title: HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib small compound.
abstract: 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.
authors.affiliation: Department of Health Sciences, University of Jaén, Jaén, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ramírez
authors.forename: Houria
authors.initials: H
authors.lastname: Boulaiz
authors.forename: Cynthia
authors.initials: C
authors.lastname: Morata-Tarifa
authors.forename: Macarena
authors.initials: M
authors.lastname: Perán
authors.forename: Gema
authors.initials: G
authors.lastname: Jiménez
authors.forename: Manuel
authors.initials: M
authors.lastname: Picon-Ruiz
authors.forename: Ahmad
authors.initials: A
authors.lastname: Agil
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-López
authors.forename: Ana
authors.initials: A
authors.lastname: Conejo-García
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Campos
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, Granada, Spain; Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain; Department of Oncology, Virgen de las Nieves, University Hospital, Granada, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: García
authors.affiliation: Department of Human Anatomy and Embryology, University of Granada, Granada, Spain; Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, Granada, Spain; Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Marchal
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010077:Oxazepines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D010077:Oxazepines; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; C556910:2,6-dichloro-9-(1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)-9H-purine; C508053:ERBB2 protein, human