ISSN 1470-3947 (print)
ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology

Published by BioScientifica
Endocrine Abstracts (2010) 22 P386 
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Everolimus reduces human ACTH-secreting pituitary adenoma in vitro cell viability

Maria Chiara Zatelli1, Mariella Minoia1, Carlo Filieri1, Federico Tagliati1, Daniela Molè1, Massimo Scanarini2, Maria Rosaria Ambrosio1 & Ettore degli Uberti1

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Everolimus (RAD001), an immunosuppressant drug, has antineoplastic activity in human neoplasia, including endocrine tumors, due to its ability to inhibit the AKT down-stream signaling pathway. It has been demonstrated that AKT is overexpressed and up-regulated in pituitary tumor, including ACTH-producing pituitary tumors, that are still orphan of an effective medical therapy. We therefore investigated the effects of RAD001 on cell viability, apoptosis and mTOR phosphorilation in 10 human ACTH-producing pituitary tumors in primary culture. Cells were treated with 10 nM–1 μM RAD001, 50 nM IGF1, and/or 10 nM SOM230 (a somatostatin receptor multiligand). After 48 h, cell viability was evaluated with a colorimetric method, apoptosis with caspase 3/7 assays and mTOR phosphorylation by a specific ELISA kit. RAD001 significantly and dose-dependently reduced cell viability in eight out of ten cultures (−15 to −25%; P<0.05), promoted apoptosis (+20 to +25%; P<0.05), reduced mTOR phosphorylation (−30 to −42%; P<0.05). IGF1 significantly promoted cell viability (+40%; P<0.01), inhibited apoptosis (−34%; P<0.05) and induced mTOR phosphorylation (+35%; P<0.05), effects that were completely abolished by co-treatment with 100 nM and 1 μM RAD001. SOM230 slightly but significantly reduced cell viability (−12%; P<0.05) and strongly potentiated RAD001 inhibitory effects (−58%; P<0.01). Our data demonstrate that RAD001 inhibits cell viability in selected ACTH-secreting pituitary adenomas, by inducing caspase 3/7 activity with a mechanism involving IGF1 signaling, which is enhanced by SOM230. Our results suggest that RAD001 acts as a pro-apoptotic stimulus, inducing the extrinsic pathway, and might represent a possible medical treatment aiming at controlling pituitary adenoma growth in Cushing’s disease.

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