HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib
Metadatos
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Ramírez, Alberto; Boulaiz Tassi, Houria; Morata Tarifa, Cynthia; Perán Quesada, Macarena; Jiménez González, Gema; Picón Ruiz, Manuel; Agil Abdalla, Mhmad Ahmad; Cruz López, Olga María; Conejo García, Ana; Campos Rosa, Joaquín María; Sánchez, Ana; García Chaves, María Ángel; Marchal Corrales, Juan AntonioEditorial
Impact Journals
Materia
HER-2 Bozepinib Protein kinases Cancer stem-like cells Metastasis
Date
2014Referencia bibliográfica
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]
Patrocinador
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).Résumé
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.