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

使用 11β-HSD2 抑制剂治疗库欣病

• 批准号: 15590975
• 负责人: IWASAKI Yasumasa
• 金额: $ 2.24万
• 依托单位: Kochi University (2004)Nagoya University (2003)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590975/
• 关键词: ACTH; Proopiomelanocortin; Cushing's disease; pituitary adenoma; glucocorticoid; apoptosis; glucocorticoid; Cushing病; 11β-hydroxysteroid dehydrogenase; SF1; corticoroph; ステロイド代謝酵素

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.

库欣氏病的特征是在高皮层血症下持续的肾上腺皮质激素分泌。为了阐明分子机制，我们检查了11B-羟基甾体脱氢酶（11β-HSD）抑制对使用鼠皮质营养肿瘤细胞抑制ACTH释放的糖皮质激素抑制的作用。我们发现11β -HSD2和-HSD1在细胞中表达，并且甲氧诺氧酚（CBX）抑制其抑制作用显着改善了糖皮质激素的负反馈效应。 CBX还增强了皮质醇诱导的凋亡。这些作用最有可能归因于抑制11-HSD2，因为在这些实验条件下仅呈现皮质醇（11β-HSD2的底物）。我们包括11β-HSD2的Ecopic表达至少部分是导致皮质营养腺瘤中糖皮质激素抑制受损的原因。抑制11β-HSD2可能适用于治疗库欣病的药物疗法。

项目成果

Inhibition of 11β-hydroxysteroid dehydrogenase eliminates impaired glucocorticoid suppression and induces apoptosis in an in vitro model of Cushing's disease

在库欣病体外模型中，抑制 11β-羟基类固醇脱氢酶可消除受损的糖皮质激素抑制并诱导细胞凋亡

• 发表时间: 2003
• 期刊: ACTH RERATED PEPTIDES 14
• 作者: Takeshi Nigawara;Yasumasa Iwasaki;Masato Asai;Masanori Yoshida;Yutaka Oiso;Toshihoro Suda
• 通讯作者: Toshihoro Suda

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