panobinostat and Inflammation

To summarize the state of chronic, treated HIV infection and its contribution to accelerated aging, and to evaluate recent research relevant to the study and treatment of aging and senescence.. Chronic treated HIV-1 infection is associated with significant risk of end-organ impairment, non-AIDS-associated malignancies, and accelerated physiologic aging. Coupled with the chronologic aging of the HIV-1-positive population, the development of therapies that target these processes is of great clinical importance. Age-related diseases are partly the result of cellular senescence. Both immune and nonimmune cell subsets are thought to mediate this senescent phenotype, a state of stable cell cycle arrest characterized by sustained release of pro-inflammatory mediators. Recent research in the field of aging has identified a number of 'senotherapeutics' to combat aging-related diseases, pharmacologic agents that act either by selectively promoting the death of senescent cells ('senolytics') or modifying senescent phenotype ('senomorphics').. Senescence is a hallmark of aging-related diseases that is characterized by stable cell cycle arrest and chronic inflammation. Chronic HIV-1 infection predisposes patients to aging-related illnesses and is similarly marked by a senescence-like phenotype. A better understanding of the role of HIV-1 in aging will inform the development of therapeutics aimed at eliminating senescent cells that drive accelerated physiologic aging.

Topics: Aging; Aniline Compounds; Antibiotics, Antineoplastic; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; CD4-CD8 Ratio; Cell Cycle Checkpoints; Cellular Senescence; Histone Deacetylase Inhibitors; HIV Infections; HIV-1; Humans; Inflammation; Janus Kinases; Nitriles; Panobinostat; Pyrazoles; Pyrimidines; Sirolimus; Sulfonamides; T-Lymphocyte Subsets

Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future.

Topics: Antineoplastic Agents; Chemistry Techniques, Synthetic; Depsipeptides; Drug Design; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Indoles; Inflammation; Isoenzymes; Neoplasm Proteins; Neoplasms; Neurodegenerative Diseases; Panobinostat; Structure-Activity Relationship; Sulfonamides; Vorinostat

To investigate the effect of the histone deacetylase inhibitor panobinostat on HIV-associated inflammation.. Sub-study of a single-arm, phase I/II clinical trial.. HIV-infected adults on suppressive antiretroviral therapy received oral panobinostat 20 mg three times per week, every other week, for 8 weeks, that is, four cycles of treatment. Plasma levels of high-sensitivity C-reactive protein, matrix metalloproteinase 9, soluble CD40 ligand and interleukin-6 were determined using human ELISA kits. Soluble endothelia selectin (E-selectin) was measured by a multiplex immunoassay. Total monocyte count, phenotype changes on monocytes and monocyte histone acetylation were analyzed using flow cytometry. Whole-genome expression in peripheral blood mononuclear cells was analyzed at baseline and on-panobinostat employing the Affymetrix Human Transcriptome Array 2.0 microarray assay. Changes from baseline were analyzed using Wilcoxon signed-rank test. For the gene-expression analyses, fold-changes, P values and false detection rate were computed using TAC software.. Panobinostat treatment led to significant reductions in multiple established plasma markers of inflammation. Notably, high-sensitivity C-reactive protein decreased by a median of 58% during treatment and this change persisted for 4 weeks after treatment. Plasma levels of interleukin-6, matrix metalloproteinase 9, E-selectin and soluble CD40 ligand also significantly decreased on and/or postpanobinostat. Additionally, we observed a significant reduction in the proportions of intermediate monocytes and tissue factor-positive monocytes. This suppression of cardiovascular risk biomarkers was associated with a prominent reduction in the expression of genes related to inflammation and atherosclerosis.. Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIV patients with high cardiovascular risk.

Topics: Adult; Anti-Retroviral Agents; Biomarkers; Cardiovascular Diseases; Histone Deacetylase Inhibitors; HIV Infections; Humans; Hydroxamic Acids; Indoles; Inflammation; Panobinostat; Treatment Outcome