Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy

Autores
Solernó, Luisina María; Sobol, Natasha Tatiana; Gottardo, María Florencia; Capobianco, Carla Sabrina; Ferrero, Maximiliano Ruben; Vásquez, Liliana; Alonso, Daniel Fernando; Garona, Juan
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Osteosarcoma is still associated with limited response to standard-of-care therapy and alarmingly elevated mortality rates, especially in low- and middle-income countries. Despite multiple efforts to repurpose β-blocker propranolol in oncology, its potential application in osteosarcoma management remains largely unexplored. Considering the unsatisfied clinical needs of this aggressive disease, we evaluated the antitumoral activity of propranolol using different in vitro and in vivo osteosarcoma preclinical models, alone or in addition to chemotherapy. Propranolol significantly impaired cellular growth in β2-adrenergic receptor-expressing MG-63 and U-2OS cells, and was capable of blocking growth-stimulating effects triggered by catecholamines. siRNA-mediated ADRB2 knockdown in MG-63 cells was associated with decreased cell survival and a significant attenuation of PPN anti-osteosarcoma activity. Direct cytostatic effects of propranolol were independent of apoptosis induction and were associated with reduced mitosis, G0/G1 cell cycle arrest and a significant down-regulation of cell cycle regulator Cyclin D1. Moreover, colony formation, 3D spheroid growth, cell chemotaxis and capillary-like tube formation were drastically impaired after propranolol treatment. Interestingly, anti-migratory activity of β-blocker was associated with altered actin cytoskeleton dynamics. In vivo, propranolol treatment (10 mg/kg/day i.p.) reduced the early angiogenic response triggered by MG-63 cells in nude mice. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agent cisplatin. Sustained administration of propranolol (10 mg/kg/day i.p., five days a week), alone and especially in addition to low-dose metronomic cisplatin (2 mg/kg/day i.p., three times a week), markedly reduced xenograft progression. After histological analysis, propranolol and cisplatin combination resulted in low tumor mitotic index and increased tumor necrosis. β-blockade using propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness. Further translational studies of propranolol repurposing in osteosarcoma are warranted.
Fil: Solernó, Luisina María. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina
Fil: Sobol, Natasha Tatiana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gottardo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina
Fil: Capobianco, Carla Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina
Fil: Ferrero, Maximiliano Ruben. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Vásquez, Liliana. Universidad de San Martín de Porres; Perú
Fil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Materia
PROPRANOLOL
OSTEOSARCOMA
DRUG REPURPOSING
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/205028
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/205028
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network_name_str CONICET Digital (CONICET)
spelling Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapySolernó, Luisina MaríaSobol, Natasha TatianaGottardo, María FlorenciaCapobianco, Carla SabrinaFerrero, Maximiliano RubenVásquez, LilianaAlonso, Daniel FernandoGarona, JuanPROPRANOLOLOSTEOSARCOMADRUG REPURPOSINGhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Osteosarcoma is still associated with limited response to standard-of-care therapy and alarmingly elevated mortality rates, especially in low- and middle-income countries. Despite multiple efforts to repurpose β-blocker propranolol in oncology, its potential application in osteosarcoma management remains largely unexplored. Considering the unsatisfied clinical needs of this aggressive disease, we evaluated the antitumoral activity of propranolol using different in vitro and in vivo osteosarcoma preclinical models, alone or in addition to chemotherapy. Propranolol significantly impaired cellular growth in β2-adrenergic receptor-expressing MG-63 and U-2OS cells, and was capable of blocking growth-stimulating effects triggered by catecholamines. siRNA-mediated ADRB2 knockdown in MG-63 cells was associated with decreased cell survival and a significant attenuation of PPN anti-osteosarcoma activity. Direct cytostatic effects of propranolol were independent of apoptosis induction and were associated with reduced mitosis, G0/G1 cell cycle arrest and a significant down-regulation of cell cycle regulator Cyclin D1. Moreover, colony formation, 3D spheroid growth, cell chemotaxis and capillary-like tube formation were drastically impaired after propranolol treatment. Interestingly, anti-migratory activity of β-blocker was associated with altered actin cytoskeleton dynamics. In vivo, propranolol treatment (10 mg/kg/day i.p.) reduced the early angiogenic response triggered by MG-63 cells in nude mice. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agent cisplatin. Sustained administration of propranolol (10 mg/kg/day i.p., five days a week), alone and especially in addition to low-dose metronomic cisplatin (2 mg/kg/day i.p., three times a week), markedly reduced xenograft progression. After histological analysis, propranolol and cisplatin combination resulted in low tumor mitotic index and increased tumor necrosis. β-blockade using propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness. Further translational studies of propranolol repurposing in osteosarcoma are warranted.Fil: Solernó, Luisina María. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Sobol, Natasha Tatiana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gottardo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Capobianco, Carla Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Ferrero, Maximiliano Ruben. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Vásquez, Liliana. Universidad de San Martín de Porres; PerúFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaNature Publishing Group2022-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/205028Solernó, Luisina María; Sobol, Natasha Tatiana; Gottardo, María Florencia; Capobianco, Carla Sabrina; Ferrero, Maximiliano Ruben; et al.; Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy; Nature Publishing Group; Scientific Reports; 12; 1; 12-2022; 1-182045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-022-18324-3info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-022-18324-3info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:19:04Zoai:ri.conicet.gov.ar:11336/205028instacron: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:34982025-09-10 13:19:05.037CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy
title Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy
spellingShingle Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy
Solernó, Luisina María
PROPRANOLOL
OSTEOSARCOMA
DRUG REPURPOSING
title_short Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy
title_full Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy
title_fullStr Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy
title_full_unstemmed Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy
title_sort Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy
dc.creator.none.fl_str_mv Solernó, Luisina María
Sobol, Natasha Tatiana
Gottardo, María Florencia
Capobianco, Carla Sabrina
Ferrero, Maximiliano Ruben
Vásquez, Liliana
Alonso, Daniel Fernando
Garona, Juan
author Solernó, Luisina María
author_facet Solernó, Luisina María
Sobol, Natasha Tatiana
Gottardo, María Florencia
Capobianco, Carla Sabrina
Ferrero, Maximiliano Ruben
Vásquez, Liliana
Alonso, Daniel Fernando
Garona, Juan
author_role author
author2 Sobol, Natasha Tatiana
Gottardo, María Florencia
Capobianco, Carla Sabrina
Ferrero, Maximiliano Ruben
Vásquez, Liliana
Alonso, Daniel Fernando
Garona, Juan
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PROPRANOLOL
OSTEOSARCOMA
DRUG REPURPOSING
topic PROPRANOLOL
OSTEOSARCOMA
DRUG REPURPOSING
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Osteosarcoma is still associated with limited response to standard-of-care therapy and alarmingly elevated mortality rates, especially in low- and middle-income countries. Despite multiple efforts to repurpose β-blocker propranolol in oncology, its potential application in osteosarcoma management remains largely unexplored. Considering the unsatisfied clinical needs of this aggressive disease, we evaluated the antitumoral activity of propranolol using different in vitro and in vivo osteosarcoma preclinical models, alone or in addition to chemotherapy. Propranolol significantly impaired cellular growth in β2-adrenergic receptor-expressing MG-63 and U-2OS cells, and was capable of blocking growth-stimulating effects triggered by catecholamines. siRNA-mediated ADRB2 knockdown in MG-63 cells was associated with decreased cell survival and a significant attenuation of PPN anti-osteosarcoma activity. Direct cytostatic effects of propranolol were independent of apoptosis induction and were associated with reduced mitosis, G0/G1 cell cycle arrest and a significant down-regulation of cell cycle regulator Cyclin D1. Moreover, colony formation, 3D spheroid growth, cell chemotaxis and capillary-like tube formation were drastically impaired after propranolol treatment. Interestingly, anti-migratory activity of β-blocker was associated with altered actin cytoskeleton dynamics. In vivo, propranolol treatment (10 mg/kg/day i.p.) reduced the early angiogenic response triggered by MG-63 cells in nude mice. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agent cisplatin. Sustained administration of propranolol (10 mg/kg/day i.p., five days a week), alone and especially in addition to low-dose metronomic cisplatin (2 mg/kg/day i.p., three times a week), markedly reduced xenograft progression. After histological analysis, propranolol and cisplatin combination resulted in low tumor mitotic index and increased tumor necrosis. β-blockade using propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness. Further translational studies of propranolol repurposing in osteosarcoma are warranted.
Fil: Solernó, Luisina María. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina
Fil: Sobol, Natasha Tatiana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gottardo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina
Fil: Capobianco, Carla Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina
Fil: Ferrero, Maximiliano Ruben. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Vásquez, Liliana. Universidad de San Martín de Porres; Perú
Fil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
description Osteosarcoma is still associated with limited response to standard-of-care therapy and alarmingly elevated mortality rates, especially in low- and middle-income countries. Despite multiple efforts to repurpose β-blocker propranolol in oncology, its potential application in osteosarcoma management remains largely unexplored. Considering the unsatisfied clinical needs of this aggressive disease, we evaluated the antitumoral activity of propranolol using different in vitro and in vivo osteosarcoma preclinical models, alone or in addition to chemotherapy. Propranolol significantly impaired cellular growth in β2-adrenergic receptor-expressing MG-63 and U-2OS cells, and was capable of blocking growth-stimulating effects triggered by catecholamines. siRNA-mediated ADRB2 knockdown in MG-63 cells was associated with decreased cell survival and a significant attenuation of PPN anti-osteosarcoma activity. Direct cytostatic effects of propranolol were independent of apoptosis induction and were associated with reduced mitosis, G0/G1 cell cycle arrest and a significant down-regulation of cell cycle regulator Cyclin D1. Moreover, colony formation, 3D spheroid growth, cell chemotaxis and capillary-like tube formation were drastically impaired after propranolol treatment. Interestingly, anti-migratory activity of β-blocker was associated with altered actin cytoskeleton dynamics. In vivo, propranolol treatment (10 mg/kg/day i.p.) reduced the early angiogenic response triggered by MG-63 cells in nude mice. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agent cisplatin. Sustained administration of propranolol (10 mg/kg/day i.p., five days a week), alone and especially in addition to low-dose metronomic cisplatin (2 mg/kg/day i.p., three times a week), markedly reduced xenograft progression. After histological analysis, propranolol and cisplatin combination resulted in low tumor mitotic index and increased tumor necrosis. β-blockade using propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness. Further translational studies of propranolol repurposing in osteosarcoma are warranted.
publishDate 2022
dc.date.none.fl_str_mv 2022-12
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info:eu-repo/semantics/publishedVersion
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info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/205028
Solernó, Luisina María; Sobol, Natasha Tatiana; Gottardo, María Florencia; Capobianco, Carla Sabrina; Ferrero, Maximiliano Ruben; et al.; Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy; Nature Publishing Group; Scientific Reports; 12; 1; 12-2022; 1-18
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/205028
identifier_str_mv Solernó, Luisina María; Sobol, Natasha Tatiana; Gottardo, María Florencia; Capobianco, Carla Sabrina; Ferrero, Maximiliano Ruben; et al.; Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy; Nature Publishing Group; Scientific Reports; 12; 1; 12-2022; 1-18
2045-2322
CONICET Digital
CONICET
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