New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo

Autores
Martinez, Santiago Jose; Vanrell, Maria Cristina; Li, Xiaomo; Carrillo, Carolina; Engman, David M.; Romano, Patricia Silvia
Año de publicación
2026
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is currently a global health problem. Its multiple forms of transmission, which favor the spread of the infection, and the limited treatment options—still restricted to only two drugs—highlight the urgent need for research and development in the field. Despite certain disadvantages, the potent trypanocidal activity of benznidazole (BNZ) and nifurtimox explains their continued use notwithstanding their high toxicity. Reducing BNZ doses through combination with another antiparasitic drug is an attractive strategy to improve tolerability while maintaining efficacy. In this work, we explored the anti-T. cruzi effect of BNZ in combination with difluoromethylornithine (DFMO), a repurposed drug currently used for the treatment of certain cancers and other pathologies. Our data showed that DFMO increases parasite susceptibility to BNZ, reducing the IC50 by half compared to BNZ monotherapy in vitro across strains from three different T. cruzi genetic lineages. Subsequently, we examined the effect of the combination in vivo. We found that mice treated with a 10-fold lower dose of BNZ combined with DFMO displayed a lower parasitemia peak and reduced tissue parasitosis during the acute stage, as well as less parasite reactivation in organs after immunosuppression in the chronic stage, compared to BNZ monotherapy. Overall, these findings support the BNZ/DFMO combination as a proof of concept for Chagas disease therapy, offering a viable strategy to mitigate BNZ-related toxicity through dose reduction without compromising therapeutic efficacy.
Fil: Martinez, Santiago Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Vanrell, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Li, Xiaomo. Cedars Sinai Medical Center; Estados Unidos
Fil: Carrillo, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; Argentina
Fil: Engman, David M.. Cedars Sinai Medical Center; Estados Unidos
Fil: Romano, Patricia Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Materia
CHAGAS DISEASE
BENZNIDAZOLE
DIFLUOROMETHYLORNITHINE
COMBINED THERAPIES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/287906
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/287906
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivoMartinez, Santiago JoseVanrell, Maria CristinaLi, XiaomoCarrillo, CarolinaEngman, David M.Romano, Patricia SilviaCHAGAS DISEASEBENZNIDAZOLEDIFLUOROMETHYLORNITHINECOMBINED THERAPIEShttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is currently a global health problem. Its multiple forms of transmission, which favor the spread of the infection, and the limited treatment options—still restricted to only two drugs—highlight the urgent need for research and development in the field. Despite certain disadvantages, the potent trypanocidal activity of benznidazole (BNZ) and nifurtimox explains their continued use notwithstanding their high toxicity. Reducing BNZ doses through combination with another antiparasitic drug is an attractive strategy to improve tolerability while maintaining efficacy. In this work, we explored the anti-T. cruzi effect of BNZ in combination with difluoromethylornithine (DFMO), a repurposed drug currently used for the treatment of certain cancers and other pathologies. Our data showed that DFMO increases parasite susceptibility to BNZ, reducing the IC50 by half compared to BNZ monotherapy in vitro across strains from three different T. cruzi genetic lineages. Subsequently, we examined the effect of the combination in vivo. We found that mice treated with a 10-fold lower dose of BNZ combined with DFMO displayed a lower parasitemia peak and reduced tissue parasitosis during the acute stage, as well as less parasite reactivation in organs after immunosuppression in the chronic stage, compared to BNZ monotherapy. Overall, these findings support the BNZ/DFMO combination as a proof of concept for Chagas disease therapy, offering a viable strategy to mitigate BNZ-related toxicity through dose reduction without compromising therapeutic efficacy.Fil: Martinez, Santiago Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Vanrell, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Li, Xiaomo. Cedars Sinai Medical Center; Estados UnidosFil: Carrillo, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: Engman, David M.. Cedars Sinai Medical Center; Estados UnidosFil: Romano, Patricia Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFrontiers Media2026-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/287906Martinez, Santiago Jose; Vanrell, Maria Cristina; Li, Xiaomo; Carrillo, Carolina; Engman, David M.; et al.; New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo; Frontiers Media; Frontiers in Cellular and Infection Microbiology; 16; 3-2026; 1-102235-2988CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fcimb.2026.1794141/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fcimb.2026.1794141info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:35:41Zoai:ri.conicet.gov.ar:11336/287906instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-08-25 14:35:42.098CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo
title New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo
spellingShingle New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo
Martinez, Santiago Jose
CHAGAS DISEASE
BENZNIDAZOLE
DIFLUOROMETHYLORNITHINE
COMBINED THERAPIES
title_short New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo
title_full New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo
title_fullStr New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo
title_full_unstemmed New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo
title_sort New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo
dc.creator.none.fl_str_mv Martinez, Santiago Jose
Vanrell, Maria Cristina
Li, Xiaomo
Carrillo, Carolina
Engman, David M.
Romano, Patricia Silvia
author Martinez, Santiago Jose
author_facet Martinez, Santiago Jose
Vanrell, Maria Cristina
Li, Xiaomo
Carrillo, Carolina
Engman, David M.
Romano, Patricia Silvia
author_role author
author2 Vanrell, Maria Cristina
Li, Xiaomo
Carrillo, Carolina
Engman, David M.
Romano, Patricia Silvia
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv CHAGAS DISEASE
BENZNIDAZOLE
DIFLUOROMETHYLORNITHINE
COMBINED THERAPIES
topic CHAGAS DISEASE
BENZNIDAZOLE
DIFLUOROMETHYLORNITHINE
COMBINED THERAPIES
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is currently a global health problem. Its multiple forms of transmission, which favor the spread of the infection, and the limited treatment options—still restricted to only two drugs—highlight the urgent need for research and development in the field. Despite certain disadvantages, the potent trypanocidal activity of benznidazole (BNZ) and nifurtimox explains their continued use notwithstanding their high toxicity. Reducing BNZ doses through combination with another antiparasitic drug is an attractive strategy to improve tolerability while maintaining efficacy. In this work, we explored the anti-T. cruzi effect of BNZ in combination with difluoromethylornithine (DFMO), a repurposed drug currently used for the treatment of certain cancers and other pathologies. Our data showed that DFMO increases parasite susceptibility to BNZ, reducing the IC50 by half compared to BNZ monotherapy in vitro across strains from three different T. cruzi genetic lineages. Subsequently, we examined the effect of the combination in vivo. We found that mice treated with a 10-fold lower dose of BNZ combined with DFMO displayed a lower parasitemia peak and reduced tissue parasitosis during the acute stage, as well as less parasite reactivation in organs after immunosuppression in the chronic stage, compared to BNZ monotherapy. Overall, these findings support the BNZ/DFMO combination as a proof of concept for Chagas disease therapy, offering a viable strategy to mitigate BNZ-related toxicity through dose reduction without compromising therapeutic efficacy.
Fil: Martinez, Santiago Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Vanrell, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Li, Xiaomo. Cedars Sinai Medical Center; Estados Unidos
Fil: Carrillo, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; Argentina
Fil: Engman, David M.. Cedars Sinai Medical Center; Estados Unidos
Fil: Romano, Patricia Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
description Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is currently a global health problem. Its multiple forms of transmission, which favor the spread of the infection, and the limited treatment options—still restricted to only two drugs—highlight the urgent need for research and development in the field. Despite certain disadvantages, the potent trypanocidal activity of benznidazole (BNZ) and nifurtimox explains their continued use notwithstanding their high toxicity. Reducing BNZ doses through combination with another antiparasitic drug is an attractive strategy to improve tolerability while maintaining efficacy. In this work, we explored the anti-T. cruzi effect of BNZ in combination with difluoromethylornithine (DFMO), a repurposed drug currently used for the treatment of certain cancers and other pathologies. Our data showed that DFMO increases parasite susceptibility to BNZ, reducing the IC50 by half compared to BNZ monotherapy in vitro across strains from three different T. cruzi genetic lineages. Subsequently, we examined the effect of the combination in vivo. We found that mice treated with a 10-fold lower dose of BNZ combined with DFMO displayed a lower parasitemia peak and reduced tissue parasitosis during the acute stage, as well as less parasite reactivation in organs after immunosuppression in the chronic stage, compared to BNZ monotherapy. Overall, these findings support the BNZ/DFMO combination as a proof of concept for Chagas disease therapy, offering a viable strategy to mitigate BNZ-related toxicity through dose reduction without compromising therapeutic efficacy.
publishDate 2026
dc.date.none.fl_str_mv 2026-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/287906
Martinez, Santiago Jose; Vanrell, Maria Cristina; Li, Xiaomo; Carrillo, Carolina; Engman, David M.; et al.; New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo; Frontiers Media; Frontiers in Cellular and Infection Microbiology; 16; 3-2026; 1-10
2235-2988
CONICET Digital
CONICET
url http://hdl.handle.net/11336/287906
identifier_str_mv Martinez, Santiago Jose; Vanrell, Maria Cristina; Li, Xiaomo; Carrillo, Carolina; Engman, David M.; et al.; New insights for an old drug: difluoromethylornithine boosts the trypanocidal action of benznidazole on Trypanosoma cruzi in vitro and in vivo; Frontiers Media; Frontiers in Cellular and Infection Microbiology; 16; 3-2026; 1-10
2235-2988
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fcimb.2026.1794141/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fcimb.2026.1794141
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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