The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells.
OBJECTIVE
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.


CONCLUSIONS
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.
Zitzmann
Kathrin
K
Department of Internal Medicine II, University Hospital Munich-Grosshadern, University of Munich, Munich, Germany.
De Toni
Enrico N
EN
Brand
Stephan
S
Göke
Burkhard
B
Meinecke
Jennifer
J
Spöttl
Gerald
G
Meyer
Heinrich H D
HH
Auernhammer
Christoph J
CJ
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017599:Neuroectodermal Tumors / Q000188:drug therapy / Q000503:physiopathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus