HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases

Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and the promotion of tumorigenesis in cancers, novel compounds endowed with histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. Indeed, the potential of HDAC inhibitors for cancer therapy has been explored in preclinical models, and some agents approved for hematologic malignancies have reached the clinical setting. HDAC inhibitors are able to mediate the induction of both apoptosis and autophagy, which are related to anticancer activity in a variety of cancer cell lines. Given the inherent resistance to apoptosis that characterizes cancer, the targeting of alternative pathways is an attractive strategy to improve anti-tumor therapy. The activation of autophagy represents novel cancer treatment targets. This paper aims to critically discuss how the anticancer potential of HDAC inhibitors may elicit a response to human cancers through different cell pathways leading to cell death.

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Reactive Oxygen Species in Mesenchymal Stem Cell Aging: Implication to Lung Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/486263 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 30

Author(s):

Se-Ran Yang ◽

Jeong-Ran Park ◽

Kyung-Sun Kang

Keyword(s):

Lung Diseases ◽

Immune Modulation ◽

Cell Aging ◽

High Morbidity ◽

Key Factors ◽

Differentiation Potential ◽

Cell Engraftment ◽

High Proliferation Rate ◽

Stem Cell Aging ◽

Therapeutic Mechanisms

MSCs have become an emerging cell source with their immune modulation, high proliferation rate, and differentiation potential; indeed, they have been challenged in clinical trials. Recently, it has shown that ROS play a dual role as both deleterious and beneficial species depending on their concentration in MSCs. Various environmental stresses-induced excessive production of ROS triggers cellular senescence and abnormal differentiation on MSCs. Moreover, MSCs have been suggested to participate in the treatment of ALI/ARDS and COPD as a major cause of high morbidity and mortality. Therapeutic mechanisms of MSCs in the treatment of ARDS/COPD were focused on cell engraftment and paracrine action. However, ROS-mediated therapeutic mechanisms of MSCs still remain largely unknown. Here, we review the key factors associated with cell cycle and chromatin remodeling to accelerate or delay the MSC aging process. In addition, the enhanced ROS production and its associated pathophysiological pathways will be discussed along with the MSC senescence process. Furthermore, the present review highlights how the excessive amount of ROS-mediated oxidative stress might interfere with homeostasis of lungs and residual lung cells in the pathogenesis of ALI/ARDS and COPD.

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Epigenetic immune-modulation by Histone Deacetylase Activity (HDAC) of tissue and organ regeneration in Xenopus laevis

10.1101/2020.02.05.936294 ◽

2020 ◽

Author(s):

Nathalia Pentagna ◽

Felipe Soares dos Santos ◽

Fernanda Martins de Almeida ◽

José Garcia Abreu ◽

Michael Levin ◽

...

Keyword(s):

Inflammatory Response ◽

Immune Modulation ◽

Temporal Dynamics ◽

Tissue Injury ◽

Hdac Inhibitors ◽

Myeloid Cells ◽

Tail Regeneration ◽

Epigenetic Control ◽

Organ Regeneration ◽

Regenerative Ability

AbstractIn the present work we propose to shed light on the epigenetic control of immune mechanisms involved during Xenopus tail regeneration. Here we show that the first 24 hour post amputation (hpa), which exclusively encompasses the first wave of myeloid differentiation, are crucial to epigenetically modulate the regenerative ability of Xenopus tadpoles. During this developmental window, HDAC activity was shown to be necessary for the proper establishment of myeloid cells dynamics in the regenerative bud, mainly contributing to modulate the behavior of monocytes/macrophages and neutrophils as well the mRNA expression pattern of the main myeloid markers, such as LURP, MPOX, Spib and mmp7. In addition, we functionally bridge the spatial and temporal dynamics of lipid droplets, the main platform of lipid mediators synthesis in myeloid cells during the inflammatory response, and the regenerative ability of Xenopus tadpoles showing that 15-LOX activity is a key player during tail regeneration. Taken together our results support a role for the epigenetic control of inflammatory response during tissue and organ regeneration, which may positively impact translational approaches for regenerative medicine.Summary statementWe propose that Epigenetic mechanisms HDAC-dependent can control myeloid cells behavior upon tissue injury and that HDAC inhibitors may be used for tissue regeneration in translational studies.

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Design, synthesis, and preliminary bioactivity studies of substituted purine hydroxamic acid derivatives as novel histone deacetylase (HDAC) inhibitors

MedChemComm ◽

10.1039/c4md00203b ◽

2014 ◽

Vol 5 (12) ◽

pp. 1887-1891 ◽

Cited By ~ 7

Author(s):

Junhua Wang ◽

Feng'e Sun ◽

Leiqiang Han ◽

Xuben Hou ◽

Xiaole Pan ◽

...

Keyword(s):

Histone Deacetylase ◽

Hydroxamic Acid ◽

Tumor Therapy ◽

Hdac Inhibitors ◽

Hydroxamic Acids ◽

Hdac Inhibition ◽

Design Synthesis ◽

Hydroxamic Acid Derivatives

Histone deacetylase (HDAC) is a clinically validated target for anti-tumor therapy. In order to increase HDAC inhibition and efficiency, we developed a series of novel substituted purine hydroxamic acids as potent HDAC inhibitors.

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