title: 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 (IC509-370 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.
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia.
authors.forename: Ming Jang
authors.initials: MJ
authors.lastname: Chua
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia.
authors.forename: Megan S J
authors.initials: MS
authors.lastname: Arnold
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: Weijun
authors.initials: W
authors.lastname: Xu
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204- CIIL -Centre D'Infection et D'Immunité de Lille, F-59000 Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Lancelot
authors.affiliation: Institut Pasteur and INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Paris, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lamotte
authors.affiliation: Institut Pasteur and INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Paris, France.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Späth
authors.affiliation: Institut Pasteur and INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Prina
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204- CIIL -Centre D'Infection et D'Immunité de Lille, F-59000 Lille, France.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pierce
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia.
authors.forename: Tina S
authors.initials: TS
authors.lastname: Skinner-Adams
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia. Electronic address: k.andrews@griffith.edu.au.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
mesh_terms: D000107:Acetylation; D000284:Administration, Oral; D000818:Animals; D047630:Depsipeptides / Q000494:pharmacology; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D008018:Life Cycle Stages / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D000077767:Panobinostat; D018512:Parasitemia / Q000188:drug therapy; D010962:Plasmodium berghei / Q000187:drug effects; D016790:Plasmodium knowlesi / Q000187:drug effects* / Q000254:growth & development; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000254:growth & development; D013449:Sulfonamides / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D013449:Sulfonamides; D000077337:Vorinostat; D000077767:Panobinostat; C087123:romidepsin; D006655:Histone Deacetylases; C487081:belinostat
keywords: Histone deacetylase; Leishmania; Panobinostat; Plasmodium; Schistosoma