Atorvastatin preferentially inhibits the growth of high ZEB‐expressing canine cancer cells

Abstract

The epithelial‐to‐mesenchymal transition (EMT) is fundamental in cancer progression and contributes to the acquisition of malignant properties. The statin class of cholesterol‐lowering drugs exhibits pleiotropic anticancer effects in vitro and in vivo, and many epidemiologic studies have reported a correlation between statin use and reduced cancer mortality. We have shown previously that sensitivity to the anti‐proliferative effect of statins varies among human cancer cells and statins are more effective against mesenchymal‐like cells than epithelial‐like ones in human cancers. There have only been few reports on the application of statins to cancer therapy in veterinary medicine, and differences in statin sensitivity among canine cancer cells have not been examined. In this study, we aimed to clarify the correlation between sensitivity to atorvastatin and epithelial/mesenchymal states in 11 canine cancer cell lines derived from mammary gland, squamous cell carcinoma, lung, and melanoma. Sensitivity to atorvastatin varied among canine cancer cells, with IC50 values ranging from 5.92 to 71.5 μM at 48 h, which were higher than the plasma concentrations clinically achieved with statin therapy. Atorvastatin preferentially attenuated the proliferation of mesenchymal‐like cells. In particular, highly statin‐sensitive cells were characterized by aberrant expression of the ZEB family of EMT‐inducing transcription factors. However, ZEB2 silencing in highly sensitive cells did not induce resistance to atorvastatin. Taken together, these results suggest that high expression of ZEB is a characteristic of highly statin‐sensitive cells and could be a molecular marker for predicting whether cancers are sensitive to statins, though ZEB itself does not confer statin sensitivity.

Comparison of the anticancer effects of various statins on canine oral melanoma cells

“…We have previously reported that even atorvastatin, which has relatively weak anticancer properties among lipophilic statins, exerts marked anticancer effects against human and canine melanoma with a mesenchymal phenotype. 10,12 Our results showed that pitavastatin was the most effective in all cell lines tested in this study, which provides novel insights into selecting the optimal statin for treating canine melanoma.…”

“…Three canine oral melanoma cell lines, previously established by Osaki et al, 20 with mesenchymal phenotype, 12…”

“…Three canine oral melanoma cell lines, previously established by Osaki et al, 20 with mesenchymal phenotype, 12 namely YCC (passage 13), ITP (passage 19) and HTR (passage 12), were used in this study. Cells were cultured in RPMI 1640 medium (Thermo Fisher Scientific, Rockford, IL, USA) containing 10% heat‐inactivated foetal bovine serum (Biosera, Boussens, France) and 1% penicillin–streptomycin (Wako Pure Chemical, Osaka, Japan) at 37°C with 5% CO 2 .…”

“…Various in vitro and in vivo studies have shown that statins exert pleiotropic anticancer effects. 9 Interestingly, statins preferentially attenuate the growth of mesenchymal cancer cells rather than epithelial cancer cells with functional E-cadherin-mediated cell cohesion [10][11][12] and are therefore possibly effective against highly malignant cancers that have undergone EMT. 13 Seven types of statins with different physicochemical properties and pharmacokinetics are currently used in clinical settings.…”

Repurposing of the Cardiovascular Drug Statin for the Treatment of Cancers: Efficacy of Statin–Dipyridamole Combination Treatment in Melanoma Cell Lines

“…Our previous studies showed that atorvastatin is effective against all melanoma cells in both human [ 14 ] and spontaneously occurring canine melanoma cell lines [ 15 , 16 ]. Furthermore, plasma levels of atorvastatin, comparable to those used for the treatment of hypercholesterolemia, have been reported to inhibit the metastasis of human melanoma cells overexpressing RhoC in a xenograft model [ 17 ].…”