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dc.contributor.author
Astorgues Xerri, Lucile
dc.contributor.author
Riveiro, Maria Eugenia
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dc.contributor.author
Tijeras Raballand, Annemila
dc.contributor.author
Serova, Maria
dc.contributor.author
Rabinovich, Gabriel Adrián
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dc.contributor.author
Bieche, Ivan
dc.contributor.author
Vidaud, Michel
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de Gramont, Armand
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Martinet, Mathieu
dc.contributor.author
Cvitkovic, Esteban
dc.contributor.author
Faivre, Sandrine
dc.contributor.author
Raymond, Eric
dc.date.available
2016-07-12T17:28:34Z
dc.date.issued
2014-07-16
dc.identifier.citation
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
dc.identifier.issn
0959-8049
dc.identifier.uri
http://hdl.handle.net/11336/6447
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Otx008
dc.subject
Galectin-1
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Cancer
dc.subject
Angiogenesis
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Apoptosis
dc.subject.classification
Inmunología
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dc.subject.classification
Medicina Básica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2016-06-15T19:09:39Z
dc.identifier.eissn
1879-0852
dc.journal.volume
50
dc.journal.number
14
dc.journal.pagination
2463-2477
dc.journal.pais
Países Bajos
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dc.journal.ciudad
Amsterdam
dc.description.fil
Fil: Astorgues Xerri, Lucile. Inserm; Francia
dc.description.fil
Fil: Riveiro, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
dc.description.fil
Fil: Tijeras Raballand, Annemila. Inserm; Francia
dc.description.fil
Fil: Serova, Maria. Inserm; Francia
dc.description.fil
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
dc.description.fil
Fil: Bieche, Ivan. Inserm; Francia
dc.description.fil
Fil: Vidaud, Michel. Inserm; Francia
dc.description.fil
Fil: de Gramont, Armand. Inserm; Francia
dc.description.fil
Fil: Martinet, Mathieu. Inserm; Francia
dc.description.fil
Fil: Cvitkovic, Esteban. Oncoethix SA; Suiza
dc.description.fil
Fil: Faivre, Sandrine. Inserm; Francia
dc.description.fil
Fil: Raymond, Eric. Inserm; Francia
dc.journal.title
European Journal Of Cancer
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.ejca.2014.06.015
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S095980491400759X
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