Sanguinarine anti-tumor activity on a model of basal-like breast cancer

The aim of this work is to study the potential anti-proliferative effects of sanguinarine on mesenchymal cancer basal-like A17 cells isolated from FVB/neuT mammary carcinomas. Studies that have reviewed the histological presentation of basal-like breast cancer demonstrate that major90% of these tumors arise from the breast ducts and are often associated with higher nuclear and histological grade, high mitotic index and more aggressive phenotypic features. This clinical subset represents one of the most important treatment challenges today because these tumors are not likely to respond to hormonal maneuvers (tamoxifen or aromatase inhibitors) nor to drugs targeting HER2 over expression (trastuzumab) [6-17]. Marchini et al compared crucial molecular pathways of A17 derived-carcinoma with that of both carcinomas and other mesenchymal phenotypes, such as mesenchymal stem cells (MSCs), breast stroma, and various types of sarcomas. They identified three mesenchymal/stromal-signatures which A17 cells share with MSCs and breast stroma, showing that these signatures significantly relates to basal-like breast cancer subtypes and significantly relates to bone metastasis [19, 20]. Sanguinarine, a natural benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis and other poppy species, could truly be an excellent candidate as a possible anticancer drug, since many different animals and human cancer cell lines have demonstrated to be highly sensitive to this alkaloid. In this work, sanguinarine shows its efficacy on A17 cell line model, both in in vitro and in in vivo experiments. Mtt, Wound-healing, motility assay and Annexin-V staining revealed that sanguinarine is able to reduce A17 viability, motility, and causes apoptotic and necrotic cell death. Most important, this alkaloid reduces Dihydrofolate Reductase (DHFR) activity, an enzyme implicated in the synthesis of Dna bases. Encouraged by these results, we managed an in vivo experiment by injecting A17 cells in FVB syngenic mice and treating them with sanguinarine: obtained results encouraged us to considered sanguinarine as a promising anticancer drug candidate in the treatment of basal-like breast cancer.