Zhang Jianli, Hong Yue, Shen Jie
Department of Respiratory Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Tumour Biol. 2015 Jul;36(7):5699-706. doi: 10.1007/s13277-015-3244-2. Epub 2015 Feb 20.
Lung cancer is a global health problem. The search for new therapeutic approaches for the treatment of lung cancer is important. Here, we reported that the AKT inhibitor perifosine and the MEK\ERK inhibitor MEK-162 synergistically induced lung cancer cell (A549 and H460 lines) growth inhibition and apoptosis. The combined efficiency was significantly higher than either agent alone. For the molecular study, perifosine and MEK-162 worked together to concurrently block AKT, mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and MEK-ERK signalings in lung cancer cells, while either agent alone only affected one or two signalings with lower efficiency. In vivo, MEK-162 and perifosine co-administration dramatically inhibited A549 lung cancer xenograft growth, without inducing apparent toxicities. The synergistic activity in vivo was again superior than either agent alone. Thus, perifosine and MEK-162 combination is biologically plausible by acting through effects on different proliferation and survival-related signaling pathways. Our in vitro and in vivo results support the feasibility of investigating the synergism regimen in clinical tests.
肺癌是一个全球性的健康问题。寻找治疗肺癌的新方法很重要。在此，我们报告AKT抑制剂哌立福新和MEK\ERK抑制剂MEK-162协同诱导肺癌细胞（A549和H460细胞系）生长抑制和凋亡。联合用药的效果明显高于单独使用任一药物。在分子研究中，哌立福新和MEK-162共同作用，同时阻断肺癌细胞中的AKT、雷帕霉素哺乳动物靶蛋白（mTOR）复合物1（mTORC1）和MEK-ERK信号通路，而单独使用任一药物仅以较低效率影响一或两个信号通路。在体内，MEK-162和哌立福新联合给药显著抑制A549肺癌异种移植瘤的生长，且未诱导明显毒性。体内的协同活性同样优于单独使用任一药物。因此，哌立福新和MEK-162联合用药通过作用于不同的增殖和生存相关信号通路在生物学上是合理的。我们的体外和体内研究结果支持在临床试验中研究协同治疗方案的可行性。
