Ramírez, AlbertoBoulaiz, HouriaMorata-Tarifa, CynthiaPerán, MacarenaJiménez, GemaPicon-Ruiz, ManuelAgil, AhmadCruz-López, OlgaConejo-García, AnaCampos, Joaquín MSánchez, AnaGarcía, María AMarchal, Juan A2016-07-132016-07-132014-06-15Ramírez A, Boulaiz H, Morata-Tarifa C, Perán M, Jiménez G, Picon-Ruiz M, et al. HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib small compound. Oncotarget. 2014 ; 5(11):3590-606http://hdl.handle.net/10668/2277Journal Article; Research Support, Non-U.S. Gov't;Identification of novel anticancer drugs presenting more than one molecular target and efficacy against cancer stem-like cells (CSCs) subpopulations represents a therapeutic need to combat the resistance and the high risk of relapse in patients. In the present work we show how Bozepinib [(RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-9H-purine], a small anti-tumor compound, demonstrated selectivity on cancer cells and showed an inhibitory effect over kinases involved in carcinogenesis, proliferation and angiogenesis. The cytotoxic effects of Bozepinib were observed in both breast and colon cancer cells expressing different receptor patterns. Bozepinib inhibited HER-2 signaling pathway and JNK and ERKs kinases. In addition, Bozepinib has an inhibitory effect on AKT and VEGF together with anti-angiogenic and anti-migratory activities. Moreover, the modulation of pathways involved in tumorigenesis by Bozepinib was also evident in microarrays analysis. Interestingly, Bozepinib inhibited both mamo- and colono-spheres formation and eliminated ALDH+ CSCs subpopulations at a low micromolar range similar to Salinomycin. Bozepinib induced the down-regulation of c-MYC, β-CATENIN and SOX2 proteins and the up-regulation of the GLI-3 hedgehog-signaling repressor. Finally, Bozepinib shows in vivo anti-tumor and anti-metastatic efficacy in xenotransplanted nude mice without presenting sub-acute toxicity. These findings support further studies on the therapeutic potential of Bozepinib in cancer patients.enHER-2BozepinibProtein kinasesCancer stem-like cellsMetastasisAnimalesCarcinogénesisNeoplasias del colonRegulación hacia abajoFemeninoErizosHumanosRatones desnudosRecurrencia local de neoplasiaCélulas madre neoplásicasOxazepinasPurinasPiranosReceptor ErbB-2Transducción de señalRegulación hacia arribaFactor A de crecimiento endotelial vascularbeta CateninaMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::CocarcinogenesisMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms::Colonic NeoplasmsMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-RegulationMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Insectivora::HedgehogsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, NudeMedical Subject Headings::Diseases::Neoplasms::Neoplastic Processes::Neoplasm Recurrence, LocalMedical Subject Headings::Anatomy::Cells::Stem Cells::Neoplastic Stem CellsMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Azepines::OxazepinesMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::PurinesMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::PyransMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor, erbB-2Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal TransductionMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-RegulationMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Angiogenic Proteins::Vascular Endothelial Growth Factors::Vascular Endothelial Growth Factor AMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Armadillo Domain Proteins::beta Cateninresearch article24946763open access1949-2553PMC4116505