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.

Inhibition of Toxoplasma gondii and Plasmodium falciparum Infections in Vitro by NSC3852, a Redox Active Antiproliferative and Tumor Cell Differentiation Agent

“…Toxoplasma gondii has devastating consequences in various host species, and widespread infections among human and animals provides an opportunity for selection of more pathogenic strains and drug resistance. Dihydrofolate reductase, farnesyl pyrophosphate synthase, and histone deacetylase exemplify drug targets that are shared by human cancer cells and T. gondii (Peaslee and Anderson, 2001;Ling et al, 2007;Strobl et al, 2007). Metabolic pathways in intracellular parasites such as T. gondii and cancer cells are more dependent upon glycolysis for energy production and more sensitive to oxidative stress than normal cells (Denton et al, 1996;McCarthy and Davis, 2003;Pino et al, 2007).…”

“…Tachyzoites of the RH strain T. gondii were propagated in bovine macrophage (BM) cells and purified for infection assays as described previously (Strobl et al, 2007).…”

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

“…Compounds 34 and 35 are two examples of this, which have T. gondii IC 50 s of 7.6 nM and 39 nM, respectively. Host cell toxicity remains a concern with compound 34; the TD 50 for human host cells is less than 10 times greater than the IC 50 for T. gondii, but compound 35 seems to fare better on host cells with a TD 50 of Ͼ10 M in HS68 cells (74,77) (Table 1). Garcinol, derived from the Garcinia indica fruit, is another compound that affects histone acetylation, targeting a family of lysine acetyltransferases (KAT) enzymes required for T. gondii tachyzoites to replicate successfully (78).…”

Chromatin regulation in schistosomes and histone modifying enzymes as drug targets

“…HDACi have also stimulated interest as anti-parasitic drugs and have been tested against P. falciparum (Andrews et al 2000(Andrews et al , 2008, Toxoplasma gondii (Strobl et al 2007) and the major kinetoplastid parasites (Mai et al 2004, Horn 2008. In the case of P. falciparum, it was possible to develop HDACi that are significantly more toxic to the parasite than toward human cells (Andrews et al 2008, Wheatley et al 2010.…”

“…Similarly, a variety of hydroxamic acid class HDACi, including TSA and SAHA at nM concentrations, were capable of inhibiting proliferation of the apicomplexan parasite T. gondii in vitro and completely protected monolayers of HS68 cells against infection (Strobl et al 2007). Moreover, in the case of the kinetoplastid parasite Trypanosoma brucei, an apicidin analogue has been shown to have potent and selective antiproliferative effects (Murray et al 2001).…”