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

• Published in: Veterinary & comparative oncology 2022-03, Vol.20 (1), p.313-323
• Main Authors: Ishikawa, Takuro, Osaki, Tomohiro, Sugiura, Akihiro, Tashiro, Jiro, Warita, Tomoko, Hosaka, Yoshinao Z., Warita, Katsuhiko
• Format: Article
• Language: English
• Subjects: Animals; atorvastatin; Atorvastatin - pharmacology; Atorvastatin - therapeutic use; cancer; canine; Cell Line, Tumor; Cell Proliferation - drug effects; Dog Diseases - drug therapy; Dogs; drug sensitivity; EMT‐inducing transcription factors; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Melanoma - veterinary
• ISSN: 1476-5810; 1476-5829
• DOI: 10.1111/vco.12778

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.