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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
In this section of the chapter, we cover recent developments demonstrating the: (a) role of histone deacetylases (HDACs) in the pathogenesis of cancer; (b) ability of pharmacological agents inhibiting HDACs for treating cancers; (c) HDAC-mediated molecular mechanisms involved in drug resistance; and (d) the potential of knocking down HDACs in promoting sensitivity of cancer cells to chemo- and radiation therapeutics. Furthermore, a brief report on ongoing and recently completed clinical trials using HDAC inhibitors (HDACis) for the treatment of cancer is provided at the end of this chapter.
Cutaneous Lymphomas
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Emily Correia, Shalini Krishnasamy, Neda Nikbakht
Management: Treatment is guided by degree of body surface area involvement and stage (Table 22.4). Early-stage MF (Stages IA–IIA) is managed with skin-directed therapies including topical corticosteroids and phototherapy. Topical bexarotene, topical nitrogen mustard, imiquimod, local radiation, and psoralen plus ultraviolet A (PUVA) are additional options. Treatment options for more advanced disease include oral bexarotene, extracorporeal photopheresis, inter-feron therapy (IFNa and IFNg), total skin electron beam therapy (TSEBT), methotrexate, monoclonal antibodies such as brentuximab vedotin and mogalizumab, and epigenetic modulators such as histone deacetylase inhibitors, including vorinostat and romidepsin, as well as single and multi-modal chemotherapy.
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Developmental progression of inhibitors associated with pharmacological studies vary widely among independent families of the enzyme. Inhibitors related to histone methyltransferase are still in a preliminary stage of preclinical studies. Various others inhibitors of histone deacetylase are presently being tested under phase I and phase II clinical trials. Although various acetylated proteins, including basic key malignant cell growth regulators, are being tested, it is not clear yet whether the inhibitors of histone deacetylase are responsible for the induction of growth inhibition results of pattern changes of histone acetylation and other certain changes in cell-signalling-based pathways that lead to the regulation of cell proliferation. Potent inhibitors of DNA methyltransferase presently are at the clinically more highly advanced position of therapeutic development than the histone deacetylase inhibitors or histamine N-methyltransferase (HMNT) inhibitors, which have extensively been tested in clinical trials of phases I–III. Further, inhibitors of the prototypical HMNT inhibitors, such as 5-azacytidine, have been approved recently by the U.S. Food and Drug Administration (FDA), represented as a specific agent of antitumor activities for myelodysplastic syndrome treatment.
Advances in Hodgkin’s lymphoma pharmacotherapy: a focus on histone deacetylase inhibitors
Published in Expert Opinion on Pharmacotherapy, 2023
Thuy Ho, Cara Coleman, Palak Shah, Victor Yazbeck
Despite the excellent prognosis for the majority of patients with Hodgkin lymphoma, outcomes for patients with refractory or relapsed HL, especially after autologous or allogeneic stem cell transplantation, remain poor with traditional chemotherapy. More recently approved therapies, such as brentuximab vedotin and PD1 inhibitors, have shown promising results in this setting. However, drug resistance to chemotherapy, targeted and immunotherapy agents eventually arise, necessitating novel therapeutic approaches. Additionally, Hodgkin Reed Sternberg cells survive through multiple mechanisms, including escape from immune detection. Targeting the TME in addition to the primary tumor is also crucial for effective disease control. One strategy to overcome these resistance mechanisms and disrupt the tumorigenic niche is through epigenetic regulation, in which histone acetylation plays a major role. To date, a great number of histone deacetylase inhibitors have been developed. These agents have demonstrated a unique safety profile as monotherapy and as part of combination treatments in relapsed/refractory Hodgkin lymphoma and other hematologic and solid malignancies. The most frequent toxicity from HDAC inhibitors is thrombocytopenia, the severity of which varies depending on the individual HDACI and the nature of the synergizing agent(s). Overall, HDAC inhibitors appear to have a more tolerable safety profile than cytotoxic chemotherapy. In terms of efficacy in relapsed/refractory HL, the results have been variable, but with a promising signal of clinical activity based on disease control rate.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
Histone deacetylases (HDAC) play a role in the regulation of chromatin structure and epigenetic gene regulation. They are over-expressed in T-ALL [67]. Panobinostat, vorinostat, and romidepsin have shown anti-leukemic efficacy in T-ALL pre-clinical models, and are currently under clinical investigations (Table 5). Panobinostat shows particular efficacy with improved survival seen in combination with chemotherapy [68]. Its efficacy over the other HDAC relates to its epigenetic inhibition of the oncogene MYC [69]. Vorinostat combined with alisertib, an Aurora kinase-A inhibitor, showed encouraging clinical activity with a manageable safety profile [70]. However, its use as prolonged maintenance therapy after HSCT was not considered optimal [71].
How do we improve histone deacetylase inhibitor drug discovery?
Published in Expert Opinion on Drug Discovery, 2020
The dynamic status of histone acetylation is under the control of histone deacetylases (HDACs) and histone acetyltransferases (HATs), which play an important role in the regulation of gene expression. While HATs mediate the acetylation of lysine residue associated with gene transcription, HDACs have the opposite effect, and deacetylation leads to a more condensed chromatin structure; this, in turn, leads to transcriptional repression of the gene [1]. Histone deacetylases are often dysregulated and have been recognized as a crucial factor in numerous diseases, including cancer, neurodegenerative and inflammatory diseases [2]. High expression of HDAC8 is correlated with poor survival and advanced disease in neuroblastoma [3]. While high expression levels of HDAC1, 2, and 3 have been shown to be associated with poor patient outcomes in gastric and ovarian cancers [4,5], HDACis have pleiotropic cellular effects including the arrest of cell growth, cell cycle progression, and the induction of apoptosis [6]. Numerous HDACis are nowadays at various stages of clinical trial development for the treatment of cancers. The natural hydroxamate Trichostatin A has served as a lead compound, for the development of the first approved HDACi vorinostat (SAHA). To date, five HDACis have been approved for the treatment of cutaneous T-cell lymphoma. These drugs can be classified into three chemical families: the class of hydroxamic acids such as vorinostat, panobinostat, and belinostat; the class of cyclic peptides such as romidepsin; and the class of o-amino anilides such as chidamide.