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Published on: October 2, 2014
Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas
Francesca Pecori Giraldi1,2, Maria Francesca Cassarino2, Antonella Sesta2
1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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
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.
Insights
Silibinin, a heat shock protein 90 (HSP90) inhibitor, reduced ACTH secretion in human corticotroph adenomas. This study suggests silibinin as a potential treatment for Cushing's disease by targeting HSP90.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Glucocorticoid receptor (GR) function is crucial for controlling corticotrophin (ACTH) secretion.
- Impaired GR sensitivity characterizes human corticotroph adenomas (Cushing's disease), a condition with limited therapeutic options.
- Silibinin, a heat shock protein 90 (HSP90) inhibitor, has shown potential in tumoral corticotroph cells.
Purpose of the Study:
- To investigate the in vitro effects of silibinin on human corticotroph adenomas.
- To assess silibinin's impact on ACTH secretion and glucocorticoid receptor (NR3C1) gene expression.
Main Methods:
- Seven human ACTH-secreting pituitary adenomas were cultured.
- Treated with varying concentrations of silibinin, with or without dexamethasone, for up to 72 hours.
- Measured ACTH levels and assessed POMC and NR3C1 gene expression.
Main Results:
- Silibinin inhibited spontaneous ACTH secretion and modulated sensitivity to steroid negative feedback in a patient-specific manner.
- POMC expression decreased in silibinin-sensitive adenomas.
- Silibinin reduced constitutive NR3C1 expression and reversed dexamethasone-induced inhibition.
Conclusions:
- Silibinin effectively inhibits ACTH synthesis and secretion in human corticotroph adenomas.
- Silibinin directly influences NR3C1 gene expression.
- These findings support silibinin as a promising therapeutic agent for Cushing's disease by targeting HSP90.
