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Vol. 85, No. 1, 2007
Issue release date: April 2007

The Novel mTOR Inhibitor RAD001 (Everolimus) Induces Antiproliferative Effects in Human Pancreatic Neuroendocrine Tumor Cells

Zitzmann K. · De Toni E.N. · Brand S. · Göke B. · Meinecke J. · Spöttl G. · Meyer H.H.D. · Auernhammer C.J.
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Abstract

Background/Aim: Tumors exhibiting constitutively activated PI(3)K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3)K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients.



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