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

Penna, Fabio; Costelli, Paola

doi:10.1080/13543784.2019.1557634

Cited by 11 publications

(4 citation statements)

References 85 publications

(96 reference statements)

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“…There are currently 18 known human HDACs, which are grouped into four classes. Classes I, II, and IV HDACs are zinc‐dependent proteins, while Class III HDACs require NAD+ 24‐26 . HDACs have been found to play a role in muscle development, as well as muscle wasting and degeneration wasting 26 .…”

Section: Discussionmentioning

confidence: 99%

Trichostatin A regulates fibro/adipogenic progenitor adipogenesis epigenetically and reduces rotator cuff muscle fatty infiltration

Liu

Lee

et al. 2020

Journal Orthopaedic Research

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Rotator cuff (RC) muscle fatty infiltration (FI) is an important factor that determines the clinical outcome of patients with RC repair. There is no effective treatment for RC muscle FI at this time. The goal of this study is to define the role Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor in regulating muscle fibro/adipogenic progenitors (FAPs) adipogenesis and treating muscle fatty degeneration after massive RC tears in a mouse model. We hypothesize that TSA reduces muscle FI after massive RC tears. HDAC activity was measured in FAPs in RC muscle after tendon/nerve transection or sham surgery. FAPs were treated with TSA for 2 weeks and FAP adipogenesis was evaluated with perilipin and Oil Red O staining, as well as reverse transcript‐polymerase chain reaction for adipogenesis‐related genes. About 0.5 mg/kg TSA or dimethyl sulfoxide was administered to C57B/L6 mice with massive rotator cuff tears through daily intraperitoneal injection for 6 weeks. Supraspinatus muscles were harvested for biochemical and histology analysis. We found that FAPs showed significantly higher HDAC activity after RC tendon/nerve transection. TSA treatment significantly reduced HDAC activity and inhibited adipogenesis of FAPs. TSA also abolished the role of bone morphogenetic protein‐7 in inducing FAP adipogenesis and promoted FAP brown/beige adipose tissue (BAT) differentiation. TSA injection significantly increased histone H3 acetylation and reduced FI of rotator cuff muscles after massive tendon tears. Results from this study showed that TSA can regulate FAP adipogenesis and promote FAP BAT differentiation epigenetically. HDAC inhibition may be a new treatment strategy to reduce muscle FI after RC tears and repair.

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Section: Discussionmentioning

confidence: 99%

Trichostatin A regulates fibro/adipogenic progenitor adipogenesis epigenetically and reduces rotator cuff muscle fatty infiltration

Liu

Lee

et al. 2020

Journal Orthopaedic Research

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“…HDAC1 is a component of the histone deacetylase complex. Histone acetyltransferases and deacetylases are critical enzymes that affect the expression of a variety of genes related to muscle wasting by modulating satellite cell activation and differentiation [7].…”

Section: Introductionmentioning

confidence: 99%

Physiactisome: A New Nanovesicle Drug Containing Heat Shock Protein 60 for Treating Muscle Wasting and Cachexia

Felice

Barone

Trovato

et al. 2022

Cells

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Currently, no commercially available drugs have the ability to reverse cachexia or counteract muscle wasting and the loss of lean mass. Here, we report the methodology used to develop Physiactisome—a conditioned medium released by heat shock protein 60 (Hsp60)—overexpressing C2C12 cell lines enriched with small and large extracellular vesicles. We also present evidence supporting its use in the treatment of cachexia. Briefly, we obtain a nanovesicle-based secretion by genetically modifying C2C12 cell lines with an Hsp60-overexpressing plasmid. The secretion is used to treat naïve C2C12 cell lines. Physiactisome activates the expression of PGC-1α isoform 1, which is directly involved in mitochondrial biogenesis and muscle atrophy suppression, in naïve C2C12 cell lines. Proteomic analyses show Hsp60 localisation inside isolated nanovesicles and the localisation of several apocrine and merocrine molecules, with potential benefits for severe forms of muscle atrophy. Considering that Physiactisome can be easily obtained following tissue biopsy and can be applied to autologous muscle stem cells, we propose a potential nanovesicle-based anti-cachexia drug that could mimic the beneficial effects of exercise. Thus, Physiactisome may improve patient survival and quality of life. Furthermore, the method used to add Hsp60 into nanovesicles can be used to deliver other drugs or active proteins to vesicles.

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“…Other HDAC inhibitors (such as MS-275) prevent contractile dysfunction during skeletal muscle disuse and reduces the extent of fiber atrophy [28]. Another potential effect of HDAC inhibitors is that these compounds could behave as exercise mimicking agents (a well-known strategy against cachexia) [29]. Bearing all this in mind, the aim of the present investigation was to explore if the combination of formoterol and AR42 has any synergistic effect on cancer-related cachexia.…”

Section: Introductionmentioning

confidence: 99%

A Combination of Formoterol and the Histone Deacetylase Inhibitor AR42 has No Effects on Muscle Mass in Tumor-Bearing Rats

Castillejo¹,

Jové²,

Noguera³

et al. 2021

IJCST

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Background: Accelerated muscle and adipose tissue loss are two of the main aspects of cancer cachexia. β2-agonists seem to be successful in the treatment of cachexia in experimental animals. The aim if the present investigation was to study the effects on body weight loss in tumor-bearing animals of a combination of formoterol and AR-42, an inhibitor of histone deacetylase (HDAC). Methods: Rats were divided into two groups, namely controls (C) and tumor-bearing (T). TB group was further divided into four subgroups: untreated (saline as a vehicle), treated with Formoterol (F) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with AR-42 (A) (20 mg/kg body weight in olive oil, intragastric (i.g.), only the last 4 days). and double-treated treated (TFA) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and AR-42 (20 mg/kg body weight in olive oil, intragastric (i.g.), only the last 4 days). 7 days after tumor transplantation, muscle weights, grip force and total physical activity were determined in all experimental groups. Results: The presence of the Yoshida AH-130 ascites hepatoma induced severe muscle wasting in rats. Treatment of the tumor-bearing animals with the beta2-agonist formoterol (0,3 mg/kg), resulted in a significant improvement in the cachectic state of the animals. Treatment of the tumor-bearing animals with AR42 did not result in any effects on muscle wasting in the cachectic rats. Furthermore, the combination of formoterol and AR42 showed no additional effects to those observed with just formoterol. Conclusion: The results presented question the previously described effects of AR42 on cancer cachexia, probably due to its effect on tumor growth.

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

Cited by 11 publications

References 85 publications

Trichostatin A regulates fibro/adipogenic progenitor adipogenesis epigenetically and reduces rotator cuff muscle fatty infiltration

Trichostatin A regulates fibro/adipogenic progenitor adipogenesis epigenetically and reduces rotator cuff muscle fatty infiltration

Physiactisome: A New Nanovesicle Drug Containing Heat Shock Protein 60 for Treating Muscle Wasting and Cachexia

A Combination of Formoterol and the Histone Deacetylase Inhibitor AR42 has No Effects on Muscle Mass in Tumor-Bearing Rats

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