Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth
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 l...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-04-01
|
| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320716301117 |
| _version_ | 1830288681651404800 |
|---|---|
| author | Ming Jang Chua Megan S.J. Arnold Weijun Xu Julien Lancelot Suzanne Lamotte Gerald F. Späth Eric Prina Raymond J. Pierce David P. Fairlie Tina S. Skinner-Adams Katherine T. Andrews |
| author_facet | Ming Jang Chua Megan S.J. Arnold Weijun Xu Julien Lancelot Suzanne Lamotte Gerald F. Späth Eric Prina Raymond J. Pierce David P. Fairlie Tina S. Skinner-Adams Katherine T. Andrews |
| author_sort | Ming Jang Chua |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T04:39:25Z |
| format | Article |
| id | doaj.art-652ca88e8de1425aa193abfb8a20b233 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-12-19T04:39:25Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-652ca88e8de1425aa193abfb8a20b2332022-12-21T20:35:39ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072017-04-0171425010.1016/j.ijpddr.2016.12.005Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growthMing Jang Chua0Megan S.J. Arnold1Weijun Xu2Julien Lancelot3Suzanne Lamotte4Gerald F. Späth5Eric Prina6Raymond J. Pierce7David P. Fairlie8Tina S. Skinner-Adams9Katherine T. Andrews10Griffith Institute for Drug Discovery, Griffith University, Queensland, AustraliaGriffith Institute for Drug Discovery, Griffith University, Queensland, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, AustraliaUniv. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204- CIIL -Centre D'Infection et D'Immunité de Lille, F-59000 Lille, FranceInstitut Pasteur and INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Paris, FranceInstitut Pasteur and INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Paris, FranceInstitut Pasteur and INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Paris, FranceUniv. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204- CIIL -Centre D'Infection et D'Immunité de Lille, F-59000 Lille, FranceInstitute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, AustraliaGriffith Institute for Drug Discovery, Griffith University, Queensland, AustraliaGriffith Institute for Drug Discovery, Griffith University, Queensland, AustraliaMalaria, 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.http://www.sciencedirect.com/science/article/pii/S2211320716301117PlasmodiumSchistosomaLeishmaniaHistone deacetylasePanobinostat |
| spellingShingle | Ming Jang Chua Megan S.J. Arnold Weijun Xu Julien Lancelot Suzanne Lamotte Gerald F. Späth Eric Prina Raymond J. Pierce David P. Fairlie Tina S. Skinner-Adams Katherine T. Andrews Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth International Journal for Parasitology: Drugs and Drug Resistance Plasmodium Schistosoma Leishmania Histone deacetylase Panobinostat |
| title | Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth |
| title_full | Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth |
| title_fullStr | Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth |
| title_full_unstemmed | Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth |
| title_short | Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth |
| title_sort | effect of clinically approved hdac inhibitors on plasmodium leishmania and schistosoma parasite growth |
| topic | Plasmodium Schistosoma Leishmania Histone deacetylase Panobinostat |
| url | http://www.sciencedirect.com/science/article/pii/S2211320716301117 |
| work_keys_str_mv | AT mingjangchua effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT megansjarnold effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT weijunxu effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT julienlancelot effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT suzannelamotte effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT geraldfspath effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT ericprina effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT raymondjpierce effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT davidpfairlie effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT tinasskinneradams effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth AT katherinetandrews effectofclinicallyapprovedhdacinhibitorsonplasmodiumleishmaniaandschistosomaparasitegrowth |