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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/32742

Title: HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib
Authors: Ramírez, Alberto
Boulaiz, Houria
Morata-Tarifa, Cynthia
Perán Quesada, Macarena
Jiménez González, Gema
Picón Ruiz, Manuel
Agil, Ahmad
Cruz López, Olga María
Conejo García, Ana
Campos Rosa, Joaquín M.
Sánchez, Ana
García Cháves, María Ángeles
Marchal Corrales, Juan Antonio
Issue Date: 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.
Sponsorship: This work was supported in part by grants from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria, projects nº. PI10/02295, CP08/00063 and PI10/00592) and the ERDF (European Regional Development Fund).
Publisher: Impact Journals
Keywords: HER-2
Protein kinases
Cancer stem-like cells
URI: http://hdl.handle.net/10481/32742
ISSN: 1949-2553
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: Ramírez, A.; et al. HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib. Oncotarget, 5(11): 3590-3606 (2014). [http://hdl.handle.net/10481/32742]
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