SCRIPTAID AND SUBEROYLANILIDE HYDROXAMIC ACID ARE HISTONE DEACETYLASE INHIBITORS WITH POTENT ANTI–TOXOPLASMA GONDII ACTIVITY IN VITRO

Abstract

Toxoplasma gondii is a well-recognized cause of disease in congenitally infected and immunocompromised individuals. Histone deacetylases (HDAC) comprise a family of enzymes that participate in the regulation of chromatin structure, gene expression, and cell signaling in eukaryotes. Toxoplasma gondii expresses a HDAC Class I enzyme homologous to human hdac3. Previous work showed that the histone deacetylase inhibitors (HDI) apicidin and valproic acid inhibit T. gondii infections in vitro. The present study compares the activity of hydroxamic-acid histone deacetylase inhibitors against the RH strain of T. gondii growing in HS68 human foreskin fibroblast cells. Nanomolar concentrations of suberoylanilide hydroxamic acid (SAHA), suberic bishydroxamic acid (SBHA), scriptaid, and trichostatin A (TSA) inhibited T. gondii tachyzoite proliferation. Scriptaid was the most potent hydroxamic acid inhibitor (IC50 = 39 nM). In comparison, the carboxylate histone deacetylase inhibitors sodium valproate, sodium butyrate, and 4-phenylbutyrate were less potent (IC50 range 1-5 mM). All of the inhibitors tested, except SBHA, completely protected the HS68 monolayers from T. gondii at concentrations 3-6 times greater than their respective IC50. In contrast, nicotinamide, an inhibitor of NADI-dependent Class III HDAC, had minimal activity against T. gondii in our in vitro assays. We conclude that the hydroxamic acid class of histone deacetylase inhibitors exhibit potent anti-T. gondii activity in vitro.