Non-Cancer Uses of Histone Deacetylase Inhibitors: Effects on Infectious Diseases and β-Hemoglobinopathies+

Abstract

After the approval of suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) for the treatment of cutaneous T cell lymphoma (CTCL), a number of HDAC inhibitors (HDACi) are currently in Phase II or III clinical trials (alone or in combination) for the treatment of a great number of tumors. In addition to these cancer uses, HDACi can be successfully used in non-cancer diseases. In this review we focused on the uses of HDACi in some infectious diseases and beta-hemoglobinopaties. In C. albicans cultures, HDACi increased the frequency of cell switching (a relevant virulence trait) in the white-to-opaque transition, reduced the azole trailing effect through reduction in azole-dependent upregulation of CDR and ERG genes, and inhibited the fluconazole-dependent resistance induction. Moreover, they inhibited germination in several strains, and caused 90% reduction in the adherence of C. albicans to human cultured pneumocytes. In HIV-1-infected cells, the treatment with HDACi reactivates the HIV-1 expression in latent cellular reservoirs. Thus, the use of HDACi as adjuvant to highly active antiretroviral therapy (HAART) can represent a new potential therapeutic strategy to eradicate the viral infection. A number of HDACi have been reported as active against P. falciparum infection. Two recent papers show some 2-aminosuberic acid-based compounds as well as a series of phenylthiazolyl suberoyl hydroxamates as very potent and selective antimalarial agents. Among the many agents capable to perform post-natal reactivation of fetal hemoglobin production, HDACi for their capacity to de-repress gamma-globin gene expression in adult red cell, are presently considered promising molecules for personalized therapy of beta-hemoglobinopathies.

Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence ofCandidaandAspergillusspecies

“…HDACis exhibit promise in the treatment of cancer and certain parasitic and viral infections. 14,109 The HDACis include trichostatin A (TSA), romidepsin/depsipeptide, suberoylanilide hydroxamic acid (SAHA; vorinostat), panobinostat and MG-CD0103 (mocetinostat). However, only SAHA and romidepsin are licensed for clinical use (for cutaneous T cell lymphoma).…”

“…However, only SAHA and romidepsin are licensed for clinical use (for cutaneous T cell lymphoma). 14,110,111 As HDACis potentiate the cytotoxicity of DNA methylation inhibitors (e.g., cisplatin, the anthracyclines, dexamethasone), they may be used together with these inhibitors. [109][110][111] Mammalian and fungal HDACs are substantially homologous and investigators have identified several classes and subclasses of HDACs in fungi (e.g., the class I enzymes RpdA and HosA, the class II enzymes HdaA and HosB).…”

“…as such resistance cannot develop in HDA1-deficient strains. 14 In addition, data have shown that HDAC6 regulates Hsp90 acetylation 119 and that hyperacetylation of the Hsp90 complex leads to inhibition of it. Finally, reduced levels of H3K56ac activity (regulated by the C. albicans RTT109 gene) have sensitized C. albicans to hydroxyurea, the azoles, and echinocandins and are associated with attenuated C. albicans virulence in mice.…”

“…29 Similarly, exposure of an A. fumigatus strain to with protein-targeted agents. [12][13][14] Many targets of new anticancer agents have homologs in fungi and are components of critical cell-signaling pathways. 10,11 Thus, studying new molecular targets and their inhibitors in the context of drug-pathogen interactions will provide insight into the pathogenesis of IFIs and may assist with antifungal drug development.…”

Erythroblast enucleation

“…Previous investigators had already identified that HDAC are required for chromatin condensation prior to enucleation of murine erythroblasts immortalized with the Friend virus. 12 Using primary normal cells, Ji et al confirmed these data by demonstrating that the HDAC inhibitors trichostatin A and valproic acid inhibit chromatin condensation of primary erythroblasts in culture. Using short interfering RNA technology, they then identified that the process of chromatin condensation is specifically dependent on HDAC2 activity while HDAC1, 3 and 5 are apparently dispensable (Figure 2).…”