International journal for parasitology. Drugs and drug resistance

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

PMID 28107750


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 inxa0vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L.xa0donovani parasites and two for inxa0vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P.xa0knowlesi malaria parasites (IC50 9-370xa0nM), 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.xa0knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC50xa0>xa020xa0μM) or S.xa0mansoni schistosomula (IC50xa0>xa010xa0μM), however romidepsin inhibited S.xa0mansoni adult worm parings and egg production (IC50 ∼10xa0μM). Modest inxa0vivo activity was observed in P.xa0berghei infected mice dosed orally with vorinostat or panobinostat (25xa0mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4-7 and 4-10 after infection (Pxa0

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Romidepsin, ≥98% (HPLC)