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

Int J Parasitol Drugs Drug Resist. 2017 Apr;7(1):42-50. doi: 10.1016/j.ijpddr.2016.12.005. Epub 2016 Dec 23.

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.

Keywords: Histone deacetylase; Leishmania; Panobinostat; Plasmodium; Schistosoma.

MeSH terms

  • Acetylation
  • Administration, Oral
  • Animals
  • Depsipeptides / pharmacology
  • HEK293 Cells
  • Histone Deacetylase Inhibitors / administration & dosage
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors / therapeutic use
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / pharmacology
  • Hydroxamic Acids / therapeutic use
  • Indoles / administration & dosage
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Inhibitory Concentration 50
  • Leishmania / drug effects*
  • Leishmania / growth & development
  • Life Cycle Stages / drug effects
  • Malaria / drug therapy
  • Malaria / parasitology
  • Mice
  • Panobinostat
  • Parasitemia / drug therapy
  • Plasmodium berghei / drug effects
  • Plasmodium knowlesi / drug effects*
  • Plasmodium knowlesi / growth & development
  • Schistosoma mansoni / drug effects*
  • Schistosoma mansoni / growth & development
  • Sulfonamides / pharmacology
  • Vorinostat

Substances

  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Indoles
  • Sulfonamides
  • Vorinostat
  • Panobinostat
  • romidepsin
  • Histone Deacetylases
  • belinostat