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

Autores
Marullo, Rossella; Castro, Mónica; Yomtoubian, Shira; Calvo Vidal, M. Nieves; Revuelta, María Victoria; Krumsiek, Jan; Cho, Andrew; Cresta Morgado, Pablo; Yang, ShaoNing; Medina, Vanina Araceli; Roth, Berta M.; Bonomi, Marcelo; Keshari, Kayvan R.; Mittal, Vivek; Navigante, Alfredo; Cerchietti, Leandro
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Fil: Marullo, Rossella. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
Fil: Castro, Mónica. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; Argentina
Fil: Yomtoubian, Shira. Cornell University. Weill Cornell Medicine. Department of Cardiothoracic Surgery; Estados Unidos
Fil: Yomtoubian, Shira. Cornell University. Weill Cornell Medicine. Department of Cell and Developmental Biology; Estados Unidos
Fil: Calvo-Vidal, M. Nieves. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
Fil: Revuelta, María Victoria. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
Fil: Krumsiek, Jan. Weill Cornell Medicine. Institute for Computational Biomedicine. Department of Physiology and Biophysics; Estados Unidos
Fil: Cho, Andrew. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; Argentina
Fil: Cresta Morgado, Pablo. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; Argentina
Fil: Yang, ShaoNing. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
Fil: Medina, Vanina A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina
Fil: Roth, Berta M. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Departamento de Radiación e Imagenología; Argentina
Fil: Medina, Vanina A. Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires; Argentina
Fil: Medina, Vanina A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisótopos; Argentina
Fil: Bonomi, Marcelo. The Ohio State University. Hematology and Oncology Division; Estados Unidos
Fil: Keshari, Kayvan R. Weill Cornell Graduate School. Department of Biochemistry and Structural Biology; Estados Unidos
Fil: Keshari, Kayvan R. Memorial Sloan Kettering Cancer Center. Department of Radiology; Estados Unidos
Fil: Keshari, Kayvan R. Memorial Sloan Kettering Cancer Center. Molecular Pharmacology Program; Estados Unidos
Fil: Mittal, Vivek. Cornell University. Weill Cornell Medicine. Department of Cardiothoracic Surgery; Estados Unidos
Fil: Mittal, Vivek. Cornell University. Weill Cornell Medicine. Department of Cell and Developmental Biology; Estados Unidos
Fil: Navigante, Alfredo. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; Argentina
Fil: Cerchietti, Leandro. Cornell University. Weill Cornell Medicine. Hematology and Oncology Division; Estados Unidos
Abstract: 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.
Fuente
Science Advances Vol.7, No.45, 2021
Materia
METASTASIS
CEREBRO
TUMORES
ARGININA
RADIACION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
Repositorio Institucional (UCA)
Institución
Pontificia Universidad Católica Argentina
OAI Identificador
oai:ucacris:123456789/14019
Acceder
id RIUCA_2b461419b935f76d560f8151ad0a79f2
oai_identifier_str oai:ucacris:123456789/14019
network_acronym_str RIUCA
repository_id_str 2585
network_name_str Repositorio Institucional (UCA)
spelling The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastasesMarullo, RossellaCastro, MónicaYomtoubian, ShiraCalvo Vidal, M. NievesRevuelta, María VictoriaKrumsiek, JanCho, AndrewCresta Morgado, PabloYang, ShaoNingMedina, Vanina AraceliRoth, Berta M.Bonomi, MarceloKeshari, Kayvan R.Mittal, VivekNavigante, AlfredoCerchietti, LeandroMETASTASISCEREBROTUMORESARGININARADIACIONFil: Marullo, Rossella. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados UnidosFil: Castro, Mónica. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; ArgentinaFil: Yomtoubian, Shira. Cornell University. Weill Cornell Medicine. Department of Cardiothoracic Surgery; Estados UnidosFil: Yomtoubian, Shira. Cornell University. Weill Cornell Medicine. Department of Cell and Developmental Biology; Estados UnidosFil: Calvo-Vidal, M. Nieves. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados UnidosFil: Revuelta, María Victoria. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados UnidosFil: Krumsiek, Jan. Weill Cornell Medicine. Institute for Computational Biomedicine. Department of Physiology and Biophysics; Estados UnidosFil: Cho, Andrew. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; ArgentinaFil: Cresta Morgado, Pablo. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; ArgentinaFil: Yang, ShaoNing. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados UnidosFil: Medina, Vanina A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; ArgentinaFil: Roth, Berta M. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Departamento de Radiación e Imagenología; ArgentinaFil: Medina, Vanina A. Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires; ArgentinaFil: Medina, Vanina A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisótopos; ArgentinaFil: Bonomi, Marcelo. The Ohio State University. Hematology and Oncology Division; Estados UnidosFil: Keshari, Kayvan R. Weill Cornell Graduate School. Department of Biochemistry and Structural Biology; Estados UnidosFil: Keshari, Kayvan R. Memorial Sloan Kettering Cancer Center. Department of Radiology; Estados UnidosFil: Keshari, Kayvan R. Memorial Sloan Kettering Cancer Center. Molecular Pharmacology Program; Estados UnidosFil: Mittal, Vivek. Cornell University. Weill Cornell Medicine. Department of Cardiothoracic Surgery; Estados UnidosFil: Mittal, Vivek. Cornell University. Weill Cornell Medicine. Department of Cell and Developmental Biology; Estados UnidosFil: Navigante, Alfredo. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; ArgentinaFil: Cerchietti, Leandro. Cornell University. Weill Cornell Medicine. Hematology and Oncology Division; Estados UnidosAbstract: 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.American Association for the Advancement of Science2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttps://repositorio.uca.edu.ar/handle/123456789/140192375-2548 (online)10.1126/sciadv.abg1964Marullo, R. et al. The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases [en línea]. Science Advances. 2021, 7 (45). doi: 10.1126/sciadv.abg1964. Disponible en: https://repositorio.uca.edu.ar/handle/123456789/14019Science Advances Vol.7, No.45, 2021reponame:Repositorio Institucional (UCA)instname:Pontificia Universidad Católica Argentinaenginfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/4.0/2025-07-03T10:58:35Zoai:ucacris:123456789/14019instacron:UCAInstitucionalhttps://repositorio.uca.edu.ar/Universidad privadaNo correspondehttps://repositorio.uca.edu.ar/oaiclaudia_fernandez@uca.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:25852025-07-03 10:58:35.325Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentinafalse
dc.title.none.fl_str_mv The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
title The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
spellingShingle The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
Marullo, Rossella
METASTASIS
CEREBRO
TUMORES
ARGININA
RADIACION
title_short The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
title_full The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
title_fullStr The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
title_full_unstemmed The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
title_sort The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases
dc.creator.none.fl_str_mv Marullo, Rossella
Castro, Mónica
Yomtoubian, Shira
Calvo Vidal, M. Nieves
Revuelta, María Victoria
Krumsiek, Jan
Cho, Andrew
Cresta Morgado, Pablo
Yang, ShaoNing
Medina, Vanina Araceli
Roth, Berta M.
Bonomi, Marcelo
Keshari, Kayvan R.
Mittal, Vivek
Navigante, Alfredo
Cerchietti, Leandro
author Marullo, Rossella
author_facet Marullo, Rossella
Castro, Mónica
Yomtoubian, Shira
Calvo Vidal, M. Nieves
Revuelta, María Victoria
Krumsiek, Jan
Cho, Andrew
Cresta Morgado, Pablo
Yang, ShaoNing
Medina, Vanina Araceli
Roth, Berta M.
Bonomi, Marcelo
Keshari, Kayvan R.
Mittal, Vivek
Navigante, Alfredo
Cerchietti, Leandro
author_role author
author2 Castro, Mónica
Yomtoubian, Shira
Calvo Vidal, M. Nieves
Revuelta, María Victoria
Krumsiek, Jan
Cho, Andrew
Cresta Morgado, Pablo
Yang, ShaoNing
Medina, Vanina Araceli
Roth, Berta M.
Bonomi, Marcelo
Keshari, Kayvan R.
Mittal, Vivek
Navigante, Alfredo
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 METASTASIS
CEREBRO
TUMORES
ARGININA
RADIACION
topic METASTASIS
CEREBRO
TUMORES
ARGININA
RADIACION
dc.description.none.fl_txt_mv Fil: Marullo, Rossella. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
Fil: Castro, Mónica. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; Argentina
Fil: Yomtoubian, Shira. Cornell University. Weill Cornell Medicine. Department of Cardiothoracic Surgery; Estados Unidos
Fil: Yomtoubian, Shira. Cornell University. Weill Cornell Medicine. Department of Cell and Developmental Biology; Estados Unidos
Fil: Calvo-Vidal, M. Nieves. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
Fil: Revuelta, María Victoria. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
Fil: Krumsiek, Jan. Weill Cornell Medicine. Institute for Computational Biomedicine. Department of Physiology and Biophysics; Estados Unidos
Fil: Cho, Andrew. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; Argentina
Fil: Cresta Morgado, Pablo. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; Argentina
Fil: Yang, ShaoNing. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
Fil: Medina, Vanina A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina
Fil: Roth, Berta M. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Departamento de Radiación e Imagenología; Argentina
Fil: Medina, Vanina A. Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires; Argentina
Fil: Medina, Vanina A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisótopos; Argentina
Fil: Bonomi, Marcelo. The Ohio State University. Hematology and Oncology Division; Estados Unidos
Fil: Keshari, Kayvan R. Weill Cornell Graduate School. Department of Biochemistry and Structural Biology; Estados Unidos
Fil: Keshari, Kayvan R. Memorial Sloan Kettering Cancer Center. Department of Radiology; Estados Unidos
Fil: Keshari, Kayvan R. Memorial Sloan Kettering Cancer Center. Molecular Pharmacology Program; Estados Unidos
Fil: Mittal, Vivek. Cornell University. Weill Cornell Medicine. Department of Cardiothoracic Surgery; Estados Unidos
Fil: Mittal, Vivek. Cornell University. Weill Cornell Medicine. Department of Cell and Developmental Biology; Estados Unidos
Fil: Navigante, Alfredo. Universidad de Buenos Aires. Instituto Oncológico Ángel Roffo. Unidad de Investigación Traslacional; Argentina
Fil: Cerchietti, Leandro. Cornell University. Weill Cornell Medicine. Hematology and Oncology Division; Estados Unidos
Abstract: 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.
description Fil: Marullo, Rossella. Cornell University. Weill Cornell Medicine.Hematology and Oncology Division; Estados Unidos
publishDate 2021
dc.date.none.fl_str_mv 2021
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 https://repositorio.uca.edu.ar/handle/123456789/14019
2375-2548 (online)
10.1126/sciadv.abg1964
Marullo, R. et al. The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases [en línea]. Science Advances. 2021, 7 (45). doi: 10.1126/sciadv.abg1964. Disponible en: https://repositorio.uca.edu.ar/handle/123456789/14019
url https://repositorio.uca.edu.ar/handle/123456789/14019
identifier_str_mv 2375-2548 (online)
10.1126/sciadv.abg1964
Marullo, R. et al. The metabolic adaptation evoked by arginine enhances the effect ofradiation in brain metastases [en línea]. Science Advances. 2021, 7 (45). doi: 10.1126/sciadv.abg1964. Disponible en: https://repositorio.uca.edu.ar/handle/123456789/14019
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Association for the Advancement of Science
publisher.none.fl_str_mv American Association for the Advancement of Science
dc.source.none.fl_str_mv Science Advances Vol.7, No.45, 2021
reponame:Repositorio Institucional (UCA)
instname:Pontificia Universidad Católica Argentina
reponame_str Repositorio Institucional (UCA)
collection Repositorio Institucional (UCA)
instname_str Pontificia Universidad Católica Argentina
repository.name.fl_str_mv Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentina
repository.mail.fl_str_mv claudia_fernandez@uca.edu.ar
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score 13.10058

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