Endocrine Abstracts (2008) 16 P483

mTOR inhibitors rapamycin and RAD001 (Everolimus) induce antiproliferative effects in GH3 cell line and human pituitary adenomas

Hadara Rubinfeld1, Alexander Gorshtein2, Efrat Kendler1, Moshe Hadani3 & Ilan Shimon1


1Institute of Endocrinology and Felsenstein Medical Research Centre, Rabin Medical Centre, Petach Tikva, Israel; 2Department of Internal Medicine, Meir Hospital, Kfar Saba, Israel; 3Department of Neurosurgery, Sheba Medical Center, Tel-Hasomer, Tel Aviv University, Tel Aviv, Israel.


The effect of mTOR inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the antiproliferative effects of these drugs.

To evaluate the in vitro effects of mTOR inhibitor rapamycin, and its orally-bioavailable analog RAD001 on pituitary cells, GH3 cells, a mammosomatotroph rat pituitary tumor cell line, and human GH-secreting and non-functioning pituitary adenoma (NFPA) cells were used.

Treatment of GH3 cells, cultured GH-secreting adenomas and NFPAs with rapamycin or RAD001 induced a significant dose- and time-dependent inhibition of cell viability. The inhibition of GH3 cell viability involved G0/G1 cell cycle arrest associated with cyclin D3 suppression. Expression of phosphorylated-p70S6K in GH3 cells, GH-secreting adenoma and NFPA cells was significantly reduced by rapamycin and RAD001. mTOR phosphorylation was significantly decreased by rapamycin and RAD001 in GH3 cells, while Akt phosphorylation was unchanged.

Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation suggesting that mTOR inhibition may be a promising antiproliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors unresponsive to current treatments.

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