1. Academic Validation
  2. HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib small compound

HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib small compound

  • Oncotarget. 2014 Jun 15;5(11):3590-606. doi: 10.18632/oncotarget.1962.
Alberto Ramírez 1 Houria Boulaiz Cynthia Morata-Tarifa Macarena Perán Gema Jiménez Manuel Picon-Ruiz Ahmad Agil Olga Cruz-López Ana Conejo-García Joaquín M Campos Ana Sánchez María A García 2 Juan A Marchal 3
Affiliations

Affiliations

  • 1 Department of Health Sciences, University of Jaén, Jaén, Spain.
  • 2 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.
  • 3 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.
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.

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