Crizotinib may be used in lewis lung carcinoma: A novel use for crizotinib

Xia,Pu; Gou,Wen-Feng; Zhao,Shuang; Zheng,Hua-Chuan

doi:10.3892/or.2013.2424

Crizotinib may be used in lewis lung carcinoma: A novel use for crizotinib

Authors:
- Pu Xia
- Wen-Feng Gou
- Shuang Zhao
- Hua-Chuan Zheng
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Affiliations: 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
Published online on: April 24, 2013 https://doi.org/10.3892/or.2013.2424
Pages: 139-148

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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.

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1	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 6:69–90. 2011. View Article : Google Scholar
2	Christensen JG, Zou HY, Arango ME, et al: Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 6:3314–3322. 2007. View Article : Google Scholar : PubMed/NCBI
3	Zou HY, Li Q, Lee JH, et al: An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 67:4408–4417. 2007. View Article : Google Scholar
4	Timofeevski SL, McTigue MA, Ryan K, et al: Enzymatic characterization of c-Met receptor tyrosine kinase oncogenic mutants and kinetic studies with aminopyridine and triazolopyrazine inhibitors. Biochemistry. 48:5339–5349. 2009. View Article : Google Scholar
5	Li Y, Ye X, Liu J, et al: Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia. 13:1–11. 2011.PubMed/NCBI
6	Ou SH, Bazhenova L, Camidge DR, et al: Rapid and dramatic radiographic and clinical response to an ALK inhibitor (crizotinib, PF02341066) in an ALK translocation-positive patient with non-small cell lung cancer. J Thorac Oncol. 5:2044–2046. 2010. View Article : Google Scholar : PubMed/NCBI
7	Crinò L, Kim D, Riely GJ, et al: Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol. 29:75142011.
8	Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 363:1693–1703. 2010. View Article : Google Scholar : PubMed/NCBI
9	Klonisch T, Wiechec E, Hombach-Klonisch S, et al: Cancer stem cell markers in common cancers - therapeutic implications. Trends Mol Med. 14:450–460. 2008. View Article : Google Scholar : PubMed/NCBI
10	Dingli D and Michor F: Successful therapy must eradicate cancer stem cells. Stem Cells. 24:2603–2610. 2006. View Article : Google Scholar : PubMed/NCBI
11	Kondo T, Setoguchi T and Taga T: Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA. 101:781–786. 2004. View Article : Google Scholar : PubMed/NCBI
12	Wu C, Wei Q, Utomo V, et al: Side population cells isolated from mesenchymal neoplasms have tumor initiating potential. Cancer Res. 67:8216–8222. 2007. View Article : Google Scholar : PubMed/NCBI
13	Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al: Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA. 103:11154–11159. 2006. View Article : Google Scholar : PubMed/NCBI
14	Krysko DV, Vanden Berghe T, D’Herde K, et al: Apoptosis and necrosis: detection, discrimination and phagocytosis. Methods. 44:205–221. 2008. View Article : Google Scholar : PubMed/NCBI
15	Alessandri G, Filippeschi S, Sinibaldi P, et al: Influence of gangliosides on primary and metastatic neoplastic growth in human and murine cells. Cancer Res. 47:4243–4247. 1987.PubMed/NCBI
16	Ivković-Kapicl T, Knelević-Usaj S, Panjković M, et al: Immunohistochemical analysis of angiogenesis in invasive ductal breast carcinoma with correlations to clinicopathological factor. Vojnosanit Pregl. 63:635–642. 2006.(In Serbian).
17	Qin BY, Lam SS, Correia JJ, et al: Smad3 allostery links TGF-β receptor kinase activation to transcriptional control. Genes Dev. 16:1950–1963. 2002.PubMed/NCBI
18	Martínez T and Pascual A: Gene expression profile in β-amyloid-treated SH-SY5Y neuroblastoma cells. Brain Res Bull. 72:225–231. 2007.
19	Zillhardt M, Christensen JG and Lengyel E: An orally available small-molecule inhibitor of c-Met, PF-2341066, reduces tumor burden and metastasis in a preclinical model of ovarian cancer metastasis. Neoplasia. 12:1–10. 2010.
20	Tumati V, Kumar S, Yu L, et al: Effect of PF-02341066 and radiation on non-small cell lung cancer cells. Oncol Rep. 29:1094–1100. 2012.PubMed/NCBI
21	Hirschmann-Jax C, Foster AE, Wulf GG, et al: A distinct ‘side population’ of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 101:14228–14233. 2004.
22	Bronte G, Rizzo S, La Paglia L, et al: Driver mutations and differential sensitivity to targeted therapies: a new approach to the treatment of lung adenocarcinoma. Cancer Treat Rev. 36(Suppl 3): S21–S29. 2010. View Article : Google Scholar : PubMed/NCBI
23	Garber K: ALK, lung cancer, and personalized therapy: portent of the future? J Natl Cancer Inst. 102:672–675. 2010. View Article : Google Scholar : PubMed/NCBI
24	Janku F, Stewart DJ and Kurzrock R: Targeted therapy in non-small-cell lung cancer - is it becoming a reality? Nat Rev Clin Oncol. 7:401–414. 2010. View Article : Google Scholar : PubMed/NCBI
25	Challen GA and Little MH: A side order of stem cells: the SP phenotype. Stem Cells. 24:3–12. 2006. View Article : Google Scholar : PubMed/NCBI
26	Hadnagy A, Gaboury L, Beaulieu R, et al: SP analysis may be used to identify cancer stem cell populations. Exp Cell Res. 312:3701–3710. 2006. View Article : Google Scholar : PubMed/NCBI
27	Shaw AT, Yeap BY, Mino-Kenudson M, et al: Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 27:4247–4253. 2009. View Article : Google Scholar : PubMed/NCBI
28	Xia P, Mou FF and Wang LW: Predictive role of computer simulation in assessing signaling pathways of crizotinib-treated A549 lung cancer cells. Asian Pac J Cancer Prev. 13:3119–3121. 2012. View Article : Google Scholar : PubMed/NCBI
29	Jacob D, Davis J, Zhu H, et al: Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter. Clin Cancer Res. 10:3535–3541. 2004. View Article : Google Scholar
30	Zhu H, Zhang L, Huang X, et al: Overcoming acquired resistance to TRAIL by chemotherapeutic agents and calpain inhibitor I through distinct mechanisms. Mol Ther. 9:666–673. 2004. View Article : Google Scholar : PubMed/NCBI
31	Grau AM, Zhang L, Wang W, et al: Induction of p21waf1 expression and growth inhibition by transforming growth factor β involve the tumor suppressor gene DPC4 in human pancreatic adenocarcinoma cells. Cancer Res. 57:3929–3934. 1997.
32	Guo Y and Kyprianou N: Overexpression of transforming growth factor (TGF) β1 type II receptor restores TGF-β1 sensitivity and signaling in human prostate cancer cells. Cell Growth Differ. 9:185–193. 1998.
33	Tang MR, Wang YX, Guo S, et al: CSMD1 exhibits antitumor activity in A375 melanoma cells through activation of the Smad pathway. Apoptosis. 17:927–937. 2012. View Article : Google Scholar : PubMed/NCBI