Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2010) 22 P386

1Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara, Italy; 2Division of Neurosurgery, University of Padova, Padova, Italy.

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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