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

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    Author(s)
    Chua, Ming Jang
    Arnold, Megan SJ
    Xu, Weijun
    Lancelot, Julien
    Lamotte, Suzanne
    Spaeth, Gerald F
    Prina, Eric
    Pierce, Raymond J
    Fairlie, David P
    Skinner-Adams, Tina S
    Andrews, Katherine T
    Griffith University Author(s)
    Andrews, Katherine T.
    Skinner-Adams, Tina
    Arnold, Megan
    Chua, MJ J.
    Year published
    2017
    Metadata
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    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 ...
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    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.
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    Journal Title
    International Journal for Parasitology: Drugs and Drug Resistance
    Volume
    7
    DOI
    https://doi.org/10.1016/j.ijpddr.2016.12.005
    Copyright Statement
    © 2017 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Subject
    Medical Microbiology not elsewhere classified
    Medical Microbiology
    Publication URI
    http://hdl.handle.net/10072/344427
    Collection
    • Journal articles

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