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Simvastatin exhibits antiproliferative effects on spheres derived from canine mammary carcinoma cells
Cristian G Torres1, Araceli Olivares2, Caroll Stoore2
1Laboratory of Biomedicine and Regenerative Medicine, Department of Clinical Sciences, Faculty of Veterinary and Animal Sciences, University of Chile, Santiago 8820808, Chile.
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.
Insights
Simvastatin effectively targets canine mammary cancer stem-like cells, reducing their self-renewal and chemoresistance. This study suggests simvastatin as a potential therapeutic agent for canine mammary cancer treatment.
Area of Science:
- Veterinary Oncology
- Cancer Stem Cell Biology
- Pharmacology
Background:
- Canine mammary cancer, the most common tumor in female dogs, often recurs or metastasizes despite surgery and chemotherapy.
- Cancer stem-like cells (CSCs) with stemness features may drive tumor progression, recurrence, and chemoresistance.
- Statins, like simvastatin, inhibit cholesterol synthesis and have shown antitumor effects, potentially by affecting protein isoprenylation.
Purpose of the Study:
- To investigate the effects of simvastatin on canine mammary CSCs derived from CF41.Mg cells.
- To analyze phenotypic and functional characteristics of these CSCs and their response to simvastatin treatment.
Main Methods:
- Generation and characterization of canine mammary spheres (representing CSCs) with stemness markers (CD44⁺/CD24⁻/low).
- Assessment of simvastatin's impact on sphere formation, cell viability, apoptosis (caspase-3/7 activity), and invasiveness.
- Evaluation of simvastatin's synergistic effect with doxorubicin and the role of geranylgeranyl pyrophosphate.
Main Results:
- Simvastatin reduced sphere-forming capacity and cell viability in a dose- and time-dependent manner.
- Simvastatin increased caspase-3/7 activity, modulated β-catenin and p53 expression, and decreased invasiveness.
- Simvastatin enhanced doxorubicin's cytotoxicity and its anti-invasive effect was reversed by geranylgeranyl pyrophosphate.
Conclusions:
- Simvastatin effectively targets canine mammary cancer stem-like cells, inhibiting their key stemness properties.
- Simvastatin demonstrates potential as a novel therapeutic agent to overcome chemoresistance and reduce invasiveness in canine mammary cancer.
- The findings support further investigation of simvastatin for treating canine mammary tumors.
