Epigenetic therapy of cancer with histone deacetylase inhibitors (original) (raw)
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Histone deacetylase inhibitors providing an epigenetic treatment in cancer
İstanbul Journal of Pharmacy, 2021
Cancer is among the leading causes of death worldwide and is therefore one of the diseases in which there have been major medical advances and which is the focus of researchers. Drugs used in cancer treatment affect rapidly proliferating normal cells as well as cancer cells. In recent years, targeted therapy has been provided by identifying specific pathways in cancer cells. Epigenetic mechanisms are among the targeted therapies in cancer treatment. Epigenetic regulators ensure the continuity of the normal process by inducing epigenetic changes through epigenetic mechanisms such as DNA methylation, histone post-translational modifications, and non-coding RNA regulation. Histone deacetylases (HDACs), which are involved in transcription-independent events such as DNA repair and mitosis, are enzymes that remove acetyl groups attached to the lysine residue in the amino terminal tails of histones. Histone deacetylase inhibitors (HDACIs) that provide epigenetic treatment of cancer, which ...
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer
Nature Reviews Cancer, 2006
Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.
DNA and Cell …, 2012
Cancer is a pathologic condition that involves genetic and epigenetic events culminating in neoplastic transformation. Alteration in epigenetic events that regulate the transcriptional activity of genes associated with various signaling pathways can influence multiple stages of tumorigenesis. In cancer cells, an imbalance often exists between histone acetyl transferase and histone deacetylase (HDAC) activities, and current research focuses actively on seeking competitive HDAC inhibitors (HDACi) for chemotherapeutic intervention. HDACi are proving useful for cancer prevention and therapy by virtue of their ability to reactivate the expression of epigenetically silenced genes, including those involved in differentiation, cell cycle regulation, apoptosis, angiogenesis, invasion, and metastasis. Furthermore, epidemiological studies suggest that different diets such as intake of cruciferous vegetables may lower the risk of different cancers, and there is growing interest in identifying the specific chemoprotective constituents and mechanistic insights of their action. Interestingly, it has been observed that cancer cells are more sensitive than nontransformed cells to apoptotic induction by some HDACi. Although the mechanistic basis for this sensitivity is unclear, yet HDACi have emerged as important epigenetic target for single and combinatorial chemotherapy. HDACi derived from diverse sources such as microbial, dietary, and synthetic increase acetylation level of cells and bring about anti-proliferative and apoptotic effects specific to cancer cells by way of their role in cell cycle regulation and expression of epigenetically silenced genes.
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...
Histone deacetylation in epigenetics: an attractive target for anticancer therapy
Medicinal research …, 2005
The reversible histone acetylation and deacetylation are epigenetic phenomena that play critical roles in the modulation of chromatin topology and the regulation of gene expression. Aberrant transcription due to altered expression or mutation of genes that encode histone acetyltransferase (HAT) or histone deacetylase (HDAC) enzymes or their binding partners, has been clearly linked to carcinogenesis. The histone deacetylase inhibitors are a new promising class of anticancer agents (some of which in clinical trials), that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell-cycle arrest, terminal differentiation, and/or apoptosis. This report reviews the chemistry and the biology of HDACs and HDAC inhibitors, laying particular emphasis on agents actually in clinical trials for cancer therapy and on new potential anticancer lead compounds more selective and less toxic. ß 2005 Wiley Periodicals, Inc. Med Res Rev, 25, No. 3, 261-309, 2005
Review Potential use of histone deacetylase inhibitors in cancer therapy
Współczesna Onkologia, 2015
Epigenetics is a branch of science that focuses on mechanisms related to control and modification of expression of genetic material without any changes to its sequences. Such mechanisms include post-translational modifications of histones. It is widely known that carcinogenesis is related to hypoacetylation of genes that influence apoptosis, the cell cycle, cell signaling, the immunologic response, angiogenesis and occurrence of metastasis. Currently conducted research focuses on several strategies related to epigenetic therapy. One such strategy is based on the use of histone deacetylase inhibitors. This paper presents mechanisms through which these compounds work and a summary of their characteristics. It also includes a review of clinical tests related to histone deacetylase inhibitors, as well as their relationship with other chemotherapeutic methods. A better understanding of the involved mechanisms will provide a rational basis to improve the therapeutic outcome of available antitumor agents.
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.
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.
Targeting histone deacetylase in cancer therapy
Medicinal Research Reviews, 2006
Histone deacetylase (HDAC) is recognized as one of the promising targets for cancer treatment as many HDAC inhibitors have entered clinical trials for both solid and liquid tumors. Nevertheless, the mechanisms underlying the antiproliferative effects of HDAC inhibitors remain elusive. Although they have been shown to regulate the transcription of a defined set of genes through chromatin remodeling, increasing evidence suggests that modifications of the epigenetic histone code may not be the primary mechanism for HDAC inhibitor-mediated growth inhibition and apoptosis in cancer cells. While histones still represent a primary target for the physiological function of HDACs, the antitumor effect of HDAC inhibitors might also be attributed to transcription-independent mechanisms by modulating the acetylation status of a series of nonhistone targets. Also noteworthy is the effect of HDAC inhibitors on Akt downregulation through the alteration of protein phosphatase 1 (PP1) complex formation. 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, (2) the chemical biology of HDACs and development of a novel class of HDAC inhibitors, and (3) the protein acetylation-independent effect of HDAC inhibitors on the activation status of signaling kinases. ß