Histone deacetylase inhibitors: A new perspective for the treatment of leukemia (original) (raw)
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Histone Deacetylase Inhibitors in the Treatment of Hematological Malignancies
Histone deacetylases (HDACs) play a central role in the epigenetic regulation of gene expression. Aberrant activity of HDACs has been found in several human cancers leading to the development of HDAC inhibitors (HDACi) as anti-tumors drugs. In fact, over the last years, a number of HDACi have been evaluated in clinical trials; these drugs have the common ability to hyperacetylate both histone and non-histone targets, resulting in a variety of effects on both cancer cells and immune responses. Clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a better clinical efficacy of these drugs in hematological malignancies. In this review, will be highlighted the mechanisms of action underlying the clinical responses obtained with these drugs and the doubts regarding the use of HDACi in cancer therapy.
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 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 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 deacetylases and epigenetic therapies of hematological malignancies
Pharmacological research : the official journal of the Italian Pharmacological Society, 2010
Histone deacetylase inhibitors (HDACi) represent a novel class of targeted drugs which alter the acetylation status of several cellular proteins. These agents, modulating both chromatin structure through histone acetylation, and the activity of several non-histone substrates, are at the same time able to determine changes in gene transcription and to induce a plethora of biological effects ranging from cell death induction, to differentiation, angiogenesis inhibition or modulation of immune responses. The impressive anticancer activity observed in both in vitro and in vivo cancer models, together with their preferential effect on cancer cells, have led to a huge effort into the identification and development of HDACi with different characteristics. To date, several clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a preferential clinical efficacy of these drugs in hematological malignancies, and in particular in cutaneous T-cell lymphoma (C...
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.
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.
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 ...
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.
Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia
British Journal of Cancer, 2016
Histone deacetylases (HDACs) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as anticancer drugs. This review discusses new results regarding the role of HDACs in cancer and the effect of HDACi on tumour cells, focusing on haematological malignancies, particularly acute myeloid leukaemia. Histone deacetylases may have opposite roles at different stages of tumour progression and in different tumour cell sub-populations (cancer stem cells), highlighting the importance of investigating these aspects for further improving the clinical use of HDACi in treating cancer. HDACS AND THE CONTROL OF HISTONE (AND NON-HISTONE) ACETYLATION The addition of acetyl groups to lysine residues in the histone tails by HATs is responsible for a relaxed and accessible chromatin structure, and is associated with transcriptional activation; conversely, HDACs remove acetyl groups and lead to a more closed chromatin structure, generally associated with transcriptional repression.