title: Crizotinib may be used in Lewis lung carcinoma: a novel use for crizotinib.
abstract: Lung cancer accounts for 13% (1.6 million) of the total cases and 18% (1.4 million) of the deaths in 2008. Crizotinib (PF-02341066) is identified as an ATP competitive small-molecular inhibitor for anaplastic lymphoma kinase (ALK). The US Food and Drug Administration (FDA) approved crizotinib to be used for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC in 2011. In the present study, the side population (SP) and main population (MP) cells were obtained from Lewis lung carcinoma cells (LLC) and analyzed by DNA dye (Hoechst 33342) and flow cytometry. LLC SP and MP cells were confirmed as no ALK fusion gene by fluorescence in situ hybridization. The effects of crizotinib on LLC SP and MP cells both in vivo and in vitro were identified. Our results indicate that crizotinib can induce apoptosis and G1 phase arrest in LLC MP cells. Crizotinib used in combination with verapamil can inhibit proliferation of LLC SP cells. Moreover, crizotinib decreased tumor size and weight and inhibited angiogenesis in established xenografted tumors. To analyze the signaling pathway involved, computer simulation, Affymetrix microarray analysis and western blot analysis were performed. In these assays, crizotinib was found to dock into Smad3 and activate the Smad signaling pathway. Overall, these studies demonstrate the antitumor activity of crizotinib in LLC cell line, and provide a novel use for crizotinib.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Pathology and Pathophysiology, School of Basic Medical Science, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Gou
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.forename: Hua-Chuan
authors.initials: HC
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000187:drug effects / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D014700:Verapamil / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D002121:Calcium Channel Blockers; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D000077547:Crizotinib; D014700:Verapamil