title: New inhibitors of angiogenesis with antitumor activity in vivo.
abstract: Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, and the development of new compounds that induce a sustained inhibition of the proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe a new antiangiogenic compound (22) that inhibits proangiogenic signaling under hypoxic conditions in breast cancer cells. Compound 22 blocks the MAPK pathway, impairs cellular migration under hypoxic conditions, and regulates a set of genes related to angiogenesis. These responses are mediated by HIF-1α, since the effects of compound 22 mostly disappear when its expression is knocked-down. Furthermore, administration of compound 22 in a xenograft model of breast cancer produced tumor growth reductions ranging from 46 to 55% in 38% of the treated animals without causing any toxic side effects. Importantly, in the responding tumors, a significant reduction in the number of blood vessels was observed, further supporting the mechanism of action of the compound. These findings provide a rationale for the development of new antiangiogenic compounds that could eventually lead to new drugs suitable for the treatment of some types of tumors either alone or in combination with other agents.
authors.affiliation: ‡CEI Campus Moncloa, UCM-UPM and CSIC, E-28040 Madrid, Spain.
authors.forename: Nagore I
authors.initials: NI
authors.lastname: Marín-Ramos
authors.forename: Dulce
authors.initials: D
authors.lastname: Alonso
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Ortega-Nogales
authors.forename: Moisés
authors.initials: M
authors.lastname: Balabasquer
authors.forename: Henar
authors.initials: H
authors.lastname: Vázquez-Villa
authors.affiliation: ∥Instituto de Investigación Hospital 12 de Octubre, E-28041 Madrid, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Andradas
authors.affiliation: ∥Instituto de Investigación Hospital 12 de Octubre, E-28041 Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Blasco-Benito
authors.affiliation: ∥Instituto de Investigación Hospital 12 de Octubre, E-28041 Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pérez-Gómez
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Canales
authors.affiliation: ⊥CIC bioGUNE, Parque Tecnológico de Bizkaia, Edif. 801A, 48160 Derio, Spain.|¶Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.affiliation: #Departamento de Investigación, Italfarmaco S.A., Calle de San Rafael, 3, E-28108 Alcobendas, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Marquina
authors.affiliation: #Departamento de Investigación, Italfarmaco S.A., Calle de San Rafael, 3, E-28108 Alcobendas, Madrid, Spain.
authors.forename: Jaime Moscoso
authors.initials: JM
authors.lastname: del Prado
authors.affiliation: ∥Instituto de Investigación Hospital 12 de Octubre, E-28041 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez
authors.forename: Mar
authors.initials: M
authors.lastname: Martín-Fontecha
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: C000599951:4-hydroxy-3-(((pyridin-3-ylmethyl)amino)carbonyl)phenyl methyl(phenyl)carbamate; D020533:Angiogenesis Inhibitors; D001549:Benzamides; D002219:Carbamates; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016222:Fibroblast Growth Factor 2; D020928:Mitogen-Activated Protein Kinases