Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma

Autores
Sobol, Natasha Tatiana; Solernó, Luisina María; Beltrán, Brady; Vásquez, Liliana; Ripoll, Giselle Vanina; Garona, Juan; Alonso, Daniel Fernando
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Osteosarcoma is the most prevalent primary bone malignancy. Due to its high aggressiveness, novel treatment strategies are urgently required to improve survival of patients with osteosarcoma, especially those with advanced disease. Desmopressin (dDAVP) is a widely used blood-saving agent that has been repurposed as an adjuvant agent for cancer management due to its antiangiogenic and antimetastatic properties. dDAVP acts as a selective agonist of the vasopressin membrane receptor type 2 (AVPR2) present in the microvascular endothelium and in some cancer cells, including breast, lung, colorectal and neuroendocrine tumor cells. Despite the fact that dDAVP has demonstrated its antitumor efficacy in a wide variety of tumor types, exploration of its potential anti-osteosarcoma activity has, to the best of our knowledge, not yet been conducted. Therefore, the aim of the present study was to evaluate the preclinical antitumor activity of dDAVP in osteosarcoma. Human MG-63 and U-2 OS osteosarcoma cell lines were used to assess in vitro and in vivo therapeutic effects of dDAVP. At low micromolar concentrations, dDAVP reduced AVPR2-expressing MG-63 cell growth in a concentration-dependent manner. In contrast, dDAVP exhibited no direct cytostatic effect on AVPR2-negative U-2 OS cells. As it would be expected for canonical AVPR2-activation, dDAVP raised intracellular cAMP levels in osteosarcoma cells, and coincubation with phosphodiesterase-inhibitor rolipram indicated synergistic antiproliferative activity. Cytostatic effects were associated with increased apoptosis, reduced mitotic index and impairment of osteosarcoma cell chemotaxis, as evaluated by TUNEL-labeling, mitotic body count in DAPI-stained cultures and Transwell migration assays. Intravenous administration of dDAVP (12 µg/kg; three times per week) to athymic mice bearing rapidly growing MG-63 xenografts, was indicated to be capable of reducing tumor progression after a 4-week treatment. No major alterations in animal weight, biochemical or hematological parameters were associated with dDAVP treatment, confirming its good tolerability and safety. Finally, AVPR2 expression was detected by immunohistochemistry in 66% of all evaluated chemotherapy-naive human conventional osteosarcoma biopsies. Taking these findings into account, repurposed agent dDAVP may represent an interesting therapeutic tool for the management of osteosarcoma. Further preclinical exploration of dDAVP activity on orthotopic or metastatic osteosarcoma models are required.
Fil: Sobol, Natasha Tatiana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Solernó, Luisina María. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Beltrán, Brady. Universidad San Martín de Porres. Facultad de Medicina Humana. Centro de Investigación de Medicina de Precisión; Perú
Fil: Vásquez, Liliana. Universidad San Martín de Porres. Facultad de Medicina Humana. Centro de Investigación de Medicina de Precisión; Perú
Fil: Ripoll, Giselle Vanina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Garona, Juan. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Alonso, Daniel Fernando. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Materia
OSTEOSARCOMA
XENOGRAFT
VASOPRESSIN RECEPTOR
DESMOPRESSIN
CYTOSTATIC
DRUG REPURPOSING
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/154925
Acceder
id CONICETDig_ed8e8a4ec738ba23e73942ca9358ace1
oai_identifier_str oai:ri.conicet.gov.ar:11336/154925
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcomaSobol, Natasha TatianaSolernó, Luisina MaríaBeltrán, BradyVásquez, LilianaRipoll, Giselle VaninaGarona, JuanAlonso, Daniel FernandoOSTEOSARCOMAXENOGRAFTVASOPRESSIN RECEPTORDESMOPRESSINCYTOSTATICDRUG REPURPOSINGhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Osteosarcoma is the most prevalent primary bone malignancy. Due to its high aggressiveness, novel treatment strategies are urgently required to improve survival of patients with osteosarcoma, especially those with advanced disease. Desmopressin (dDAVP) is a widely used blood-saving agent that has been repurposed as an adjuvant agent for cancer management due to its antiangiogenic and antimetastatic properties. dDAVP acts as a selective agonist of the vasopressin membrane receptor type 2 (AVPR2) present in the microvascular endothelium and in some cancer cells, including breast, lung, colorectal and neuroendocrine tumor cells. Despite the fact that dDAVP has demonstrated its antitumor efficacy in a wide variety of tumor types, exploration of its potential anti-osteosarcoma activity has, to the best of our knowledge, not yet been conducted. Therefore, the aim of the present study was to evaluate the preclinical antitumor activity of dDAVP in osteosarcoma. Human MG-63 and U-2 OS osteosarcoma cell lines were used to assess in vitro and in vivo therapeutic effects of dDAVP. At low micromolar concentrations, dDAVP reduced AVPR2-expressing MG-63 cell growth in a concentration-dependent manner. In contrast, dDAVP exhibited no direct cytostatic effect on AVPR2-negative U-2 OS cells. As it would be expected for canonical AVPR2-activation, dDAVP raised intracellular cAMP levels in osteosarcoma cells, and coincubation with phosphodiesterase-inhibitor rolipram indicated synergistic antiproliferative activity. Cytostatic effects were associated with increased apoptosis, reduced mitotic index and impairment of osteosarcoma cell chemotaxis, as evaluated by TUNEL-labeling, mitotic body count in DAPI-stained cultures and Transwell migration assays. Intravenous administration of dDAVP (12 µg/kg; three times per week) to athymic mice bearing rapidly growing MG-63 xenografts, was indicated to be capable of reducing tumor progression after a 4-week treatment. No major alterations in animal weight, biochemical or hematological parameters were associated with dDAVP treatment, confirming its good tolerability and safety. Finally, AVPR2 expression was detected by immunohistochemistry in 66% of all evaluated chemotherapy-naive human conventional osteosarcoma biopsies. Taking these findings into account, repurposed agent dDAVP may represent an interesting therapeutic tool for the management of osteosarcoma. Further preclinical exploration of dDAVP activity on orthotopic or metastatic osteosarcoma models are required.Fil: Sobol, Natasha Tatiana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Solernó, Luisina María. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Beltrán, Brady. Universidad San Martín de Porres. Facultad de Medicina Humana. Centro de Investigación de Medicina de Precisión; PerúFil: Vásquez, Liliana. Universidad San Martín de Porres. Facultad de Medicina Humana. Centro de Investigación de Medicina de Precisión; PerúFil: Ripoll, Giselle Vanina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Garona, Juan. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Alonso, Daniel Fernando. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaSpandidos Publications2021-03-26info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/154925Sobol, Natasha Tatiana; Solernó, Luisina María; Beltrán, Brady; Vásquez, Liliana; Ripoll, Giselle Vanina; et al.; Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma; Spandidos Publications; Experimental and Therapeutic Medicine; 21; 6; 26-3-2021; 1-111792-09811792-1015CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.spandidos-publications.com/10.3892/etm.2021.9998info:eu-repo/semantics/altIdentifier/doi/10.3892/etm.2021.9998info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:41:55Zoai:ri.conicet.gov.ar:11336/154925instacron: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:34982025-09-29 10:41:56.028CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma
title Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma
spellingShingle Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma
Sobol, Natasha Tatiana
OSTEOSARCOMA
XENOGRAFT
VASOPRESSIN RECEPTOR
DESMOPRESSIN
CYTOSTATIC
DRUG REPURPOSING
title_short Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma
title_full Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma
title_fullStr Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma
title_full_unstemmed Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma
title_sort Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma
dc.creator.none.fl_str_mv Sobol, Natasha Tatiana
Solernó, Luisina María
Beltrán, Brady
Vásquez, Liliana
Ripoll, Giselle Vanina
Garona, Juan
Alonso, Daniel Fernando
author Sobol, Natasha Tatiana
author_facet Sobol, Natasha Tatiana
Solernó, Luisina María
Beltrán, Brady
Vásquez, Liliana
Ripoll, Giselle Vanina
Garona, Juan
Alonso, Daniel Fernando
author_role author
author2 Solernó, Luisina María
Beltrán, Brady
Vásquez, Liliana
Ripoll, Giselle Vanina
Garona, Juan
Alonso, Daniel Fernando
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv OSTEOSARCOMA
XENOGRAFT
VASOPRESSIN RECEPTOR
DESMOPRESSIN
CYTOSTATIC
DRUG REPURPOSING
topic OSTEOSARCOMA
XENOGRAFT
VASOPRESSIN RECEPTOR
DESMOPRESSIN
CYTOSTATIC
DRUG REPURPOSING
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Osteosarcoma is the most prevalent primary bone malignancy. Due to its high aggressiveness, novel treatment strategies are urgently required to improve survival of patients with osteosarcoma, especially those with advanced disease. Desmopressin (dDAVP) is a widely used blood-saving agent that has been repurposed as an adjuvant agent for cancer management due to its antiangiogenic and antimetastatic properties. dDAVP acts as a selective agonist of the vasopressin membrane receptor type 2 (AVPR2) present in the microvascular endothelium and in some cancer cells, including breast, lung, colorectal and neuroendocrine tumor cells. Despite the fact that dDAVP has demonstrated its antitumor efficacy in a wide variety of tumor types, exploration of its potential anti-osteosarcoma activity has, to the best of our knowledge, not yet been conducted. Therefore, the aim of the present study was to evaluate the preclinical antitumor activity of dDAVP in osteosarcoma. Human MG-63 and U-2 OS osteosarcoma cell lines were used to assess in vitro and in vivo therapeutic effects of dDAVP. At low micromolar concentrations, dDAVP reduced AVPR2-expressing MG-63 cell growth in a concentration-dependent manner. In contrast, dDAVP exhibited no direct cytostatic effect on AVPR2-negative U-2 OS cells. As it would be expected for canonical AVPR2-activation, dDAVP raised intracellular cAMP levels in osteosarcoma cells, and coincubation with phosphodiesterase-inhibitor rolipram indicated synergistic antiproliferative activity. Cytostatic effects were associated with increased apoptosis, reduced mitotic index and impairment of osteosarcoma cell chemotaxis, as evaluated by TUNEL-labeling, mitotic body count in DAPI-stained cultures and Transwell migration assays. Intravenous administration of dDAVP (12 µg/kg; three times per week) to athymic mice bearing rapidly growing MG-63 xenografts, was indicated to be capable of reducing tumor progression after a 4-week treatment. No major alterations in animal weight, biochemical or hematological parameters were associated with dDAVP treatment, confirming its good tolerability and safety. Finally, AVPR2 expression was detected by immunohistochemistry in 66% of all evaluated chemotherapy-naive human conventional osteosarcoma biopsies. Taking these findings into account, repurposed agent dDAVP may represent an interesting therapeutic tool for the management of osteosarcoma. Further preclinical exploration of dDAVP activity on orthotopic or metastatic osteosarcoma models are required.
Fil: Sobol, Natasha Tatiana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Solernó, Luisina María. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Beltrán, Brady. Universidad San Martín de Porres. Facultad de Medicina Humana. Centro de Investigación de Medicina de Precisión; Perú
Fil: Vásquez, Liliana. Universidad San Martín de Porres. Facultad de Medicina Humana. Centro de Investigación de Medicina de Precisión; Perú
Fil: Ripoll, Giselle Vanina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Garona, Juan. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Alonso, Daniel Fernando. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
description Osteosarcoma is the most prevalent primary bone malignancy. Due to its high aggressiveness, novel treatment strategies are urgently required to improve survival of patients with osteosarcoma, especially those with advanced disease. Desmopressin (dDAVP) is a widely used blood-saving agent that has been repurposed as an adjuvant agent for cancer management due to its antiangiogenic and antimetastatic properties. dDAVP acts as a selective agonist of the vasopressin membrane receptor type 2 (AVPR2) present in the microvascular endothelium and in some cancer cells, including breast, lung, colorectal and neuroendocrine tumor cells. Despite the fact that dDAVP has demonstrated its antitumor efficacy in a wide variety of tumor types, exploration of its potential anti-osteosarcoma activity has, to the best of our knowledge, not yet been conducted. Therefore, the aim of the present study was to evaluate the preclinical antitumor activity of dDAVP in osteosarcoma. Human MG-63 and U-2 OS osteosarcoma cell lines were used to assess in vitro and in vivo therapeutic effects of dDAVP. At low micromolar concentrations, dDAVP reduced AVPR2-expressing MG-63 cell growth in a concentration-dependent manner. In contrast, dDAVP exhibited no direct cytostatic effect on AVPR2-negative U-2 OS cells. As it would be expected for canonical AVPR2-activation, dDAVP raised intracellular cAMP levels in osteosarcoma cells, and coincubation with phosphodiesterase-inhibitor rolipram indicated synergistic antiproliferative activity. Cytostatic effects were associated with increased apoptosis, reduced mitotic index and impairment of osteosarcoma cell chemotaxis, as evaluated by TUNEL-labeling, mitotic body count in DAPI-stained cultures and Transwell migration assays. Intravenous administration of dDAVP (12 µg/kg; three times per week) to athymic mice bearing rapidly growing MG-63 xenografts, was indicated to be capable of reducing tumor progression after a 4-week treatment. No major alterations in animal weight, biochemical or hematological parameters were associated with dDAVP treatment, confirming its good tolerability and safety. Finally, AVPR2 expression was detected by immunohistochemistry in 66% of all evaluated chemotherapy-naive human conventional osteosarcoma biopsies. Taking these findings into account, repurposed agent dDAVP may represent an interesting therapeutic tool for the management of osteosarcoma. Further preclinical exploration of dDAVP activity on orthotopic or metastatic osteosarcoma models are required.
publishDate 2021
dc.date.none.fl_str_mv 2021-03-26
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/11336/154925
Sobol, Natasha Tatiana; Solernó, Luisina María; Beltrán, Brady; Vásquez, Liliana; Ripoll, Giselle Vanina; et al.; Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma; Spandidos Publications; Experimental and Therapeutic Medicine; 21; 6; 26-3-2021; 1-11
1792-0981
1792-1015
CONICET Digital
CONICET
url http://hdl.handle.net/11336/154925
identifier_str_mv Sobol, Natasha Tatiana; Solernó, Luisina María; Beltrán, Brady; Vásquez, Liliana; Ripoll, Giselle Vanina; et al.; Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma; Spandidos Publications; Experimental and Therapeutic Medicine; 21; 6; 26-3-2021; 1-11
1792-0981
1792-1015
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.spandidos-publications.com/10.3892/etm.2021.9998
info:eu-repo/semantics/altIdentifier/doi/10.3892/etm.2021.9998
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https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Spandidos Publications
publisher.none.fl_str_mv Spandidos Publications
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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