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 µ<sc>m</sc> silibinin with/without dexamethasone for up to 72 h. 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 in both 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.

• Authors: Francesca Pecori Giraldi, Maria Francesca Cassarino, Antonella Sesta, Giovanni Lasio, Marco Losa
• Journal: Neuroendocrinology (Neuroendocrinology) Vol. 113 Issue 6 Pg. 606-614 ( 2023) ISSN: 1423-0194 [Electronic] Switzerland
• PMID: 36791678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: The Author(s). Published by S. Karger AG, Basel.

Chemical References

• Receptors, Glucocorticoid
• Silybin
• Pro-Opiomelanocortin
• Adrenocorticotropic Hormone
• Antineoplastic Agents
• Dexamethasone

Topics

• Humans
• ACTH-Secreting Pituitary Adenoma (genetics)
• Receptors, Glucocorticoid (genetics)
• Silybin (pharmacology)
• Pituitary ACTH Hypersecretion (drug therapy)
• Pro-Opiomelanocortin (metabolism)
• Adenoma (metabolism)
• Adrenocorticotropic Hormone (metabolism)
• Antineoplastic Agents
• Dexamethasone (pharmacology)