Crizotinib may be used in Lewis lung carcinoma: a novel use for crizotinib

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.