Division of Urology, McGill University Health Center, Montreal, QC, CA.
Cancer Biol Ther. 2009 Dec;8(24):2339-47. doi: 10.4161/cbt.8.24.9987. Epub 2009 Dec 2.
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.
我们研究了雷帕霉素(RAD001,依维莫司)对膀胱癌的治疗是否有效。RAD001 在体外以剂量和敏感性依赖的方式显著抑制了 9 个人类尿路上皮癌细胞系的增殖。FACS 分析显示,RAD001 处理 48 小时后,所有细胞系均在 G0/G1 期发生细胞周期阻滞,而不会引发细胞凋亡。此外,RAD001 还显著抑制了所有细胞系中 mTOR 下游 S6 的磷酸化和 VEGF 的产生。我们还发现,与安慰剂组相比,RAD001 处理的裸鼠携带的人 KU-7 皮下异种移植瘤的肿瘤重量显著降低。这种肿瘤生长抑制与细胞增殖率和血管生成的显著降低有关,而细胞死亡没有变化。总之,在膀胱癌模型中抑制 mTOR 信号通路表现出显著的体内外抗肿瘤活性。这是第一项表明 RAD001 可作为膀胱癌潜在治疗策略的研究。