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.

The impact of melatonin and carbon ion irradiation on cancer stem cells

“…A number of studies demonstrated the existence of stem cells in canine and human breast cancer cell lines [83][84][85][86][87][88][89]. The study of Dontu and colleagues demonstrated that the stemness of tumor cells is assessed in vitro by their capability to produce mammospheres [90].…”

Salinomycin inhibits canine mammary carcinoma in vitro by targeting cancer stem cells

“…Previous studies have used this method to analyze the sphere-forming ability of canine mammary CSCs (15,23). This method has also been used to investigate novel therapeutic drugs in humans and canines (14,24). In the present study, it was observed that spheres from canine mammary carcinoma cell lines overexpressed the stem cell markers CD44 and Oct-4, and exhibited chemoresistance to DOX and DDP.…”

“…Furthermore, activation of the Wnt/β-catenin, Hedgehog and Notch signaling pathways confers resistance and survival to CSCs in human cancer (13). Similar to what has been observed in human cancer, canine mammary CSCs upregulate stem cell-associated genes (9) and activate the Wnt/β-catenin signaling pathway (14). Canine mammary CSCs are highly tumorigenic, and exhibit multidrug resistance and invasive potential (9,15); therefore, they serve an important role in the treatment resistance, recurrence and metastasis of canine mammary tumors.…”

Identification and characterization of cancer stem cells in canine mammary tumors

“…The same cells were resistant to radiation doses of 1–5 Gy and exhibited a reduced loss of colony formation ability. Increased resistance to doxorubicin and no response to paclitaxel treatment were also observed by three other groups [27, 31, 35]. Barbieri et al [31] did not observe any reduction in cell viability, even at the highest concentrations (5–10 µM) of the drugs.…”

“…Human breast CSC have been previously characterized as CD44 + /CD24 −/low [15]. Detection of CD44 + /CD24 −/low cells has also been reported in CMT [27, 30, 35]. A study by Michishita et al [27] demonstrated that 85% of cells were CD44 + /CD24 −/low in spheres derived from a canine mammary adenocarcinoma cell line.…”