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.
Highlights
Cancer represents the second cause of death by disease in the world, being colorectal and breast cancer two diseases with important incidence in most countries [1]
Better results were obtained in breast cancer cell lines where the inhibitory concentration 50 (IC50) values determined for the MCF-10A non-tumor cell line were more than five times higher that the IC50 determined for MCF-7 and SKBR-3 breast cancer cell lines and almost double that of the value determined for MDA-MB 468 cancer cells, presenting the MDA-MB 231 a therapeutic index (TI) equal to 11 (Table 1)
We described the role of protein kinase PKR as a target of Bozepinib involved in the apoptosis of breast and colon cancer cells [18], here we have made a profound study of the mechanism of action of this drug
Summary
Cancer represents the second cause of death by disease in the world, being colorectal and breast cancer two diseases with important incidence in most countries [1]. Some of the main signaling pathways involved in cancer are related with cell proliferation, differentiation and survival, which represent exciting www.impactjournals.com/oncotarget targets for developing new anti-tumor drugs. In this way, the epidermal growth factor receptors EGFR and HER2 are frequently over-expressed in several human cancers of epithelial origin and play essential roles in the development and progression of cancer [2, 3]. Kinase inhibitors that reduce the excessive proliferation signaling are revealed as one of the most important emergent therapies against cancer [6]. Kinome profiling has arisen as an important tool to develop targeted therapies against kinases with aberrant expression directly involved in cancer pathology [7]
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