S Noguchi1,2, S Shibutani3, K Fukushima4, T Mori5, M Igase6, T Mizuno2,4. 1. Laboratory of Veterinary Radiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan. 2. Biomedical Science Center for Translational Research, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan. 3. Laboratory of Veterinary Hygiene, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan. 4. Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan. 5. Laboratory of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan. 6. The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.
Abstract
BACKGROUND: SRC kinase (SRC proto-oncogene, non-receptor tyrosine kinase) is a promising target for the treatment of solid cancers including human melanoma. Bosutinib (Bosu), a SRC inhibitor, has already been applied to the treatment of human chronic myelogenous leukemia and also has been assessed its safety in dogs. AIM: The aim of this study was to clarify a novel anti-tumour mechanism of Bosu in canine and human melanoma cells. MATERIALS AND METHODS: The canine and human melanoma cells were treated with Bosu and its effects were evaluated by the cell viability, the protein expression levels such as caspase-3 and LC3, Annexin V/Propidium iodide staining, and confocal immunostaining. RESULTS: Bosu induced the massive caspase-independent cell death, and blocked autophagy flux, which resulted from lysosomal dysfunction. Lysosomal dysfunction caused by Bosu was due to lysosomal membrane permeabilization (LMP), which resulted in the release of lysosomal hydrolases including cathepsin B. CONCLUSION: Our data suggest that Bosu induces the cell death through induction of LMP in melanoma cells and is a promising therapeutic agent for treatment of melanoma in both dogs and humans.
BACKGROUND:SRC kinase (SRC proto-oncogene, non-receptor tyrosine kinase) is a promising target for the treatment of solid cancers including humanmelanoma. Bosutinib (Bosu), a SRC inhibitor, has already been applied to the treatment of human chronic myelogenous leukemia and also has been assessed its safety in dogs. AIM: The aim of this study was to clarify a novel anti-tumour mechanism of Bosu in canine and humanmelanoma cells. MATERIALS AND METHODS: The canine and humanmelanoma cells were treated with Bosu and its effects were evaluated by the cell viability, the protein expression levels such as caspase-3 and LC3, Annexin V/Propidium iodide staining, and confocal immunostaining. RESULTS:Bosu induced the massive caspase-independent cell death, and blocked autophagy flux, which resulted from lysosomal dysfunction. Lysosomal dysfunction caused by Bosu was due to lysosomal membrane permeabilization (LMP), which resulted in the release of lysosomal hydrolases including cathepsin B. CONCLUSION: Our data suggest that Bosu induces the cell death through induction of LMP in melanoma cells and is a promising therapeutic agent for treatment of melanoma in both dogs and humans.