Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoinooka, Imabari, Ehime 794-8555, Japan.
Can J Vet Res. 2021 Oct;85(4):302-308.
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.
虽然糖皮质激素治疗犬肥大细胞瘤（MCT）已取得显著效果，但在某些情况下，糖皮质激素无法缩小肿瘤体积，导致治疗后肿瘤复发。迄今为止，犬 MCT 中糖皮质激素抵抗的相关机制仍未明确。本研究旨在通过长期用地塞米松（Dex）处理建立糖皮质激素敏感细胞系衍生的糖皮质激素耐药犬 MCT 细胞系。实时聚合酶链反应（RT-PCR）显示，与亲本 Dex 敏感细胞系相比，Dex 刺激后 Dex 耐药细胞系中糖皮质激素受体（GR）调控基因的表达升高受到抑制。这表明 Dex 耐药细胞系中 GR 调控的转录受到抑制。在 Dex 耐药细胞系中未检测到 GR 表达不足。mRNA 表达显示 Dex 耐药细胞系中 GR 调控转录的可能抑制剂增加。此外，还确定 Dex 耐药细胞系中药物外排泵和抗凋亡因子的 mRNA 表达更高。总之，已建立了源自糖皮质激素敏感细胞系的糖皮质激素耐药犬 MCT 细胞系。这些细胞系表明，犬 MCT 细胞中糖皮质激素抵抗涉及多种机制。可以使用这些细胞系进一步研究长期治疗后糖皮质激素抵抗的机制，并开发针对糖皮质激素耐药犬 MCT 细胞的新治疗策略。
