Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Pavillon 4, Av, de Beaumont, 1011 Lausanne, Switzerland.
BMC Cancer. 2012 Mar 8;12:86. doi: 10.1186/1471-2407-12-86.
The mammalian target of rapamycin (mTOR) is frequently activated in colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) pathway. Targeting mTOR with allosteric inhibitors of mTOR such as rapamycin reduces colon cancer progression in several experimental models. Recently, a new class of mTOR inhibitors that act as ATP-competitive inhibitors of mTOR, has been developed. The effectiveness of these drugs in colon cancer cells has however not been fully characterized.
LS174T, SW480 and DLD-1 colon cancer cell lines were treated with PP242 an ATP-competitive inhibitor of mTOR, NVP-BEZ235, a dual PI3K/mTOR inhibitor or rapamycin. Tumor cell growth, proliferation and survival were assessed by MTS assay, 5-bromo-2'-deoxyuridine (BrDU) incorporation or by quantification of DNA fragmentation respectively. In vivo, the anticancer activity of mTOR inhibitors was evaluated on nude mice bearing colon cancer xenografts.
PP242 and NVP-BEZ235 reduced the growth, proliferation and survival of LS174T and DLD-1 colon cancer cells more efficiently than rapamycin. Similarly, PP242 and NVP-BEZ235 also decreased significantly the proliferation and survival of SW480 cells which were resistant to the effects of rapamycin. In vivo, PP242 and NVP-BEZ235 reduced the growth of xenografts generated from LS174T and SW480 cells. Finally, we also observed that the efficacy of ATP-competitive inhibitors of mTOR was enhanced by U0126, a MEK inhibitor.
Taken together, these results show that ATP-competitive inhibitors of mTOR are effective in blocking colon cancer cell growth in vitro and in vivo and thus represent a therapeutic option in colon cancer either alone or in combination with MEK inhibitors.
由于磷脂酰肌醇 3-激酶 (PI3K) 途径的突变，哺乳动物雷帕霉素靶蛋白 (mTOR) 在结肠癌中经常被激活。用雷帕霉素等 mTOR 的变构抑制剂靶向 mTOR 可减少几种实验模型中的结肠癌进展。最近，开发了一类新的 mTOR 抑制剂，它们作为 mTOR 的 ATP 竞争性抑制剂。然而，这些药物在结肠癌细胞中的有效性尚未得到充分表征。
用 ATP 竞争性 mTOR 抑制剂 PP242、双重 PI3K/mTOR 抑制剂 NVP-BEZ235 或雷帕霉素处理 LS174T、SW480 和 DLD-1 结肠癌细胞系。通过 MTS 测定、5-溴-2'-脱氧尿苷 (BrDU) 掺入或定量 DNA 片段化分别评估肿瘤细胞生长、增殖和存活。在体内，用携带结肠癌异种移植物的裸鼠评估 mTOR 抑制剂的抗癌活性。
PP242 和 NVP-BEZ235 比雷帕霉素更有效地减少 LS174T 和 DLD-1 结肠癌细胞的生长、增殖和存活。同样，PP242 和 NVP-BEZ235 还显著降低了对雷帕霉素作用有抗性的 SW480 细胞的增殖和存活。在体内，PP242 和 NVP-BEZ235 减少了来自 LS174T 和 SW480 细胞的异种移植物的生长。最后，我们还观察到 mTOR 的 ATP 竞争性抑制剂的功效通过 MEK 抑制剂 U0126 增强。
总之，这些结果表明，ATP 竞争性 mTOR 抑制剂在体外和体内有效阻断结肠癌细胞生长，因此无论是单独使用还是与 MEK 抑制剂联合使用，都是结肠癌的治疗选择。
