The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs.
Background Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such th...
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ftdoajarticles:oai:doaj.org/article:4e0617f643d64ddcac83ccd16c054427 2023-05-15T15:12:34+02:00 The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. Hugo Rolando Vaca Ana María Celentano María Agustina Toscanini Tino Heimburg Ehab Ghazy Patrik Zeyen Alexander-Thomas Hauser Guilherme Oliveira María Celina Elissondo Manfred Jung Wolfgang Sippl Federico Camicia Mara Cecilia Rosenzvit 2021-03-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009226 https://doaj.org/article/4e0617f643d64ddcac83ccd16c054427 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009226 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009226 https://doaj.org/article/4e0617f643d64ddcac83ccd16c054427 PLoS Neglected Tropical Diseases, Vol 15, Iss 3, p e0009226 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009226 2022-12-31T08:01:16Z Background Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti). Methodology/principal findings Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them -entinostat, TH65, and TH92- had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed. Conclusion, significance The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 3 e0009226 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Hugo Rolando Vaca Ana María Celentano María Agustina Toscanini Tino Heimburg Ehab Ghazy Patrik Zeyen Alexander-Thomas Hauser Guilherme Oliveira María Celina Elissondo Manfred Jung Wolfgang Sippl Federico Camicia Mara Cecilia Rosenzvit The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Background Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti). Methodology/principal findings Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them -entinostat, TH65, and TH92- had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed. Conclusion, significance The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave ... |
format |
Article in Journal/Newspaper |
author |
Hugo Rolando Vaca Ana María Celentano María Agustina Toscanini Tino Heimburg Ehab Ghazy Patrik Zeyen Alexander-Thomas Hauser Guilherme Oliveira María Celina Elissondo Manfred Jung Wolfgang Sippl Federico Camicia Mara Cecilia Rosenzvit |
author_facet |
Hugo Rolando Vaca Ana María Celentano María Agustina Toscanini Tino Heimburg Ehab Ghazy Patrik Zeyen Alexander-Thomas Hauser Guilherme Oliveira María Celina Elissondo Manfred Jung Wolfgang Sippl Federico Camicia Mara Cecilia Rosenzvit |
author_sort |
Hugo Rolando Vaca |
title |
The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. |
title_short |
The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. |
title_full |
The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. |
title_fullStr |
The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. |
title_full_unstemmed |
The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. |
title_sort |
potential for histone deacetylase (hdac) inhibitors as cestocidal drugs. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0009226 https://doaj.org/article/4e0617f643d64ddcac83ccd16c054427 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 3, p e0009226 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009226 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009226 https://doaj.org/article/4e0617f643d64ddcac83ccd16c054427 |
op_doi |
https://doi.org/10.1371/journal.pntd.0009226 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
3 |
container_start_page |
e0009226 |
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1766343227947876352 |