Oncotarget

Research Papers:

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

Alberto Ramírez, 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, _ Juan A. Marchal

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Oncotarget. 2014; 5:3590-3606. https://doi.org/10.18632/oncotarget.1962

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Abstract

Alberto Ramírez1, Houria Boulaiz2,3,4, Cynthia Morata-Tarifa3,4, Macarena Perán1, Gema Jiménez2,3,4, Manuel Picon-Ruiz3,5, Ahmad Agil6, Olga Cruz-López4,7, Ana Conejo-García4,7, Joaquín M. Campos4,7, Ana Sánchez8, María A. García3,4,9, Juan A. Marchal2,3,4

1 Department of Health Sciences, University of Jaén, Jaén, Spain

2 Department of Human Anatomy and Embryology, University of Granada, Granada, Spain

3 Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, Granada, Spain

4 Biosanitary Institute of Granada (ibs.GRANADA), Hospitales Universitarios de Granada-Universidad de Granada, Granada, Spain

5 Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA

6 Department of Pharmacology and Neurosciences Institute, Faculty of Medicine, Spain

7 Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Granada, Spain

8 Andalusian Public Health System Biobank, Granada, Spain

9 Department of Oncology, Virgen de las Nieves, University Hospital, Granada, Spain

Correspondence:

Juan Antonio Marchal, email:

María A. García, email:

Keywords: HER-2, bozepinib, protein kinases, cancer stem-like cells, metastasis

Received: March 12, 2014 Accepted: May 12, 2014 Published: May 13, 2014

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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