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• W2022762775 abstract "Background Adrenostatic compounds are frequently used in the treatment of patients with Cushing's syndrome and act via direct inhibition of steroidogenic enzymes. However, additional mechanisms may be involved in the blockade of adrenal steroid secretion. We therefore investigated the effects of aminoglutethimide (AG), metyrapone (MTP) and etomidate (ETO) in the human NCI‐h295 adrenocortical carcinoma cell line. Materials and methods Cells were incubated with increasing doses of the adrenostatic compounds. Steroid hormone secretion (cortisol, 17‐OH‐progesterone, DHEA‐S) and cAMP synthesis were determined and Northern blot analysis and cell proliferation experiments were performed. Results ETO was the most potent adrenostatic compound inhibiting P450c11 hydroxylase at low concentrations (IC 50 15 nM), and also blocking P450 side‐chain cleavage (scc) enzyme (IC 50 400 nM) at higher concentrations. The pattern of enzyme inhibition was similar for MTP with an IC 50 of 3á5 μM for P450c11 and 17 μM for P450scc, while AG blocked P450scc with an IC 50 of 10 μM. AG significantly suppressed the baseline ACTH‐R mRNA expression in a dose‐dependent fashion (300 μM AG: 5% ± 1%; 30 μM AG: 64% ± 1%; 3 μM AG: 108% ± 19% compared with control cells: 100% ± 11%) but increased glucocorticoid receptor mRNA. The reduced ACTH‐R mRNA was paralleled by low ACTH‐induced cAMP accumulation indicating reduced expression of ACTH‐R protein. The simultaneous incubation of hydrocortisone together with AG reversed the inhibitory effect of AG on the ACTH‐R expression. AG and ETO inhibited cell proliferation in the NCI‐h295 cells, but ETO was much more potent and showed antiproliferative effects at concentrations of 6 μM. The growth inhibition was not reversed by administration of hydrocortisone. Conclusions Our data demonstrate that adrenostatic compounds not only act by suppression of steroidogenic enzymes but can also influence both ACTH‐R expression and cell proliferation in adrenal cells. As these effects occur in vitro at concentrations that are reached during treatment with theses drugs in patients, they are probably also of clinical relevance. Particularly the antiproliferative activity of ETO may be useful in Cushing's syndrome due to adrenocortical cancer. The interaction of steroidogenesis, ACTH‐R and glucocorticoid receptor expression as well as cell proliferation provides a new concept of the intra‐adrenal response to stress in humans." @default.
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• W2022762775 date "2000-12-01" @default.
• W2022762775 modified "2023-09-27" @default.
• W2022762775 title "New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line" @default.
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• W2022762775 doi "https://doi.org/10.1046/j.1365-2362.2000.0300s3076.x" @default.
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