are well tolerated by patients, both in monotherapy as well as in combination therapy with other drugs. This paper reviews the most recent developments in HDAC inhibitor design, particularly in the context of anticancer therapy, and other possible pharmaceutical applications.
Histone deacetylase inhibitors as a potential therapeutic agent for human cancer treatment
Targeted Oncology, 2006
Recent evidence pointed that remodeling of the chromatin template by inhibition of the enzyme histone deacetylase could be a promising approach for the treatment of human cancer. Alterations in histone acetylation may lead to changes in chromatin structure and transcriptional dysregulation of genes that are implicated in controlling cell cycle progression or pathways regulating cell differentiation and apoptosis. The histone deacetylase (HDAC) inhibitors are currently a new class of antineoplastic agents. They bind DNA tightly to histones, preventing the transcription of several tumor suppression genes without modifying DNA sequence. At present, there are already too many HDAC inhibitors available and hopefully some of them could help substantially in the prevention and treatment of cancer. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to be becoming possible. Several ongoing National Institute of Health (NIH) trials are investigating the use of these agents in combination with potent chemotherapeutic agents, with the aim of increasing their efficiency. Further studies are needed to delineate the optimal dosage, the duration of therapy and possibly the efficacy of other agents able to synergize with HDAC inhibitors in the fight against cancer.
Histone Deacetylase Inhibitors in the Treatment of Hematological Malignancies and Solid Tumors
Journal of Biomedicine and Biotechnology, 2011
The human genome is epigenetically organized through a series of modifications to the histone proteins that interact with the DNA. In cancer, many of the proteins that regulate these modifications can be altered in both function and expression. One example of this is the family of histone deacetylases (HDACs), which as their name implies remove acetyl groups from the histone proteins, allowing for more condensed nucleosomal structure. HDACs have increased expression in cancer and are also believed to promote carcinogenesis through the acetylation and interaction with key transcriptional regulators. Given this, small molecule histone deacetylases inhibitors have been identified and developed, which not only inhibit HDACs, but can also lead to growth arrest, differentiation, and/or apoptosis in tumors bothin vitroandin vivo. Here, we will discuss some of the recent developments in clinical trials utilizing HDACs inhibitors for the treatment of both hematological malignancies as well a...
Histone Deacetylase Inhibitor as a Novel Anticancer Agent: A Review
2015
Histone Deacetylase (HDAC) inhibitors are an exciting new class of drugs that are targeted as anti- cancer agents. These compounds can induce growth arrest, apoptosis and/ or terminal differentiation in a variety of solid and hematological neoplasms in patients with advanced disease. Accumulation of acetylated histones in both normal and tumour cells can be used as a marker of biological activity. Hydroxamic acid based compounds are among the most promising HDAC inhibitors as potential anti-cancer drugs. There is still much to be understood about the family of HDACs, including the varying functions of different HDACs and the range of HDAC substrates. The development of selective HDAC inhibitors might be important in defining their biological role and potential as therapeutic agents. Clinically, the optimal dose, timing and duration of therapy, as well as the most appropriate agents to combine with HDAC inhibitors, are still to be defined.
Histone Deacetylase Inhibitors: A New Wave of Molecular Targeted Anticancer Agents
Recent Patents on Anti-Cancer Drug Discovery, 2007
Epigenetics as well as post-translational modifications of proteins are emerging as novel attractive targets for anti-cancer therapy. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two classes of enzymes regulating histone acetylation and whose altered activity has been identified in several cancers. In particular, imbalance in histone acetylation can lead to changes in chromatin structure and transcriptional dysregulation of genes that are involved in the control of proliferation, cell-cycle progression, differentiation and/or apoptosis. In addition, several non histone protein substrates such as transcription factors, chaperone proteins or tubulin, undergo acetylation as key post-translation modification regulating their half-life and function. On this regard, several inhibitors of HDAC, selected by academic as well as industrial research, have been recently shown to induce growth arrest and apoptosis in a variety of human cancer cells and have been patented as anti-cancer agents. Although several clinical studies with HDAC inhibitors are ongoing, their mechanism of action cannot be solely attributed to the level of histone acetylation and molecular basis for their tumor selectivity remains unknown, presenting a challenge for the cancer research community.
Directing The Role of Histone Deacetylase Inhibitors in Cancer Therapy: A Review
2019
Histone deacetylase inhibitors have been dynamicallyexposed in epigenetic changes,they mark the genetic processes covering the cell cycle,apoptosis,DNA repair ,cell cycle control,autophagy, metabolism,senescence and chaperone function.Several families of histone deacetylase (HDAC) inhibitors have been synthesized and evaluated with their optimistic effects on the cell cycle that have been confirmed in biological models and in clinical trials. Vorinostat,Romidepsin and Belinostat are recently approved for oncologic indications of refractory cutaneous and peripheral T cell Lymphoma.These advances havedelivered the stimulus to develop more potent and selective inhibitors and target other pathologic conditions with these drugs..To provide an overview of the use of HDAC inhibitors in cancer treatment, this review addresses the following subjects: (1) the physiological relevance of HDAC-mediated acetylation of histone and nonhistone substrates, and (2) the protein acetylation-independent ...
Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review
Molecular Pharmacology, 2005
The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifi-cally the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy.
Histone Deacetylases: A Saga of Perturbed Acetylation Homeostasis in Cancer
Journal of Histochemistry & Cytochemistry, 2014
In the current era of genomic medicine, diseases are identified as manifestations of anomalous patterns of gene expression. Cancer is the principal example among such maladies. Although remarkable progress has been achieved in the understanding of the molecular mechanisms involved in the genesis and progression of cancer, its epigenetic regulation, particularly histone deacetylation, demands further studies. Histone deacetylases (HDACs) are one of the key players in the gene expression regulation network in cancer because of their repressive role on tumor suppressor genes. Higher expression and function of deacetylases disrupt the finely tuned acetylation homeostasis in both histone and non-histone target proteins. This brings about alterations in the genes implicated in the regulation of cell proliferation, differentiation, apoptosis and other cellular processes. Moreover, the reversible nature of epigenetic modulation by HDACs makes them attractive targets for cancer remedy. This review summarizes the current knowledge of HDACs in tumorigenesis and tumor progression as well as their contribution to the hallmarks of cancer. The present report also describes briefly various assays to detect histone deacetylase activity and discusses the potential role of histone deacetylase inhibitors as emerging epigenetic drugs to cure cancer.