Medical therapy for Cushing's disease using 11β-HSD2 inhibitor

库欣病的特征是在高皮质醇血症下持续分泌促肾上腺皮质激素。为了阐明其分子机制，我们使用小鼠促肾上腺皮质激素肿瘤细胞检测了11 β-羟基类固醇脱氢酶（11β-HSD）抑制对糖皮质激素抑制ACTH释放的影响。结果发现，细胞中11β-HSD 2和-HSD 1均表达，甘珀酸（CBX）抑制11β-HSD 2和-HSD 1表达可显著增强糖皮质激素的负反馈效应。CBX还可增强皮质醇诱导的细胞凋亡。这些效应最有可能归因于11-HSD 2的抑制，因为在这些实验条件下仅存在皮质醇（11β-HSD 2的底物）。我们的结论是，11β-HSD 2的异位表达是，至少部分，负责受损的糖皮质激素抑制在促肾上腺皮质激素腺瘤。抑制11β-HSD 2可能成为治疗库欣病的药物。

Cushing's disease is characterized by persistent adrenocorticotropin secretion under hypercortisolemia. To clarify the molecular mechanism, we examined the effect of 11b-hydroxysteroid dehydrogenase (11β-HSD) inhibition on glucocorticoid suppression of ACTH release using murine corticotroph tumor cells. We found that 11β-HSD2 as well as -HSD1 was expressed in the cells, and that its inhibition by carbenoxolone (CBX) significantly improved the negative feedback effect of glucocorticoid. CBX also enhanced apoptosis induced by cortisol. These effects are most likely attributable to inhibition of 11-HSD2, because only cortisol, a substrate of 11β-HSD2, was present in these experimental conditions. We conclude that ectopic expression of 11β-HSD2 is, at least in part, responsible for the impaired glucocorticoid suppression in corticotroph adenoma. Inhibition of 11β-HSD2 may be applicable to the medical therapy for Cushing's disease.