title: Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Respiratory Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Zhang
authors.forename: Yue
authors.initials: Y
authors.lastname: Hong
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases