Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas

Abstract

Introduction. The glucocorticoid receptor is pivotal to control corticotrophin (ACTH) secretion and its function is closely linked to the heat shock protein 90 (HSP90) chaperone complex. Impaired sensitivity to glucocorticoid feedback is a hallmark of human corticotroph adenomas, i.e., Cushing’s disease, a disorder with few medical treatment options. Silibinin, a HSP90 inhibitor, has been studied in tumoral corticotroph cells and its use proposed in Cushing’s disease. Aim of the present study was to further investigate the effect of silibinin on human corticotroph adenomas in vitro. Methods. Seven human ACTH-secreting pituitary adenomas were established in culture and treated with 10 – 50 µM silibinin with/without dexamethasone for up to 72 hours. ACTH medium levels were measured and POMC and glucocorticoid receptor, i.e., NR3C1, gene expression assessed. Results. Silibinin reduced spontaneous ACTH secretion and restored sensitivity to steroid negative feedback to a different extent in individual adenomas. POMC expression was decreased both in control and dexamethasone-treated wells in specimens sensitive to silibinin. Interestingly, silibinin reduced constitutive NR3C1 expression and reversed the dexamethasone-induced inhibition. Conclusions. Our findings indicate that silibinin can inhibit ACTH synthesis and secretion in individual human corticotroph adenomas and directly affects NR3C1 gene expression. These results reveal promising effects of this HSP90 inhibitor on human corticotroph adenomas and support an innovative target treatment for patients with Cushing’s disease.

High-throughput screening for Cushing’s disease: therapeutic potential of thiostrepton via cell cycle regulation

“…Our screening included 2480 bioactive compounds, covering a broader range of drugs, thus allowing us to explore various classes (43). Some of the hit compounds listed in Table 1 and Supplementary Table 1 have been validated in terms of their potent efficacy against ACTH-secreting PitNETs; these include HDAC inhibitors (18–21), HSP90 inhibitors (22–24), PI3K inhibitors (18), proteasome inhibitors (25), an adrenergic receptor antagonist (44), and epidermal growth factor receptor inhibitors (45, 46). These results support the relevancy of our HTS results in terms of identifying therapeutic agents for Cushing’s disease.…”

“…Among the 20 compounds with significant effects at 1 μM, histone deacetylase (HDAC) inhibitors (18)(19)(20)(21), heat shock protein 90 (HSP90) inhibitors (22)(23)(24), phosphatidylinositol-3 kinase (PI3K) inhibitors (18), and proteasome inhibitors (25) have been reported to have antitumor effects against ACTH-secreting PitNETs. After excluding the compounds belonging to these classes, we focused on TS, a natural compound containing a thiazole ring.…”

Gut microbiota composition and metabolic characteristics in patients with Craniopharyngioma

“…It is also possible that liver damage in patients with CP, caused by excessive obesity, triggers a protective response in the body [ 20 – 22 ]. Additionally, studies indicate that silibinin may suppress Adrenocorticotropic hormone (ACTH) secretion, potentially explaining the diminished cortisol levels in patient with CP [ 23 ].…”

Gut Microbiota Composition and Metabolic Characteristics in Patients with Craniopharyngioma

“…It is also possible that liver damage in patients with CP, caused by excessive obesity, triggers a protective response in the body [20][21][22]. Additionally, studies indicate that silibinin may suppress Adrenocorticotropic hormone (ACTH) secretion, potentially explaining the diminished cortisol levels in patient with CP [23].…”