Investigation of the cytotoxic effect of flavopiridol in canine lymphoma cell lines

• Published in: Veterinary & comparative oncology 2016-08, Vol.14 (S1), p.95-106
• Main Authors: Ema, Y., Igase, M., Takeda, Y., Yanase, T., Umeki, S., Hiraoka, H., Okuda, M., Mizuno, T.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; apoptosis; Blotting, Western - veterinary; canine; Cell Death - drug effects; Cell Line, Tumor - drug effects; Cell Proliferation - drug effects; cyclin-dependent kinase; Cyclin-Dependent Kinases - drug effects; Disease Models, Animal; Dog Diseases - drug therapy; Dog Diseases - pathology; Dogs; Flavonoids - pharmacology; flavopiridol; lymphoma; Lymphoma, Non-Hodgkin - drug therapy; Lymphoma, Non-Hodgkin - pathology; Lymphoma, Non-Hodgkin - veterinary; Mice; Mice, Inbred NOD; Piperidines - pharmacology
• ISSN: 1476-5810; 1476-5829
• DOI: 10.1111/vco.12130

The cyclin‐dependent kinase (CDK) inhibitor, flavopiridol, was tested as a potential new cancer therapeutic agent to treat canine lymphoma by examining its effect on cell growth of canine lymphoma cell lines in vitro. Flavopiridol induced profound cell death in all eight lymphoma cell lines at 400 nM, and in all cases cell death was due to apoptosis. Apoptosis was inhibited by caspase inhibitor, despite the variable sensitivities between cell lines. Analysis of the mechanism of flavopiridol‐induced apoptosis showed that Rb phosphorylation was inhibited, possibly due to CDK4 or CDK6 inhibition. There was also decreased expression of Rb protein and anti‐apoptotic proteins, Mcl‐1 and XIAP, possibly through transcriptional regulation by inhibition of CDK7 or CDK9 activation. Canine lymphoma cell line‐xenotransplanted mice were then treated with flavopiridol and profound tumour shrinkage was observed. This study describes a new therapeutic approach using flavopiridol for canine lymphoma treatment.