RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregulating thymidylate synthase.
We evaluated RAD001, an inhibitor of the mammalian target of rapamycin (mTOR) in human gastric cancer cell lines and determined the molecular mechanisms. RAD001 has marked growth inhibitory activity against the SNU-1 and SNU-216 cells. It inhibited phosphorylation of mTOR and S6K, and induced G1 cell cycle arrest. Synergistic growth-inhibitory effects in combination with 5-fluorouracil (5-FU) was identified. Furthermore, RAD001 conferred sensitivity to 5-FU-resistant cell lines by downregulating thymidylate synthase (TS). In conclusion, RAD001 showed growth inhibitory activity against gastric cancer cells and acted synergistically with cytotoxic agents such as 5-FU by downregulating TS.
Lee
Kyung-Hun
KH
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Hur
Hyung-Seok
HS
Im
Seock-Ah
SA
Lee
Juhee
J
Kim
Hwang-Phill
HP
Yoon
Young-Kwang
YK
Han
Sae-Won
SW
Song
Sang-Hyun
SH
Oh
Do-Youn
DY
Kim
Tae-You
TY
Bang
Yung-Jue
YJ
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D005472:Fluorouracil / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D000068338:Everolimus; D013940:Thymidylate Synthase; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil; D020123:Sirolimus