Long-term in-vitro glucocorticoid treatment induces glucocorticoid resistance in canine mast cell tumors.

Although glucocorticoid administration has produced impressive results in treating canine mast cell tumors (MCTs), in some cases, glucocorticoids fail to reduce the tumor volume, leading to tumor relapse even after treatment. To date, mechanisms involved in glucocorticoid resistance in canine MCTs remain poorly defined. The objective of this study was to establish glucocorticoid-resistant canine MCT cell lines derived from glucocorticoid-sensitive cell lines after prolonged treatment with dexamethasone (Dex). Real-time polymerase chain reaction (RT-PCR) revealed that elevation of glucocorticoid receptor (GR)-regulated gene expression was suppressed in Dex-resistant cell lines after Dex stimulation compared with parent Dex-sensitive cell lines. This indicated that GR-regulated transcription was suppressed in Dex-resistant cell lines. Insufficient expression of GRs was not detected in Dex-resistant cell lines. Possible inhibitors of GR-regulated transcription were increased in mRNA expression in Dex-resistant cell lines. In addition, it was determined that mRNA expression of drug efflux pumps and anti-apoptosis factors was higher in Dex-resistant cell lines. In conclusion, glucocorticoid-resistant canine MCT cell lines have been established that are derived from glucocorticoid-sensitive cell lines. These cell lines suggest that multiple mechanisms contribute to glucocorticoid resistance in canine MCT cells. The mechanisms of glucocorticoid resistance after long-term treatment can be further investigated using these cell lines and a novel therapeutic strategy for glucocorticoid-resistant canine MCT cells can be developed.