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

Chua, Ming Jang, Arnold, Megan S. J., Xu, Weijun, Lancelot, Julien, Lamotte, Suzanne, Spath, Gerald F., Prina, Eric, Pierce, Raymond J., Fairlie, David P., Skinner-Adams, Tina S. and Andrews, Katherine T. (2017) Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth. International Journal for Parasitology: Drugs and Drug Resistance, 7 1: 42-50. doi:10.1016/j.ijpddr.2016.12.005


Author Chua, Ming Jang
Arnold, Megan S. J.
Xu, Weijun
Lancelot, Julien
Lamotte, Suzanne
Spath, Gerald F.
Prina, Eric
Pierce, Raymond J.
Fairlie, David P.
Skinner-Adams, Tina S.
Andrews, Katherine T.
Title Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth
Formatted title
Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth
Journal name International Journal for Parasitology: Drugs and Drug Resistance   Check publisher's open access policy
ISSN 2211-3207
Publication date 2017-04-01
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ijpddr.2016.12.005
Open Access Status DOI
Volume 7
Issue 1
Start page 42
End page 50
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Elsevier
Language eng
Subject 2405 Parasitology
2725 Infectious Diseases
2736 Pharmacology (medical)
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 (IC 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 (IC > 20 μM) or S. mansoni schistosomula (IC > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC ∼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.
Formatted 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.
Keyword Histone deacetylase
Leishmania
Panobinostat
Plasmodium
Schistosoma
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1093378
602080
1027369
CE140100011
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
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