Histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits anti-inflammatory activities through induction of mitochondrial damage and apoptosis in activated lymphocytes

Shi, Zi-Jian; Ouyang, Dong-Yun; Zhu, Jun-Shan; Xu, Lihui; He, Xian-Hui

doi:10.1016/j.intimp.2012.02.005

Cited by 6 publications

(1 citation statement)

References 39 publications

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“…This is particularly true in the case of HDACis, which are known to exert potent and diverse effects on both the innate and adaptive immune system (reviewed in [14] and [15]). A number of HDACis, including SAHA, have been shown to suppress the production of inflammatory cytokines by both T-cells and innate immune cells, in vitro and in vivo [16]–[21]. SAHA, romidepsin, and other HDACis have also been shown to interfere with the differentiation of monocytes into dendritic cells (DCs), as well as to block the ability of DCs to upregulate CD1a, CD80, CD83 and other co-stimulatory molecules, resulting in impaired priming of T-cells [22]–[26].…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes

et al. 2014

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Resting memory CD4+ T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-γ production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia.

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Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes

et al. 2014

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Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

et al. 2015

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Here, we explored the effects of suberoylanilide hydroxamic acid (SAHA) on the viability and apoptosis of rheumatoid arthritis of fibroblast-like synoviocytes (rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS)). FLS obtained from RA patients were treated with SAHA. SAHA significantly inhibited the viability of RA FLS in a concentration-dependent manner up to 5 μM. SAHA-treated FLS showed a significant increase in the percentage of apoptosis and the expression and activity of caspase-3 and higher intracellular ROS levels. N-acetyl-l-cysteine (NAC) pretreatment significantly attenuated SAHA-induced apoptosis, decreasing the percentage of apoptosis by about 60 %. A significant decline in phosphorylated IκBα and nuclear factor kappa B (NF-κB) p65 and concomitant increase in total IκBα were shown in SAHA-treated FLS. Additionally, the levels of anti-apoptotic Bcl-2 proteins (Bcl-xL and Mcl-1) were significantly reduced by SAHA. Collectively, SAHA induces apoptosis of RA FLS, at least partially, through generation of ROS and suppression of NF-κB activation and Bcl-xL and Mcl-1 expression.

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A structure–activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities

Tapadar

Fathi

Raji

et al. 2015

Bioorganic & Medicinal Chemistry

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Inhibition of the enzymatic activity of histone deacetylase (HDAC) is a promising therapeutic strategy for cancer treatment and several distinct small molecule histone deacetylase inhibitors (HDACi) have been reported. We have previously identified a new class of non-peptide macrocyclic HDACi derived from 14- and 15-membered macrolide skeletons. In these HDACi, the macrocyclic ring is linked to the zinc chelating hydroxamate moiety through a para-substituted aryl-triazole cap group. To further delineate the depth of the SAR of this class of HDACi, we have synthesized series of analogous compounds and investigated the influence of various substitution patterns on their HDAC inhibitory, anti-proliferative and anti-inflammatory activities. We identified compounds 25b and 38f with robust anti-proliferative activities and compound 26f (IC50 47.2 nM) with superior anti-inflammatory (IC50 88 nM) activity relative to SAHA.

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Histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits anti-inflammatory activities through induction of mitochondrial damage and apoptosis in activated lymphocytes

Cited by 6 publications

References 39 publications

Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes

Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes

Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

A structure–activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities

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