Endocrine Abstracts

Silibinin, a milk thistle extract with known hepatoprotective effects, has recently been shown to act upon tumoral corticotropes and revert the Cushingoid phenotype in an allograft mouse model (Riebold et al. 2015). Silbinin is known to inhibit HSP90 -a chaperone to the glucocorticoid receptor-thereby restoring sensitivity to glucocorticoid negative feedback in tumoral corticotropes. Aim of the present study was to assess the effect of silibinin on ACTH synthesis and secretion by human corticotrope adenomas in vitro.

Methods: Eight human ACTH-secreting pituitary adenomas were collected during surgery and established in culture as per our protocol (Pecori Giraldi et al. 2011). Specimens were treated with 10–50 µM silibinin for up to 72 hours. ACTH medium levels were measured by Elisa; POMC expression was assessed by RT-PCR (Cassarino et al. 2017).

Results: Silibinin reduced spontaneous ACTH secretion to a variable extent in individual adenomas: from 32 to 79% of baseline at 4 h, and 54–85% of baseline at 48 and 72 h. Silibinin was also effective in reinstating or enhancing sensitivity to steroid negative feedback: ACTH decreases during 10–50 µM silibinin incubation ranged from 10 to 63% of dexamethasone-treated wells at 4 hours, 70–80% at 48 hours and 36 to 80% at 72 hours, indicating long-lasting effect on glucocorticoid sensitivity. Silibinin induced a variable decrease in POMC expression, both as regards expression in control and dexamethasone-treated wells; some specimens exhibited a marked sensitivity to the inhibitory effect, with POMC expression decreasing to less than 50% of control.

Conclusions: This data suggests that silibinin can inhibit ACTH secretion and POMC synthesis and restore sensitivity to negative glucocorticoid feedback.

References

1. Cassarino et al. Proopiomelanocortin, glucocorticoid, and CRH receptor expression in human ACTH-secreting pituitary adenomas. Endocrine 2017 55 853–860.

2. Pecori Giraldi et al. Responses to corticotrophin-releasing hormone and dexamethasone in a large series of human adrenocorticotrophic hormone-secreting pituitary adenomas in vivo reveal manifold corticotroph tumoural phenotypes. Journal of Neuroendocrinology 2011 23 1214–21.

3. Riebold et al. A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease. Nature Medicine 2015 21 276–280.

This study was sponsored by IBI-Lorenzini, Aprilia (LT).