Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer.
We examined whether mTOR inhibition by RAD001 (Everolimus) could be therapeutically efficacious in the treatment of bladder cancer. RAD001 markedly inhibited proliferation of nine human urothelial carcinoma cell lines in dose- and sensitivity-dependent manners in vitro. FACS analysis showed that treatment with RAD001 for 48 h induced a cell cycle arrest in the G(0)/G(1) phase in all cell lines, without eliciting apoptosis. Additionally, RAD001 significantly inhibited the phosphorylation of S6 downstream of mTOR and VEGF production in all cell lines. We also found tumor weights from nude mice bearing human KU-7 subcutaneous xenografts treated with RAD001 were significantly reduced as compared to placebo-treated mice. This tumor growth inhibition was associated with significant decrease in cell proliferation rate and angiogenesis without changes in cell death. In conclusion inhibition of mTOR signaling in bladder cancer models demonstrated remarkable antitumor activity both in vitro and in vivo. This is the first study showing that RAD001 could be exploited as a potential therapeutic strategy in bladder cancer.
Mansure
Jose J
JJ
Division of Urology, McGill University Health Center, Montreal, QC, CA.
Nassim
Roland
R
Chevalier
Simone
S
Rocha
Joice
J
Scarlata
Eleonora
E
Kassouf
Wassim
W
D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D019459:Urothelium / Q000473:pathology*
D047908:Intracellular Signaling Peptides and Proteins; D000068338:Everolimus; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus