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

ABSTRACT

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 and on the quality of life of the patient, however, no effective therapy is available yet.

Areas covered: This review focuses on the use of histone deacetylase inhibitors as pharmacological tools to prevent or delay cachexia, with reference to muscle wasting.

Expert opinion: Novel histone deacetylase inhibitors could be considered as exercise mimetics and this supports their use as a treatment for muscle-wasting associated diseases, such as cachexia. The ability of some of these inhibitors to modulate the release of extracellular vesicles from tumor cells is a potential tool for restricting the development of cancer-induced muscle protein depletion. There are few clinical trials that are testing histone deacetylase inhibitors as a treatment for cachexia; this reflects the lack of robust experimental evidence of effectiveness. The determination of the pathogenic mechanisms of muscle wasting and the identification of suitable histone deacetylase inhibitors that target such mechanisms are necessary.

KEYWORDS:

• Cachexia
• skeletal muscle wasting
• myogenesis
• protein breakdown
• energy metabolism acetylation/deacetylation

Article Highlights

• Despite several potential therapeutic approaches for cachexia have been proposed on the basis of experimental studies, very few have been explored in clinical trials, rendering cachexia a still untreatable condition;

• The balance between protein acetylation and deacetylation, mainly dependent on HAT/HDAC equilibrium, appears crucial in the regulation of muscle homeostasis in both physiology and pathology;

• First generation HDAC inhibitors, characterized by broad action, can be ineffective to prevent/delay cachexia, or should be used at doses that can even become detrimental to the organism;

• Several studies suggest that HDAC inhibitors, being able to target specific mechanisms among which myogenesis and to behave as exercise mimetic agents, could be considered pharmacological tools suitable for preventing or at least delaying muscle wasting in chronic diseases;

• Novel HDAC inhibitors, more specific or endowed with additional activity could reveal useful to address at least some of the metabolic alterations occurring in cachexia and, in theory, might be included in combination treatment schedules. However, this hypothesis remains to be tested, since the number of clinical trials is still very low;

• Since the pathogenesis of cancer cachexia is multifactorial and no effective therapeutic strategies are actually available, a selectively tailored multidirectional approach to cachexia could benefit from the introduction of HDAC inhibitors.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.