Effects of Class II-Selective Histone Deacetylase Inhibitor on Neuromuscular Function and Disease Progression in SOD1-ALS Mice

Introduction: Cachexia is a frequent feature of chronic diseases. This syndrome includes loss of body weight, depletion of skeletal muscle mass and altered metabolic homeostasis. Acceleration of protein and energy metabolism, impaired myogenesis and systemic inflammation contribute to cachexia. Its occurrence impinges on treatment tolerance as well as on patient quality of life, however, no effective therapy is still available. Areas covered in this review: This review will focus on the use of histone deacetylase inhibitors as pharmacological tools to prevent/delay cachexia, with particular reference to muscle wasting. Expert opinion: Besides their interference with histone acetylation, novel histone deacetylase inhibitors could be considered as exercise mimetics, supporting their use to treat muscle wastingassociated diseases such as cachexia. In addition, the ability displayed by some of these inhibitors in modulating the release of extracellular vesicles from tumor cells might be an interesting tool to interfere with the development of cancer-induced muscle protein depletion. At present there are few clinical trials testing histone deacetylase inhibitors to treat cachexia, reflecting the lack of robust experimental evidence of effectiveness. Further investigation uncovering the pathogenic mechanisms of muscle wasting coupled with the identification of suitable histone deacetylase inhibitors targeting such alterations is needed.

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“…Consistently with this hypothesis, the positive effects induced in SOD1-G93A mice by MC1568 are lost in late disease stages [67].…”

Section: Expert Opinionsupporting

confidence: 65%

“…In this regard, a recent study has explored the effects of a new selective class II HDAC inhibitor, namely MC1568, on SOD1-G93A mice. The results show that MC1568 administration leads to improved motor activity, mainly associated with increased muscle electrical potential and expression of myogenic genes [67].…”

Section: Effects On Muscle Mass and Functionmentioning

confidence: 93%

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

Penna

Costelli

2018

Expert Opinion on Investigational Drugs

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“…Increased HDAC4 expression in skeletal muscle has been reported to occur in SOD mice or ALS patients [10,12,19]. To evaluate the expression levels of HDAC4 in ALS over time, we analyzed HDAC4 mRNA and protein expression levels in the GA muscles of SOD mice, at a preonset (12 weeks) and at a symptomatic (15 weeks) stage, compared to healthy control (CTR) muscles.…”

Section: Resultsmentioning

confidence: 99%

“…However, these compounds failed in a phase-II clinical trial [17,18]. Importantly, no changes in the expression of the different members of the HDAC superfamily were registered in the spinal cords of ALS mice, while a significant increase in the expression of the members of class II HDACs was detected in the skeletal muscle with the progression of the disease [19]. Specific inhibition of class II HDACs in ALS mice induced motor improvement and increased skeletal muscle electrical potentials, although no effects on body weight loss or survival were registered [19].…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase 4 protects from denervation and skeletal muscle atrophy in a murine model of amyotrophic lateral sclerosis

et al. 2019

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BackgroundHistone deacetylase 4 (HDAC4) has been proposed as a target for Amyotrophic Lateral Sclerosis (ALS) because it mediates nerve-skeletal muscle interaction and since its expression in skeletal muscle correlates with the severity of the disease. However, our recent studies on the skeletal muscle response upon long-term denervation highlighted the importance of HDAC4 in maintaining muscle integrity.MethodsTo fully identify the yet uncharacterized HDAC4 functions in ALS, we genetically deleted HDAC4 in skeletal muscles of a mouse model of ALS. Body weight, skeletal muscle, innervation and spinal cord were analyzed over time by morphological and molecular analyses. Transcriptome analysis was also performed to delineate the signaling modulated by HDAC4 in skeletal muscle of a mouse model of ALS.FindingsHDAC4 deletion in skeletal muscle caused earlier ALS onset, characterized by body weight loss, muscle denervation and atrophy, and compromised muscle performance, although the main catabolic pathways were not activated. Transcriptome analysis identified the gene networks modulated by HDAC4 in ALS, revealing UCP1 as a top regulator that may be implicated in worsening ALS features.InterpretationHDAC4 plays an important role in preserving innervations and skeletal muscle in ALS, likely by modulating the UCP1 gene network. Our study highlights a possible risk in considering HDAC inhibitors for the treatment of ALS.FundThis work was supported by FIRB grant (RBFR12BUMH) from Ministry of Education, Universities and Research, by Fondazione Veronesi, by Sapienza research project 2017 (RM11715C78539BD8) and Polish National Science Center grant (UMO-2016/21/B/NZ3/03638).

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“…In fact, several HDAC inhibitors have been applied for treatment of T-cell lymphoma, such as SAHA (suberoylanilide hydroxamic acid, Vorinostat) (Negmeldin and Pflum, 2017) and Belinostat (Poole, 2014), and Panobinostat (Garnock-Jones, 2015). Unfortunately, these FDA approved drugs are relatively non-selective and inhibit most of the zincdependent HDAC subtypes (Yang, 2011;Qiao et al, 2013), which could cause several mild or severe toxic effects associated with the treatment, such as dehydration, thrombocytopenia, anorexia, and cardiac arrhythmia (Chakrabarti et al, 2016;Buonvicino et al, 2018;Cosenza and Pozzi, 2018;Laino et al, 2019). In addition, due to the physicochemical properties of hydroxamic acid group as the ZBG, some drawbacks have been exposed, including poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity, making the design and discovery of HDAC inhibitors with novel zinc binding group (ZBG) more necessary (Di Micco et al, 2008;Botta et al, 2011;Burli et al, 2013;Zhao et al, 2018;Banerjee et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

Wang

Liu

et al. 2020

Front. Chem.

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Vorinostat (SAHA) with great therapeutic potential has been approved by the FDA for the treatment of cutaneous T-cell lymphoma as the first HDACs inhibitor, but the drawbacks associated with hydroxamic acid group (poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity) have been exposed during the continuous clinical application. Based on the pharmacophore of HDAC inhibitors, two series of compounds with novel zinc binding group (ZBG) were designed and synthesized, and the antitumor bioactivities were evaluated in four human cancer cell lines (A549, Hela, HepG2, and MCF-7). Among the synthesized compounds, compounds a6, a9, a10, b8, and b9 exhibited promising inhibitory activities against the selected tumor cell lines, especially compounds a9 and b8 on Hela's cytostatic activity (a9: IC 50 = 11.15 ± 3.24 µM; b8: IC 50 = 13.68 ± 1.31 µM). The enzyme inhibition assay against Hela extracts and HDAC1&6 subtypes showed that compound a9 had a certain broad-spectrum inhibitory activity, while compound b8 had selective inhibitory activity against HDAC6, which was consistent with Western blot results. In addition, the inhibitory mechanism of compounds a9 and b8 in HDAC1&6 were both compared through computational approaches, and the binding interactions between the compounds and the enzymes target were analyzed from the perspective of energy profile and conformation. In summary, the compounds with novel ZBG exhibited certain antitumor activities, providing valuable hints for the discovery of novel HDAC inhibitors.

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Effects of Class II-Selective Histone Deacetylase Inhibitor on Neuromuscular Function and Disease Progression in SOD1-ALS Mice

Cited by 20 publications

References 49 publications

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

Histone deacetylase 4 protects from denervation and skeletal muscle atrophy in a murine model of amyotrophic lateral sclerosis

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

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