Targeting Catecholamines to Develop New Drugs for Attention Deficit Hyperactivity Disorder

The prevalence of attention deficit hyperactivity disorder (ADHD), a developmental neuropsychiatric disorder, is high among children and adolescents. The pathogenesis of ADHD is mediated with genetic, biological, and environmental factors. Most therapeutic drugs for ADHD have so far targeted biological causes, primarily by regulating catecholaminergic neurotransmitters. However, ADHD drugs that are clinically treated have various problems in their addictiveness and drug stability; thus, it is recommended that efficacy and safety should be secured through simultaneous prescription of multiple drugs rather than a single drug treatment. Accordingly, it is necessary to develop drugs that newly target pathogenic mechanisms of ADHD. In this study, we attempt to confirm the possibility of developing new drugs by reviewing dopamine-related developmental mechanisms of neurons and their correlation with ADHD. Histone deacetylase inhibitors (HDACi) can regulate the concentration of intracellular dopamine in neurons by expressing vesicular monoamine transporter 2 and inducing the exocytosis of neurotransmitters to the synaptic cleft, thereby promoting the development of neurons and signal transmission. This cellular modulation of HDACi is expected to treat ADHD by regulating endogenous catecholamines such as dopamine. Although studies are still in the preclinical stage, HDAC inhibitors clearly have potential as a therapeutic agent with low addictiveness and high efficacy for ADHD treatment.

Designing HDAC-PROTACs: lessons learned so far

Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of therapeutic importance. Recently, two heterobifunctional degraders targeting hormone receptors headed into Phase II clinical trials. Compared to traditional drug design and common modes of action, the PROTAC approach offers new opportunities for the drug research field. Histone deacetylase inhibitors (HDACi) are well-established drugs for the treatment of hematological malignancies. The integration of HDAC binding motifs in PROTACs explores the possibility of targeted, chemical HDAC degradation. This review provides an overview and a perspective about the key steps in the structure development of HDAC–PROTACs. In particular, the influence of the three canonical PROTAC elements on HDAC–PROTAC efficacy and selectivity are discussed, the HDACi, the linker and the E3 ligase ligand.

Usefulness of Melatonin and Other Compounds as Antioxidants and Epidrugs in the Treatment of Head and Neck Cancer

Along with genetic mutations, aberrant epigenetic alterations are the initiators of head and neck cancer carcinogenesis. Currently, several drugs are being developed to correct these epigenetic alterations, known as epidrugs. Some compounds with an antioxidant effect have been shown to be effective in preventing these malignant lesions and in minimizing the complications derived from cytotoxic treatment. Furthermore, in vitro and in vivo studies show a promising role in the treatment of head and neck squamous cell carcinoma (HNSCC). This is the case of supplements with DNA methylation inhibitory function (DNMTi), such as epigallocatechin gallate, sulforaphane, and folic acid; histone deacetylase inhibitors (HDACi), such as sodium butyrate and melatonin or histone acetyltransferase inhibitors (HATi), such as curcumin. The objective of this review is to describe the role of some antioxidants and their epigenetic mechanism of action, with special emphasis on melatonin and butyric acid given their organic production, in the prevention and treatment of HNSCC.

Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a severe prognosis, and with a long-standing need for more effective therapeutic approaches. However, treatment with immune checkpoint inhibitors is becoming an increasingly effective strategy for MPM patients. In this scenario, epigenetic modifications may negatively regulate the interplay between immune and malignant cells within the tumor microenvironment, thus contributing to the highly immunosuppressive contexture of MPM that may limit the efficacy of immunotherapy. Aiming to further improve prospectively the clinical efficacy of immunotherapeutic approaches in MPM, we investigated the immunomodulatory potential of different classes of epigenetic drugs (i.e., DNA hypomethylating agent (DHA) guadecitabine, histone deacetylase inhibitors VPA and SAHA, or EZH2 inhibitors EPZ-6438) in epithelioid, biphasic, and sarcomatoid MPM cell lines, by cytofluorimetric and real-time PCR analyses. We also characterized the effects of the DHA, guadecitabine, on the gene expression profiles (GEP) of the investigated MPM cell lines by the nCounter platform. Among investigated drugs, exposure of MPM cells to guadecitabine, either alone or in combination with VPA, SAHA and EPZ-6438 demonstrated to be the main driver of the induction/upregulation of immune molecules functionally crucial in host-tumor interaction (i.e., HLA class I, ICAM-1 and cancer testis antigens) in all three MPM subtypes investigated. Additionally, GEP demonstrated that treatment with guadecitabine led to the activation of genes involved in several immune-related functional classes mainly in the sarcomatoid subtype. Furthermore, among investigated MPM subtypes, DHA-induced CDH1 expression that contributes to restoring the epithelial phenotype was highest in sarcomatoid cells. Altogether, our results contribute to providing the rationale to develop new epigenetically-based immunotherapeutic approaches for MPM patients, potentially tailored to the specific histologic subtypes.

Manipulating Histone Acetylation Leads to Adverse Effects in Hemangiosarcoma Cells

Canine hemangiosarcoma (HSA) is a malignant tumour derived from endothelial cells. No effective treatment has yet been developed because of the lack of understanding of its pathogenesis. Histone acetylation, an epigenetic modification, is highly associated with cancer pathogenesis. Manipulating histone acetylation by histone deacetylase inhibitors (HDACi) or bromodomain and extraterminal domain inhibitors (BETi) is one approach to treat various cancers. However, the role of histone acetylation in HSA remains unknown. This study aimed to investigate how histone acetylation functions in HSA pathogenesis using two HDACi, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), and one BETi, JQ1, in vitro and in vivo. Histone acetylation levels were high in cell lines and heterogeneous in clinical cases. SAHA and JQ1 induced apoptosis in HSA cell lines. SAHA and VPA treatment in HSA cell lines upregulated inflammatory-related genes, thereby attracting macrophages. This implies that SAHA and VPA can induce anti-tumour immunity. JQ1 stimulated autophagy and inhibited the cell cycle. Finally, JQ1 suppressed HSA tumour cell proliferation in vivo. These results suggest that HDACi and BETi can be alternative drugs for HSA treatment. Although further research is required, this study provides useful insights for developing new treatments for HSA.

The Effect of Organoselenium Compounds on Histone Deacetylase Inhibition and Their Potential for Cancer Therapy

Genetic and epigenetic changes alter gene expression, contributing to cancer. Epigenetic changes in cancer arise from alterations in DNA and histone modifications that lead to tumour suppressor gene silencing and the activation of oncogenes. The acetylation status of histones and non-histone proteins are determined by the histone deacetylases and histone acetyltransferases that control gene transcription. Organoselenium compounds have become promising contenders in cancer therapeutics. Apart from their anti-oxidative effects, several natural and synthetic organoselenium compounds and metabolites act as histone deacetylase inhibitors, which influence the acetylation status of histones and non-histone proteins, altering gene transcription. This review aims to summarise the effect of natural and synthetic organoselenium compounds on histone and non-histone protein acetylation/deacetylation in cancer therapy.