Role of the novel mTOR inhibitor RAD001 (everolimus) in anaplastic thyroid cancer.
Activation of the phosphatidylinositol-3-kinase (PI3K) signaling cascade is increasingly recognized as a common feature of thyroid follicular neoplasms. Among the PI3K downstream effectors, the main kinase, directly responsible for the increased cell growth and proliferation, is called mammalian target of rapamycin (mTOR). This central kinase might be directly inhibited via rapamycin and its derivatives. The aim of the present study was to examine whether RAD001 (everolimus) can selectively suppress the proliferation of different anaplastic thyroid cancer (ATC) cells. Five different human ATC cell lines were exposed to different concentrations of RAD001. Importantly, we found a dose-dependent growth inhibition in two ATC cell lines at concentrations of 43.5 and 94.5 nM although not as intensive as within the RAD001 responding K562cell line. The other cell lines revealed a GI (50) between 168 to 234 nM. In parallel, quantitative PCR of PCNA displayed a reduced expression of PCNA within the responding cell lines, respectively. In summary, we found a good responding effect in a part of ATC cell lines, which may have a clinical impact.
Papewalis
C
C
Endocrine Cancer Center, Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany. claudia.papewalis@uni-duesseldorf.de
Wuttke
M
M
Schinner
S
S
Willenberg
H S
HS
Baran
A M
AM
Scherbaum
W A
WA
Schott
M
M
D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D007166:Immunosuppressive Agents; D018809:Proliferating Cell Nuclear Antigen; D012313:RNA; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus