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

Dante      Rotili; Giovanna      Simonetti; Andrea      Savarino; Anna   T.   Palamara; Anna   R.   Migliaccio; Antonello      Mai

doi:10.2174/156802609788085296

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 β-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 γ-globin gene expression in adult red cell, are presently considered promising molecules for personalized therapy of β-hemoglobinopathies.

Keywords: epigenetics, HDAC inhibitors, fungal infection, Candida albicans, HIV-1 latency, Plasmodium falciparum, β-thalassemia, sickle cell disease