The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases

Autores
Marullo, Rossella; Castro, Monica; Yomtoubian, Shira; Nieves Calvo Vidal, M.; Revuelta, María Victoria; Krumsiek, Jan; Nicholas, Andrew P.; Cresta Morgado, Pablo; Yang, ShaoNing; Medina, Vanina Araceli; Roth, Berta María Cristina; Bonomi, Marcelo; Keshari, Kayvan R.; Mittal, Vivek; Navigante, Alfredo Hugo; Cerchietti, Leandro
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we showed that administration of l-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that l-arginine radiosensitization is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumor lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage. These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumor-infiltrating lymphocytes.
Fil: Marullo, Rossella. Cornell University; Estados Unidos
Fil: Castro, Monica. Universidad de Buenos Aires; Argentina
Fil: Yomtoubian, Shira. Cornell University; Estados Unidos
Fil: Nieves Calvo Vidal, M.. Cornell University; Estados Unidos
Fil: Revuelta, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Krumsiek, Jan. Cornell University; Estados Unidos
Fil: Nicholas, Andrew P.. Cornell University; Estados Unidos
Fil: Cresta Morgado, Pablo. Universidad de Buenos Aires; Argentina
Fil: Yang, ShaoNing. Cornell University; Estados Unidos
Fil: Medina, Vanina Araceli. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
Fil: Roth, Berta María Cristina. Universidad de Buenos Aires; Argentina
Fil: Bonomi, Marcelo. Ohio State University; Estados Unidos
Fil: Keshari, Kayvan R.. Memorial Sloan Kettering Cancer Center; Estados Unidos
Fil: Mittal, Vivek. Cornell University; Estados Unidos
Fil: Navigante, Alfredo Hugo. Universidad de Buenos Aires; Argentina
Fil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Materia
ARGININE
BRAIN METASTASIS
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:11336/169891
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastasesMarullo, RossellaCastro, MonicaYomtoubian, ShiraNieves Calvo Vidal, M.Revuelta, María VictoriaKrumsiek, JanNicholas, Andrew P.Cresta Morgado, PabloYang, ShaoNingMedina, Vanina AraceliRoth, Berta María CristinaBonomi, MarceloKeshari, Kayvan R.Mittal, VivekNavigante, Alfredo HugoCerchietti, LeandroARGININEBRAIN METASTASIShttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we showed that administration of l-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that l-arginine radiosensitization is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumor lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage. These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumor-infiltrating lymphocytes.Fil: Marullo, Rossella. Cornell University; Estados UnidosFil: Castro, Monica. Universidad de Buenos Aires; ArgentinaFil: Yomtoubian, Shira. Cornell University; Estados UnidosFil: Nieves Calvo Vidal, M.. Cornell University; Estados UnidosFil: Revuelta, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Krumsiek, Jan. Cornell University; Estados UnidosFil: Nicholas, Andrew P.. Cornell University; Estados UnidosFil: Cresta Morgado, Pablo. Universidad de Buenos Aires; ArgentinaFil: Yang, ShaoNing. Cornell University; Estados UnidosFil: Medina, Vanina Araceli. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Roth, Berta María Cristina. Universidad de Buenos Aires; ArgentinaFil: Bonomi, Marcelo. Ohio State University; Estados UnidosFil: Keshari, Kayvan R.. Memorial Sloan Kettering Cancer Center; Estados UnidosFil: Mittal, Vivek. Cornell University; Estados UnidosFil: Navigante, Alfredo Hugo. Universidad de Buenos Aires; ArgentinaFil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaScience Advances is the American Association for the Advancement of Science2021-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/169891Marullo, Rossella; Castro, Monica; Yomtoubian, Shira; Nieves Calvo Vidal, M.; Revuelta, María Victoria; et al.; The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases; Science Advances is the American Association for the Advancement of Science; Science Advances; 7; 45; 11-2021; 1-172375-2548CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1126/sciadv.abg1964info:eu-repo/semantics/altIdentifier/url/https://www.science.org/doi/10.1126/sciadv.abg1964info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-29T11:50:30Zoai:ri.conicet.gov.ar:11336/169891instacron: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:34982025-10-29 11:50:31.007CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases
title The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases
spellingShingle The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases
Marullo, Rossella
ARGININE
BRAIN METASTASIS
title_short The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases
title_full The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases
title_fullStr The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases
title_full_unstemmed The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases
title_sort The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases
dc.creator.none.fl_str_mv Marullo, Rossella
Castro, Monica
Yomtoubian, Shira
Nieves Calvo Vidal, M.
Revuelta, María Victoria
Krumsiek, Jan
Nicholas, Andrew P.
Cresta Morgado, Pablo
Yang, ShaoNing
Medina, Vanina Araceli
Roth, Berta María Cristina
Bonomi, Marcelo
Keshari, Kayvan R.
Mittal, Vivek
Navigante, Alfredo Hugo
Cerchietti, Leandro
author Marullo, Rossella
author_facet Marullo, Rossella
Castro, Monica
Yomtoubian, Shira
Nieves Calvo Vidal, M.
Revuelta, María Victoria
Krumsiek, Jan
Nicholas, Andrew P.
Cresta Morgado, Pablo
Yang, ShaoNing
Medina, Vanina Araceli
Roth, Berta María Cristina
Bonomi, Marcelo
Keshari, Kayvan R.
Mittal, Vivek
Navigante, Alfredo Hugo
Cerchietti, Leandro
author_role author
author2 Castro, Monica
Yomtoubian, Shira
Nieves Calvo Vidal, M.
Revuelta, María Victoria
Krumsiek, Jan
Nicholas, Andrew P.
Cresta Morgado, Pablo
Yang, ShaoNing
Medina, Vanina Araceli
Roth, Berta María Cristina
Bonomi, Marcelo
Keshari, Kayvan R.
Mittal, Vivek
Navigante, Alfredo Hugo
Cerchietti, Leandro
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ARGININE
BRAIN METASTASIS
topic ARGININE
BRAIN METASTASIS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we showed that administration of l-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that l-arginine radiosensitization is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumor lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage. These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumor-infiltrating lymphocytes.
Fil: Marullo, Rossella. Cornell University; Estados Unidos
Fil: Castro, Monica. Universidad de Buenos Aires; Argentina
Fil: Yomtoubian, Shira. Cornell University; Estados Unidos
Fil: Nieves Calvo Vidal, M.. Cornell University; Estados Unidos
Fil: Revuelta, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Krumsiek, Jan. Cornell University; Estados Unidos
Fil: Nicholas, Andrew P.. Cornell University; Estados Unidos
Fil: Cresta Morgado, Pablo. Universidad de Buenos Aires; Argentina
Fil: Yang, ShaoNing. Cornell University; Estados Unidos
Fil: Medina, Vanina Araceli. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
Fil: Roth, Berta María Cristina. Universidad de Buenos Aires; Argentina
Fil: Bonomi, Marcelo. Ohio State University; Estados Unidos
Fil: Keshari, Kayvan R.. Memorial Sloan Kettering Cancer Center; Estados Unidos
Fil: Mittal, Vivek. Cornell University; Estados Unidos
Fil: Navigante, Alfredo Hugo. Universidad de Buenos Aires; Argentina
Fil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
description Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we showed that administration of l-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that l-arginine radiosensitization is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumor lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage. These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumor-infiltrating lymphocytes.
publishDate 2021
dc.date.none.fl_str_mv 2021-11
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/11336/169891
Marullo, Rossella; Castro, Monica; Yomtoubian, Shira; Nieves Calvo Vidal, M.; Revuelta, María Victoria; et al.; The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases; Science Advances is the American Association for the Advancement of Science; Science Advances; 7; 45; 11-2021; 1-17
2375-2548
CONICET Digital
CONICET
url http://hdl.handle.net/11336/169891
identifier_str_mv Marullo, Rossella; Castro, Monica; Yomtoubian, Shira; Nieves Calvo Vidal, M.; Revuelta, María Victoria; et al.; The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases; Science Advances is the American Association for the Advancement of Science; Science Advances; 7; 45; 11-2021; 1-17
2375-2548
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1126/sciadv.abg1964
info:eu-repo/semantics/altIdentifier/url/https://www.science.org/doi/10.1126/sciadv.abg1964
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 Science Advances is the American Association for the Advancement of Science
publisher.none.fl_str_mv Science Advances is the American Association for the Advancement of Science
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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score 13.10058

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