The Safety, Efficacy and Therapeutic Potential of Histone Deacetylase Inhibitors with Special Reference to Panobinostat in Gastrointestinal Tumors: A Review of Preclinical and Clinical Studies

2018 ◽  
Vol 18 (8) ◽  
pp. 720-736 ◽  
Author(s):  
Avineesh Singh ◽  
Preeti Patel ◽  
Jageshwar ◽  
Vijay Kumar Patel ◽  
Deepak Kumar Jain ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential ◽  
Clinical Investigation ◽  
Regulation Of Gene Expression ◽  
Cancer Therapeutics ◽  
Nonhistone Proteins ◽  
The Status ◽  
Us Fda ◽  
Preclinical And Clinical Studies

Histone deacetylase inhibitors (HDACi) have been demonstrated as an emerging class of anticancer drugs involved in regulation of gene expression and chromatin remodeling thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac®, LBH589) is developed by Novartis Pharmaceuticals and a newly US FDA approved drug for the multiple myeloma. It is under clinical investigation for a range of hematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and nonhistone proteins as well as various apoptotic, autophagy-mediated targets and various tumorigenesis pathways involved in the development of cancer. The current article summarizes the status of panobinostat in gastrointestinal cancers. Preclinical and clinical data suggest that panobinostat has potential inhibitory activity in hepatocellular, pancreatic, colorectal, gastric and gastrointestinal stromal tumors. Clinical evaluations of panobinostat are currently underway. Herein, we have also reviewed the rationale behind the combination therapy under the trials and possible future prospective for the treatment of GI tumors.

Therapeutic potential of histone deacetylase inhibitors in pancreatic cancer

2014 ◽  
Vol 347 (2) ◽  
pp. 183-190 ◽  
Author(s):  
Wan Feng ◽  
Bin Zhang ◽  
Dawei Cai ◽  
Xiaoping Zou
Keyword(s):  
Pancreatic Cancer ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential

scholarly journals The Effect of Organoselenium Compounds on Histone Deacetylase Inhibition and Their Potential for Cancer Therapy

2021 ◽  
Vol 22 (23) ◽  
pp. 12952
Author(s):  
Theolan Adimulam ◽  
Thilona Arumugam ◽  
Ashmika Foolchand ◽  
Terisha Ghazi ◽  
Anil A. Chuturgoon
Keyword(s):  
Cancer Therapy ◽  
Histone Deacetylase ◽  
Gene Transcription ◽  
Histone Deacetylase Inhibitors ◽  
Cancer Therapeutics ◽  
Epigenetic Changes ◽  
Organoselenium Compounds ◽  
Histone Proteins ◽  
Acetylation Status ◽  
Natural And Synthetic

Genetic and epigenetic changes alter gene expression, contributing to cancer. Epigenetic changes in cancer arise from alterations in DNA and histone modifications that lead to tumour suppressor gene silencing and the activation of oncogenes. The acetylation status of histones and non-histone proteins are determined by the histone deacetylases and histone acetyltransferases that control gene transcription. Organoselenium compounds have become promising contenders in cancer therapeutics. Apart from their anti-oxidative effects, several natural and synthetic organoselenium compounds and metabolites act as histone deacetylase inhibitors, which influence the acetylation status of histones and non-histone proteins, altering gene transcription. This review aims to summarise the effect of natural and synthetic organoselenium compounds on histone and non-histone protein acetylation/deacetylation in cancer therapy.

scholarly journals Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

2020 ◽  
Vol 8 ◽  
Author(s):  
Alexandre Perla ◽  
Lívia Fratini ◽  
Paula S. Cardoso ◽  
Carolina Nör ◽  
André T. Brunetto ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Pediatric Brain

Recent Progress in Histone Deacetylase Inhibitors as Anticancer Agents

2020 ◽  
Vol 27 (15) ◽  
pp. 2449-2493 ◽  
Author(s):  
Loredana Cappellacci ◽  
Diego R. Perinelli ◽  
Filippo Maggi ◽  
Mario Grifantini ◽  
Riccardo Petrelli
Keyword(s):  
Clinical Trials ◽  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Cyclic Peptide ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Rational Drug Design ◽  
Modeling Tools ◽  
Anti Cancer

Histone Deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval by the FDA of four HDAC inhibitors, vorinostat, romidepsin, belinostat and panobinostat, used for the treatment of cutaneous/peripheral T-cell lymphoma and multiple myeloma. Many more HDAC inhibitors are at different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. In the intensifying efforts to discover new, hopefully, more therapeutically efficacious HDAC inhibitors, molecular modelingbased rational drug design has played an important role. In this review, we summarize four major structural classes of HDAC inhibitors (hydroxamic acid derivatives, aminobenzamide, cyclic peptide and short-chain fatty acids) that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

Zinc Dependent Histone Deacetylase Inhibitors in Cancer Therapeutics: Recent Update

2020 ◽  
Vol 26 (40) ◽  
pp. 7212-7280 ◽  
Author(s):  
Faria Sultana ◽  
Kesari Lakshmi Manasa ◽  
Siddiq Pasha Shaik ◽  
Srinivasa Reddy Bonam ◽  
Ahmed Kamal
Keyword(s):  
Gene Expression ◽  
Drug Therapy ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Rational Drug Design ◽  
Combination Drug Therapy ◽  
Combination Drug

Background: Histone deacetylases (HDAC) are an important class of enzymes that play a pivotal role in epigenetic regulation of gene expression that modifies the terminal of core histones leading to remodelling of chromatin topology and thereby controlling gene expression. HDAC inhibitors (HDACi) counter this action and can result in hyperacetylation of histones, thereby inducing an array of cellular consequences such as activation of apoptotic pathways, generation of reactive oxygen species (ROS), cell cycle arrest and autophagy. Hence, there is a growing interest in the potential clinical use of HDAC inhibitors as a new class of targeted cancer therapeutics. Methodology and Result: Several research articles spanning between 2016 and 2017 were reviewed in this article and presently offer critical insights into the important strategies such as structure-based rational drug design, multi-parameter lead optimization methodologies, relevant SAR studies and biology of various class of HDAC inhibitors, such as hydroxamic acids, benzamides, cyclic peptides, aliphatic acids, summarising the clinical trials and results of various combination drug therapy till date. Conclusion: This review will provide a platform to the synthetic chemists and biologists to cater the needs of both molecular targeted therapy and combination drug therapy to design and synthesize safe and selective HDAC inhibitors in cancer therapeutics.

Effect of epigenetic modulation on interleukin-6 (IL-6) gene expression with adjuvant selenomethionine (Se-Met) with imatinib mesylate (IM) in remission of chronic myelogenous leukemia (CML-cp) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17022-e17022
Author(s):  
Eugene McPherson
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Kinase Inhibitors ◽  
Regulation Of Gene Expression ◽  
Myelogenous Leukemia ◽  
Abl Tyrosine Kinase ◽  
Nfkb Activation ◽  
Epigenetic Modulation

e17022 Background: Histone deacetylase (HDAC) are enzymes involved remodeling chromatin and epigenetic regulation of gene expression. Histone deacetylase inhibitors (HDACI) can reverse aberrant epigenetic changes in CML stem cells. BCR-abl tyrosine kinase inhibitors IM is effective in inducing remission in CML-cp patients but residual leukemia stem cells (LSC) may give rise to resistance and relapse. Pan-HDACI may arrest this with downregulation of IL-6, and NFkb activation when adjuvant Se-Met is combined with IM. Methods: CML-cp , CML-bc cases were presented with evidence of overexpression of BCR-abl fusion protein reported previously in elderly patients. A 91 YOF with CML-cp , subclinical hypothyroidism with elevated IL-6, CRP, sIL-2R, VEGF, NFkb, and IGF-1 was treated for seven years with adjuvant Se-Met, IM and levothyroxine ith normalization, minmal toxicity and extended trending down of IL-6, CRP,sIL-2R. Results: After seven years of adjuvant therapy with Se-Met, IM, and Levothyroxine a significant reduction of IL-6, CRP of 9.8075 down from 30.783 mg/L. Subsequuent normalization of the other pro-inflammatory cytokines were normalized. Conclusions: HDACI activity expressed in synergism of Se-Met with IM and Levothyroxine may lower the apoptotic threshold in CML-cp stem cells decreasing BCR-abl expression and rescuing quiescent progenitor cells that may prolong remission and decrease disease relapse.

Abstract C152: Therapeutic potential of histone deacetylase inhibitors in human liposarcomas

2009 ◽  
Author(s):  
Thomas Mühlenberg ◽  
Florence Pedeutour ◽  
Jonathan A. Fletcher ◽  
Martin Schuler ◽  
Sebastian Bauer
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential
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