Review Potential use of histone deacetylase inhibitors in cancer therapy (original) (raw)
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Epigenetic therapy of cancer with histone deacetylase inhibitors
Journal of cancer research and therapeutics
Epigenetics is the study of heritable alterations in gene expression that are not accompanied by the corresponding change in DNA sequence. Three interlinked epigenetic processes regulate gene expression at the level of chromatin, namely DNA methylation, nucleosomal remodeling and histone covalent modifications. Post-translational modifications that occur on certain amino acid residues of the tails of histone proteins modify chromatin structure and form the basis for "histone code". The enzymes Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) control the level of acetylation of histones and thereby alter gene expression. In many cancers, the balance between HAT and HDAC is altered. HDAC enzymes are grouped into four different classes namely Class I (HDAC1, HDAC2, HDAC3, and HDAC8), Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), Class III HDAC and Class IV (HDAC11). Histone Deacetylase Inhibitors (HDACI) exert anticancer activity by promoting acetyl...
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 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
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.
Current perspective of histone deacetylase inhibitors: A review
IP Innovative Publication Pvt. Ltd., 2018
Epigenetic therapeutics are the new generation of chemotherapeutics for treatment of cancer, and histone deacetylase inhibitors have been actively discovered in this category They target the biological processes including 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. Their positive effects on the cell cycle have been demonstrated in biological models and in clinical trials. Recently Food and Drug Administration has approved Vorinostat, Romidepsin and Belinostat for oncologic indications of refractory cutaneous and peripheral T cell Lymphoma. These advances have provided the motivation to develop more potent and selective inhibitors and target other pathologic conditions with these drugs. Major ongoing efforts are to develop inhibition as monotherapy, rational combination with chemotherapy and other targeted drugs. Some progress is made into developing isoform specific drugs. In this perspective, the biological functions and potential substrates of histone deacetylase enzymes are reviewed and the characteristics of this inhibitors are discussed in respect with anticancer activity and further therapeutic interest. Keywords: Epigenetic therapeutics, Histone deacetylase inhibitors, Anticancer, Classification, Food and drug administration approved drugs.
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.
Histone deacetylase inhibitors as anti-neoplastic agents
Cancer Letters, 2009
Histone deacetylase inhibitors (HDACIs) constitute a novel class of targeted drugs that alter the acetylation status of histones and other important cellular proteins. These agents modulate chromatin structure leading to transcriptional changes, induce pleiotropic effects on functional pathways and activate cell death signaling in cancer cells. Anti-neoplastic activity in vitro was shown in several experimental models of cancer, but the exact mechanism of cytotoxicity and responses are not clearly understood. Phase I/II clinical trials of various HDACIs as single agents conducted to date have shown substantial activity in cutaneous T cell lymphoma (CTCL), preliminary activity in Hodgkin's disease and modest activity in myeloid neoplasms. Responses have been rare in solid tumors. Several agents are being tested in combination therapy clinical trials, either as chemosensitizers for cytotoxic chemotherapy or radiation therapy, or in association with DNA methylation inhibitors based on in vitro synergy. In this review, we focus on recent basic and clinical data that highlight the anti-neoplastic role of HDACIs.
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 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...