title: Simvastatin exhibits antiproliferative effects on spheres derived from canine mammary carcinoma cells.
abstract: Mammary cancer is the most frequent type of tumor in the female canine. Treatments are mainly limited to surgery and chemotherapy; however, these tumors may develop clinical recurrence, metastasis and chemoresistance. The existence of a subpopulation of cancer cells with stemness features called cancer stem-like cells, may explain in part these characteristics of tumor progression. The statins, potent blockers of cholesterol synthesis, have also shown antitumor effects on cancer mammary cells, changes mediated by a decrease in the isoprenylation of specific proteins. Few studies have shown that simvastatin, a lipophilic statin, sensitizes cancer stem-like cells eliminating drug resistance. The aim of the present study was to evaluate the effects of simvastatin on spheres derived from CF41.Mg canine mammary tumor cells, which were characterized by phenotypic and functional analyses. Spheres exhibited characteristics of stemness, primarily expressing a CD44⁺/CD24⁻/low phenotype, displaying auto-renewal and relative chemoresistance. Exposure to simvastatin induced a decrease in the sphere-forming capacity and cell viability, accompanied by a concentration- and time-dependent increase in caspase-3/7 activity. In addition, modulation of β-catenin and p53 expression was observed. Simvastatin triggered a synergistic effect with doxorubicin, sensitizing the spheres to the cytotoxic effect exerted by the drug. Invasiveness of spheres was decreased in response to simvastatin and this effect was counteracted by the presence of geranylgeranyl pyrophosphate. Our results suggest that simvastatin targets canine mammary cancer stem-like cells, supporting its therapeutical application as a novel agent to treat canine mammary cancer.
authors.affiliation: Laboratory of Biomedicine and Regenerative Medicine, Department of Clinical Sciences, Faculty of Veterinary and Animal Sciences, University of Chile, Santiago 8820808, Chile.
authors.forename: Cristian G
authors.initials: CG
authors.lastname: Torres
authors.affiliation: School of Veterinary Medicine, Faculty of Ecology and Natural Resources, Andres Bello University, Santiago 8370251, Chile.
authors.forename: Araceli
authors.initials: A
authors.lastname: Olivares
authors.affiliation: School of Veterinary Medicine, Faculty of Ecology and Natural Resources, Andres Bello University, Santiago 8370251, Chile.
authors.forename: Caroll
authors.initials: C
authors.lastname: Stoore
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004283:Dog Diseases / Q000473:pathology*; D004285:Dogs; D005260:Female; D005434:Flow Cytometry; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin