Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth. - Institut Pasteur Access content directly
Journal Articles International journal for parasitology. Drugs and drug resistance Year : 2017

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.
Fichier principal
Vignette du fichier
1-s2.0-S2211320716301117-main.pdf (903.3 Ko) Télécharger le fichier
Origin Publication funded by an institution
Loading...

Dates and versions

pasteur-01451045 , version 1 (31-01-2017)

Licence

Identifiers

Cite

Ming Jang Chua, Megan S J Arnold, Weijun Xu, Julien Lancelot, Suzanne Lamotte, et al.. Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth.. International journal for parasitology. Drugs and drug resistance, 2017, 7 (1), pp.42-50. ⟨10.1016/j.ijpddr.2016.12.005⟩. ⟨pasteur-01451045⟩
559 View
425 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More