OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis

Autores
Astorgues Xerri, Lucile; Riveiro, Maria Eugenia; Tijeras Raballand, Annemila; Serova, Maria; Rabinovich, Gabriel Adrián; Bieche, Ivan; Vidaud, Michel; de Gramont, Armand; Martinet, Mathieu; Cvitkovic, Esteban; Faivre, Sandrine; Raymond, Eric
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background Galectin-1 (Gal1), a carbohydrate-binding protein is implicated in cancer cell proliferation, invasion and tumour angiogenesis. Several Gal1-targeting compounds have recently emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic β-sheet conformation. Our study contributes to the current understanding of the role of Gal1 in cancer progression, providing mechanistic insights into the anti-tumoural activity of a novel small molecule Gal1-inhibitor. Methods We evaluated in vitro OTX008 effects in a panel of human cancer cell lines. For in vivo studies, an ovarian xenograft model was employed to analyse the antitumour activity. Finally, combination studies were performed to analyse potential synergistic effects of OTX008. Results In cultured cancer cells, OTX008 inhibited proliferation and invasion at micromolar concentrations. Antiproliferative effects correlated with Gal1 expression across a large panel of cell lines. Furthermore, cell lines expressing epithelial differentiation markers were more sensitive than mesenchymal cells to OTX008. In SQ20B and A2780-1A9 cells, OTX008 inhibited Gal1 expression and ERK1/2 and AKT-dependent survival pathways, and induced G2/M cell cycle arrest through CDK1. OTX008 enhanced the antiproliferative effects of Semaphorin-3A (Sema3A) in SQ20B cells and reversed invasion induced by exogenous Gal1. In vivo, OTX008 inhibited growth of A2780-1A9 xenografts. OTX008 treatment was associated with downregulation of Gal1 and Ki67 in treated tumours, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with several cytotoxic and targeted therapies, principally when OTX008 was administered first. Conclusion This study provides insights into the role of Gal1 in cancer progression as well as OTX008 mechanism of action, and supports its further development as an anticancer agent.
Fil: Astorgues Xerri, Lucile. Inserm; Francia
Fil: Riveiro, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Tijeras Raballand, Annemila. Inserm; Francia
Fil: Serova, Maria. Inserm; Francia
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Bieche, Ivan. Inserm; Francia
Fil: Vidaud, Michel. Inserm; Francia
Fil: de Gramont, Armand. Inserm; Francia
Fil: Martinet, Mathieu. Inserm; Francia
Fil: Cvitkovic, Esteban. Oncoethix SA; Suiza
Fil: Faivre, Sandrine. Inserm; Francia
Fil: Raymond, Eric. Inserm; Francia
Materia
Otx008
Galectin-1
Cancer
Angiogenesis
Apoptosis
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:11336/6447
Acceder
id CONICETDig_eba1099553cfed11d0840a80d7fa1573
oai_identifier_str oai:ri.conicet.gov.ar:11336/6447
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesisAstorgues Xerri, LucileRiveiro, Maria EugeniaTijeras Raballand, AnnemilaSerova, MariaRabinovich, Gabriel AdriánBieche, IvanVidaud, Michelde Gramont, ArmandMartinet, MathieuCvitkovic, EstebanFaivre, SandrineRaymond, EricOtx008Galectin-1CancerAngiogenesisApoptosishttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background Galectin-1 (Gal1), a carbohydrate-binding protein is implicated in cancer cell proliferation, invasion and tumour angiogenesis. Several Gal1-targeting compounds have recently emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic β-sheet conformation. Our study contributes to the current understanding of the role of Gal1 in cancer progression, providing mechanistic insights into the anti-tumoural activity of a novel small molecule Gal1-inhibitor. Methods We evaluated in vitro OTX008 effects in a panel of human cancer cell lines. For in vivo studies, an ovarian xenograft model was employed to analyse the antitumour activity. Finally, combination studies were performed to analyse potential synergistic effects of OTX008. Results In cultured cancer cells, OTX008 inhibited proliferation and invasion at micromolar concentrations. Antiproliferative effects correlated with Gal1 expression across a large panel of cell lines. Furthermore, cell lines expressing epithelial differentiation markers were more sensitive than mesenchymal cells to OTX008. In SQ20B and A2780-1A9 cells, OTX008 inhibited Gal1 expression and ERK1/2 and AKT-dependent survival pathways, and induced G2/M cell cycle arrest through CDK1. OTX008 enhanced the antiproliferative effects of Semaphorin-3A (Sema3A) in SQ20B cells and reversed invasion induced by exogenous Gal1. In vivo, OTX008 inhibited growth of A2780-1A9 xenografts. OTX008 treatment was associated with downregulation of Gal1 and Ki67 in treated tumours, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with several cytotoxic and targeted therapies, principally when OTX008 was administered first. Conclusion This study provides insights into the role of Gal1 in cancer progression as well as OTX008 mechanism of action, and supports its further development as an anticancer agent.Fil: Astorgues Xerri, Lucile. Inserm; FranciaFil: Riveiro, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Tijeras Raballand, Annemila. Inserm; FranciaFil: Serova, Maria. Inserm; FranciaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bieche, Ivan. Inserm; FranciaFil: Vidaud, Michel. Inserm; FranciaFil: de Gramont, Armand. Inserm; FranciaFil: Martinet, Mathieu. Inserm; FranciaFil: Cvitkovic, Esteban. Oncoethix SA; SuizaFil: Faivre, Sandrine. Inserm; FranciaFil: Raymond, Eric. Inserm; FranciaElsevier2014-07-16info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/6447Astorgues Xerri, Lucile ; Riveiro, Maria Eugenia; Tijeras Raballand, Annemila ; Serova, Maria ; Rabinovich, Gabriel Adrián; et al.; OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis; Elsevier; European Journal Of Cancer; 50; 14; 16-7-2014; 2463-24770959-80491879-0852enginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejca.2014.06.015info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S095980491400759Xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:28Zoai:ri.conicet.gov.ar:11336/6447instacron: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:34982025-09-03 10:09:29.294CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
title OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
spellingShingle OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
Astorgues Xerri, Lucile
Otx008
Galectin-1
Cancer
Angiogenesis
Apoptosis
title_short OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
title_full OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
title_fullStr OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
title_full_unstemmed OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
title_sort OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
dc.creator.none.fl_str_mv Astorgues Xerri, Lucile
Riveiro, Maria Eugenia
Tijeras Raballand, Annemila
Serova, Maria
Rabinovich, Gabriel Adrián
Bieche, Ivan
Vidaud, Michel
de Gramont, Armand
Martinet, Mathieu
Cvitkovic, Esteban
Faivre, Sandrine
Raymond, Eric
author Astorgues Xerri, Lucile
author_facet Astorgues Xerri, Lucile
Riveiro, Maria Eugenia
Tijeras Raballand, Annemila
Serova, Maria
Rabinovich, Gabriel Adrián
Bieche, Ivan
Vidaud, Michel
de Gramont, Armand
Martinet, Mathieu
Cvitkovic, Esteban
Faivre, Sandrine
Raymond, Eric
author_role author
author2 Riveiro, Maria Eugenia
Tijeras Raballand, Annemila
Serova, Maria
Rabinovich, Gabriel Adrián
Bieche, Ivan
Vidaud, Michel
de Gramont, Armand
Martinet, Mathieu
Cvitkovic, Esteban
Faivre, Sandrine
Raymond, Eric
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Otx008
Galectin-1
Cancer
Angiogenesis
Apoptosis
topic Otx008
Galectin-1
Cancer
Angiogenesis
Apoptosis
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background Galectin-1 (Gal1), a carbohydrate-binding protein is implicated in cancer cell proliferation, invasion and tumour angiogenesis. Several Gal1-targeting compounds have recently emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic β-sheet conformation. Our study contributes to the current understanding of the role of Gal1 in cancer progression, providing mechanistic insights into the anti-tumoural activity of a novel small molecule Gal1-inhibitor. Methods We evaluated in vitro OTX008 effects in a panel of human cancer cell lines. For in vivo studies, an ovarian xenograft model was employed to analyse the antitumour activity. Finally, combination studies were performed to analyse potential synergistic effects of OTX008. Results In cultured cancer cells, OTX008 inhibited proliferation and invasion at micromolar concentrations. Antiproliferative effects correlated with Gal1 expression across a large panel of cell lines. Furthermore, cell lines expressing epithelial differentiation markers were more sensitive than mesenchymal cells to OTX008. In SQ20B and A2780-1A9 cells, OTX008 inhibited Gal1 expression and ERK1/2 and AKT-dependent survival pathways, and induced G2/M cell cycle arrest through CDK1. OTX008 enhanced the antiproliferative effects of Semaphorin-3A (Sema3A) in SQ20B cells and reversed invasion induced by exogenous Gal1. In vivo, OTX008 inhibited growth of A2780-1A9 xenografts. OTX008 treatment was associated with downregulation of Gal1 and Ki67 in treated tumours, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with several cytotoxic and targeted therapies, principally when OTX008 was administered first. Conclusion This study provides insights into the role of Gal1 in cancer progression as well as OTX008 mechanism of action, and supports its further development as an anticancer agent.
Fil: Astorgues Xerri, Lucile. Inserm; Francia
Fil: Riveiro, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Tijeras Raballand, Annemila. Inserm; Francia
Fil: Serova, Maria. Inserm; Francia
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Bieche, Ivan. Inserm; Francia
Fil: Vidaud, Michel. Inserm; Francia
Fil: de Gramont, Armand. Inserm; Francia
Fil: Martinet, Mathieu. Inserm; Francia
Fil: Cvitkovic, Esteban. Oncoethix SA; Suiza
Fil: Faivre, Sandrine. Inserm; Francia
Fil: Raymond, Eric. Inserm; Francia
description Background Galectin-1 (Gal1), a carbohydrate-binding protein is implicated in cancer cell proliferation, invasion and tumour angiogenesis. Several Gal1-targeting compounds have recently emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic β-sheet conformation. Our study contributes to the current understanding of the role of Gal1 in cancer progression, providing mechanistic insights into the anti-tumoural activity of a novel small molecule Gal1-inhibitor. Methods We evaluated in vitro OTX008 effects in a panel of human cancer cell lines. For in vivo studies, an ovarian xenograft model was employed to analyse the antitumour activity. Finally, combination studies were performed to analyse potential synergistic effects of OTX008. Results In cultured cancer cells, OTX008 inhibited proliferation and invasion at micromolar concentrations. Antiproliferative effects correlated with Gal1 expression across a large panel of cell lines. Furthermore, cell lines expressing epithelial differentiation markers were more sensitive than mesenchymal cells to OTX008. In SQ20B and A2780-1A9 cells, OTX008 inhibited Gal1 expression and ERK1/2 and AKT-dependent survival pathways, and induced G2/M cell cycle arrest through CDK1. OTX008 enhanced the antiproliferative effects of Semaphorin-3A (Sema3A) in SQ20B cells and reversed invasion induced by exogenous Gal1. In vivo, OTX008 inhibited growth of A2780-1A9 xenografts. OTX008 treatment was associated with downregulation of Gal1 and Ki67 in treated tumours, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with several cytotoxic and targeted therapies, principally when OTX008 was administered first. Conclusion This study provides insights into the role of Gal1 in cancer progression as well as OTX008 mechanism of action, and supports its further development as an anticancer agent.
publishDate 2014
dc.date.none.fl_str_mv 2014-07-16
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/11336/6447
Astorgues Xerri, Lucile ; Riveiro, Maria Eugenia; Tijeras Raballand, Annemila ; Serova, Maria ; Rabinovich, Gabriel Adrián; et al.; OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis; Elsevier; European Journal Of Cancer; 50; 14; 16-7-2014; 2463-2477
0959-8049
1879-0852
url http://hdl.handle.net/11336/6447
identifier_str_mv Astorgues Xerri, Lucile ; Riveiro, Maria Eugenia; Tijeras Raballand, Annemila ; Serova, Maria ; Rabinovich, Gabriel Adrián; et al.; OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis; Elsevier; European Journal Of Cancer; 50; 14; 16-7-2014; 2463-2477
0959-8049
1879-0852
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejca.2014.06.015
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S095980491400759X
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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 Elsevier
publisher.none.fl_str_mv Elsevier
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
_version_ 1842270082980380672
score 13.13397

Publicaciones similares