The anthelmintic agent oxfendazole inhibits cell growth in non‑small cell lung cancer by suppressing c‑Src activation

Xu,Dafu; Tian,Wenze; Jiang,Chao; Huang,Ziming; Zheng,Shiying

doi:10.3892/mmr.2019.9897

The anthelmintic agent oxfendazole inhibits cell growth in non‑small cell lung cancer by suppressing c‑Src activation

Authors:
- Dafu Xu
- Wenze Tian
- Chao Jiang
- Ziming Huang
- Shiying Zheng
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Affiliations: Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Department of Thoracic Surgery, Huai'an First People's Hospital, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China, Department of Oncology, Huai'an First People's Hospital, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China, Department of Emergency Surgery, Huai'an First People's Hospital, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
Published online on: January 28, 2019 https://doi.org/10.3892/mmr.2019.9897
Pages: 2921-2926

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Abstract

The c‑Src protein family of tyrosine kinases are important in the tumorigenesis of many types of tumors, and may be a potential target for antitumor drug discovery. In the present study, immunoblotting was performed to analyze protein expression, CCK‑8 assay was carried out to assess cell viability and cell cycle was analyzed using a flow cytometer. The anthelmintic agent oxfendazole was observed to be a novel c‑Src inhibitor that blocked the activation of c‑Src. Oxfendazole also suppressed the cell growth of non‑small cell lung cancer (NSCLC) cells, and overexpression of c‑Src decreased the cytotoxicity of oxfendazole against NSCLC cells. In addition, oxfendazole induced cell cycle arrest at the G0/G1 phase, and downregulated the protein levels of Cyclin‑dependent kinase (CDK)‑4, CDK6, retinoblastoma protein and E2 transcription factor 1, and upregulated the expression levels of p53 and p21 in NSCLC cells. Furthermore, oxfendazole enhanced the cytotoxicity of cisplatin against NSCLC cells. These results demonstrated that oxfendazole exerted its antitumor activity by suppressing c‑Src signaling, and it was also indicated that the anthelmintic agent oxfendazole may be effective for anti‑NSCLC therapy in the clinic as a single agent or in combination with other antitumor drugs.

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1	Ling C, Chen G, Chen G, Zhang Z, Cao B, Han K, Yin J, Chu A, Zhao Y and Mao X: A Deuterated analog of dasatinib disrupts cell cycle progression and displays anti-non-small cell lung cancer activity in vitro and in vivo. Int J Cancer. 131:2411–2419. 2012. View Article : Google Scholar : PubMed/NCBI
2	Pasquini G and Giaccone G: C-MET inhibitors for advanced non-small cell lung cancer. Expert Opin Investig Drugs. 27:363–375. 2018. View Article : Google Scholar : PubMed/NCBI
3	Mazzarella L, Guida A and Curigliano G: Cetuximab for treating non-small cell lung cancer. Expert Opin Biol Ther. 18:483–493. 2018. View Article : Google Scholar : PubMed/NCBI
4	Sun YW, Xu J, Zhou J and Liu WJ: Targeted drugs for systemic therapy of lung cancer with brain metastases. Oncotarget. 9:5459–5472. 2018. View Article : Google Scholar : PubMed/NCBI
5	Thomas SM and Brugge JS: Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 13:513–609. 1997. View Article : Google Scholar : PubMed/NCBI
6	Koppikar P, Choi SH, Egloff AM, Cai Q, Suzuki S, Freilino M, Nozawa H, Thomas SM, Gooding WE, Siegfried JM and Grandis JR: Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma. Clin Cancer Res. 14:4284–4291. 2008. View Article : Google Scholar : PubMed/NCBI
7	Nan Y, Du J, Ma L, Jiang H, Jin F and Yang S: Early Candidate biomarkers of non-small cell lung cancer are screened and identified in premalignant lung lesions. Technol Cancer Res Treat. 16:66–74. 2017. View Article : Google Scholar : PubMed/NCBI
8	Zhang J, Kalyankrishna S, Wislez M, Thilaganathan N, Saigal B, Wei W, Ma L, Wistuba II, Johnson FM and Kurie JM: SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. Am J Pathol. 170:366–376. 2007. View Article : Google Scholar : PubMed/NCBI
9	Johnson FM, Saigal B, Talpaz M and Donato NJ: Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 11:6924–6932. 2005. View Article : Google Scholar : PubMed/NCBI
10	Ceppi P, Papotti M, Monica V, Lo Iacono M, Saviozzi S, Pautasso M, Novello S, Mussino S, Bracco E, Volante M and Scagliotti GV: Effects of Src kinase inhibition induced by dasatinib in non-small cell lung cancer cell lines treated with cisplatin. Mol Cancer Ther. 8:3066–3074. 2009. View Article : Google Scholar : PubMed/NCBI
11	Kiefer PE, Wegmann B, Bacher M, Erbil C, Heidtmann H and Havemann K: Different pattern of expression of cellular oncogenes in human non-small-cell lung cancer cell lines. J Cancer Res Clin Oncol. 116:29–37. 1990. View Article : Google Scholar : PubMed/NCBI
12	Xu X, Han K, Zhu J, Mao H, Lin X, Zhang Z, Cao B, Zeng Y and Mao X: An inhibitor of cholesterol absorption displays anti-myeloma activity by targeting the JAK2-STAT3 signaling pathway. Oncotarget. 7:75539–75550. 2016. View Article : Google Scholar : PubMed/NCBI
13	Han K, Xu X, Chen G, Zeng Y, Zhu J, Du X, Zhang Z, Cao B, Liu Z and Mao X: Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization. J Hematol Oncol. 7:92014. View Article : Google Scholar : PubMed/NCBI
14	Xu X, Wang J, Han K, Li S, Xu F and Yang Y: Antimalarial drug mefloquine inhibits nuclear factor kappa B signaling and induces apoptosis in colorectal cancer cells. Cancer Sci. 109:1220–1229. 2018. View Article : Google Scholar : PubMed/NCBI
15	Xu X, Han K, Tang X, Zeng Y, Lin X, Zhao Y, Zhang Z, Cao B, Wu D and Mao X: The ring finger protein RNF6 induces leukemia cell proliferation as a direct target of pre-B-cell leukemia homeobox 1. J Biol Chem. 291:9617–9628. 2016. View Article : Google Scholar : PubMed/NCBI
16	Chen G, Xu X, Tong J, Han K, Zhang Z, Tang J, Li S, Yang C, Li J, Cao B, et al: Ubiquitination of the transcription factor c-MAF is mediated by multiple lysine residues. Int J Biochem Cell Biol. 57:157–166. 2014. View Article : Google Scholar : PubMed/NCBI
17	Xu X, Zhang J, Han K, Zhang Z, Chen G, Zhang J, Mao X and Cao B: Natural pesticide dihydrorotenone arrests human plasma cancer cells at the G0/G1 phase of the cell cycle. J Biochem Mol Toxicol. 28:232–238. 2014. View Article : Google Scholar : PubMed/NCBI
18	Kohlmaier A, Fassnacht C, Jin Y, Reuter H, Begum J, Dutta D and Edgar BA: Src kinase function controls progenitor cell pools during regeneration and tumor onset in the Drosophila intestine. Oncogene. 34:2371–2384. 2015. View Article : Google Scholar : PubMed/NCBI
19	Chan CM, Jing X, Pike LA, Zhou Q, Lim DJ, Sams SB, Lund GS, Sharma V, Haugen BR and Schweppe RE: Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis. Clin Cancer Res. 18:3580–3591. 2012. View Article : Google Scholar : PubMed/NCBI
20	Alinari L, Prince CJ, Edwards RB, Towns WH, Mani R, Lehman A, Zhang X, Jarjoura D, Pan L, Kinghorn AD, et al: Dual targeting of the Cyclin/Rb/E2F and mitochondrial pathways in mantle cell lymphoma with the translation inhibitor silvestrol. Clin Cancer Res. 18:4600–4611. 2012. View Article : Google Scholar : PubMed/NCBI
21	O'Connor PM, Jackman J, Jondle D, Bhatia K, Magrath I and Kohn KW: Role of the p53 tumor suppressor gene in cell cycle arrest and radiosensitivity of Burkitt's lymphoma cell lines. Cancer Res. 53:4776–4780. 1993.PubMed/NCBI
22	Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW and Elledge SJ: p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 9:650–662. 1995. View Article : Google Scholar : PubMed/NCBI
23	Sarin N, Engel F, Kalayda GV, Mannewitz M, Cinatl J Jr, Rothweiler F, Michaelis M, Saafan H, Ritter CA, Jaehde U and Frötschl R: Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PLoS One. 12:e01810812017. View Article : Google Scholar : PubMed/NCBI
24	Qin X, Qiu F and Zou Z: TRIM25 is associated with cisplatin resistance in non-small-cell lung carcinoma A549 cell line via downregulation of 14-3-3sigma. Biochem Biophys Res Commun. 493:568–572. 2017. View Article : Google Scholar : PubMed/NCBI
25	Feng X, Liu H, Zhang Z, Gu Y, Qiu H and He Z: Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells. J Exp Clin Cancer Res. 36:1232017. View Article : Google Scholar : PubMed/NCBI
26	Ochi N, Takigawa N, Harada D, Yasugi M, Ichihara E, Hotta K, Tabata M, Tanimoto M and Kiura K: Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. Exp Cell Res. 322:168–177. 2014. View Article : Google Scholar : PubMed/NCBI
27	Remon J, Vilariño N and Reguart N: Immune checkpoint inhibitors in non-small cell lung cancer (NSCLC): Approaches on special subgroups and unresolved burning questions. Cancer Treat Rev. 64:21–29. 2018. View Article : Google Scholar : PubMed/NCBI
28	Janning M and Loges S: Anti-angiogenics: Their value in lung cancer therapy. Oncol Res Treat. 41:172–180. 2018. View Article : Google Scholar : PubMed/NCBI
29	Han B, Yang L, Wang X and Yao L: Efficacy of pemetrexed-based regimens in advanced non-small cell lung cancer patients with activating epidermal growth factor receptor mutations after tyrosine kinase inhibitor failure: a systematic review. Onco Targets Ther. 11:2121–2129. 2018. View Article : Google Scholar : PubMed/NCBI
30	Rho O, Kim DJ, Kiguchi K and Digiovanni J: Growth factor signaling pathways as targets for prevention of epithelial carcinogenesis. Mol Carcinog. 50:264–279. 2011. View Article : Google Scholar : PubMed/NCBI
31	Elsberger B1, Stewart B, Tatarov O and Edwards J: Is Src a viable target for treating solid tumours? Curr Cancer Drug Targets. 10:683–694. 2010. View Article : Google Scholar : PubMed/NCBI
32	Gu Z, Fang X, Li C, Chen C, Liang G, Zheng X and Fan Q: Increased PTPRA expression leads to poor prognosis through c-Src activation and G1 phase progression in squamous cell lung cancer. Int J Oncol. 51:489–497. 2017. View Article : Google Scholar : PubMed/NCBI