Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth

Abstract

Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC50 9–370 nM), with belinostat, panobinostat and vorinostat having 8–45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF) or human embryonic kidney (HEK 293) cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC50 > 20 μM) or S. mansoni schistosomula (IC50 > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC50 ∼10 μM). Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4–7 and 4–10 after infection (P < 0.05), respectively.

Activity of epigenetic inhibitors against Plasmodium falciparum asexual and sexual blood stages

“…respectively. Despite differences in methodology and parasite strains, these agree well with results for 8 of these compounds that had been screened against either asexual stages or gametocytes in earlier studies (10)(11)(12)(13)(14). Thirty-one of the most active compounds (EC90s < 1 µM) were selected for more detailed dose-response studies ( Figure 1B).…”

“…Many of these genes likely also play key roles during the substantial chromatin remodeling that occurs during the early stages of gametocytogenesis (8,9). Earlier studies involving a limited number of epigenetic inhibitors found activity against malaria parasites (10)(11)(12)(13)(14) and several have already been approved for clinical use or are currently in clinical trials for treatment of various cancers (15). To evaluate the promise of targeting epigenetic processes more broadly, we decided to screen the two largest commercially available libraries of epigenetic inhibitors against both asexual blood stages and gametocytes of Plasmodium falciparum, the most widespread and virulent human malaria parasite.…”

Investigating the Antiparasitic Potential of the Marine Sesquiterpene Avarone, Its Reduced Form Avarol, and the Novel Semisynthetic Thiazinoquinone Analogue Thiazoavarone

“…For example, artemisinin and its derivatives, a potent class of antimalarial agents, have been proved to be beneficial for other infectious diseases such as schistosomiasis and leishmaniasis [6]. Furthermore, histone deacetylases (HDAC) inhibitors have been shown to have activity both against some Plasmodium species as well as Leishmania and Schistosoma parasites [7]. Importantly, the blood parasites, Plasmodium and Schistosoma, both feeding on human hemoglobin, can detoxify the free heme groups through the synthesis of insoluble hemozoin pigments [8].…”

Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐Plasmodium Activity

“…The anti-(tetra)-acetylh istone H4 antibody detected an~11 kDa band that corresponds to the expected size of H4, as well as ad oubleto f~13-14kDa and ab and of~16 kDa band which likelyc orrespond to hyperacetylated forms of H2B/H2Bv and H2A.Z, respectively (see Experimental Section, Histone hyperacetylation assays), as previously reported. [22] Using this antibody,a ll compounds, except 1b with at rityl in the R 1 position, caused am ean1 .5 to 3.4fold increased signal relative to the vehicle control, irrespective of whether density of all bands (Figure 3; grey bars) or only the~11 kDa band correspondingt oH 4 ( Figure 3; whiteb ars) were analyzed. As expected the control HDAC inhibitor SAHA, but not the negative control drug chloroquine, also caused hyperacetylation with mean % 3-fold increased signal relative to vehicle control (Figure3).…”