title: Perifosine and ABT-737 synergistically inhibit lung cancer cells in vitro and in vivo.
abstract: Here we explored the potential synergism between the novel Bcl-2 antagonist ABT-737 and the AKT inhibitor perifosine in lung cancer cells. Our in vitro results showed that perifosine and ABT-737 synergistically induced growth inhibition and apoptosis in both established (A549 and H460 lines) and patient-derived lung cancer cells. The combined activity was dramatically more potent than either single agent. For the molecular study, we showed that perifosine downregulated Mcl-1 expression, thus potentiating ABT-737 lethality against lung cancer cells. Exogenous over-expression of Mcl-1 remarkably attenuated perifosine plus ABT-737 combo-induced lung cancer cell apoptosis. In vivo, perifosine and ABT-737 co-administration strikingly inhibited A549 lung cancer xenograft growth in nude mice. The combined treatment in vivo was again superior than single treatment establishing a synergistic activity. Mcl-1 expression was also downregulated in combo-treated A549 tumors. The results of this preclinical study support the feasibility of further investigation of the perifosine plus ABT-737 regimen in future lung cancer clinical tests.
authors.affiliation: Department of Thoracic Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Respiratory Diseases, Shaoxing Municipal Hospital, Shaoxing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Thoracic Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China. Electronic address: caiwenjieyeah@yeah.net.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009596:Nitrophenols / Q000008:administration & dosage* / Q000494:pharmacology; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D010767:Phosphorylcholine; C105905:perifosine
keywords: ABT-737; Lung cancer; Mcl-1; Perifosine; Synergism