Matrine increases the inhibitory effects of afatinib on H1975 cells via the IL‑6/JAK1/STAT3 signaling pathway

Chen,Shui‑Fang; Zhang,Ze‑Ying; Zhang,Jian‑Li

doi:10.3892/mmr.2017.6865

Matrine increases the inhibitory effects of afatinib on H1975 cells via the IL‑6/JAK1/STAT3 signaling pathway

Authors:
- Shui‑Fang Chen
- Ze‑Ying Zhang
- Jian‑Li Zhang
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Affiliations: Respiratory Department, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: June 27, 2017 https://doi.org/10.3892/mmr.2017.6865
Pages: 2733-2739
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Resistance to epidermal growth factor receptor (EGFR) inhibitors is of primary concern in the treatment of non‑small‑cell lung cancer (NSCLC) with EGFR mutations. To investigate the effects of matrine on H1975 cells and to examine a novel, potential treatment option for NSCLC, the present study measured cell viability, apoptotic rate, interleukin 6 (IL‑6) expression and activation of the janus kinase (JAK) 1/signal transducer and activator of transcription (STAT)3 signaling pathway in cells treated with or without matrine, in the presence or absence of afatinib. The results demonstrated that matrine treatment inhibited cell growth, decreased B‑cell lymphoma 2 (Bcl‑2) expression and induced apoptosis. Matrine treatment additionally decreased the mRNA and protein levels of IL‑6 and inhibited activation of the JAK1/STAT3 signaling pathway in H1975 cells in a dose‑dependent manner. H1975 cells treated with IL‑6 small interfering RNA exhibited a decrease in Bcl‑2 expression levels and cell viability. Treatment with a combination of matrine and afatinib demonstrated increased inhibitory effects on the growth rate of H1975 cells. The findings of the present study suggested that matrine treatment decreases IL‑6 expression, inhibits activation of the JAK1/STAT3 signaling pathway, reduces the expression levels of Bcl‑2 and inhibits cell growth. Furthermore, matrine treatment was demonstrated to increase the inhibitory effects of afatinib on H1975 cells with the T790M EGFR mutation.

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1	Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Engl J Med. 359:1367–1380. 2008. View Article : Google Scholar : PubMed/NCBI
2	Spira A and Ettinger DS: Multidisciplinary management of lung cancer. N Engl J Med. 350:379–392. 2004. View Article : Google Scholar : PubMed/NCBI
3	Lanaya H, Natarajan A, Komposch K, Li L, Amberg N, Chen L, Wculek SK, Hammer M, Zenz R, Peck-Radosavljevic M, et al: EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol. 16:972–981. 2014. View Article : Google Scholar : PubMed/NCBI
4	Pao W and Chmielecki J: Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 10:760–774. 2010. View Article : Google Scholar : PubMed/NCBI
5	Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
6	Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, de Marinis F, Eberhardt WE, Paz-Ares L, Störkel S, et al: EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: Analysis of data from the phase 3 FLEX study. Lancet Oncol. 13:33–42. 2012. View Article : Google Scholar : PubMed/NCBI
7	Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, et al: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13:239–246. 2012. View Article : Google Scholar : PubMed/NCBI
8	Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG and Halmos B: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 352:786–792. 2005. View Article : Google Scholar : PubMed/NCBI
9	Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, Travis WD, Bornmann W, Veach D, Clarkson B and Bromberg JF: Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 117:3846–3856. 2007. View Article : Google Scholar : PubMed/NCBI
10	Kim SM, Kwon OJ, Hong YK, Kim JH, Solca F, Ha SJ, Soo RA, Christensen JG, Lee JH and Cho BC: Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol Cancer Ther. 11:2254–2264. 2012. View Article : Google Scholar : PubMed/NCBI
11	Li J, Lan T, Zhang C, Zeng C, Hou J, Yang Z, Zhang M, Liu J and Liu B: Reciprocal activation between IL-6/STAT3 and NOX4/Akt signaling promotes proliferation and survival of non-small cell lung cancer cells. Oncotarget. 6:1031–1048. 2015. View Article : Google Scholar : PubMed/NCBI
12	Abulaiti A, Shintani Y, Funaki S, Nakagiri T, Inoue M, Sawabata N, Minami M and Okumura M: Interaction between non-small-cell lung cancer cells and fibroblasts via enhancement of TGF-β1 signaling by IL-6. Lung Cancer. 82:204–213. 2013. View Article : Google Scholar : PubMed/NCBI
13	Chen J, Lan T, Zhang W, Dong L, Kang N, Zhang S, Fu M, Liu B, Liu K and Zhan Q: Feed-forward reciprocal activation of PAFR and STAT3 regulates epithelial-mesenchymal transition in non-small cell lung cancer. Cancer Res. 75:4198–4210. 2015. View Article : Google Scholar : PubMed/NCBI
14	Zhang FQ, Yang WT, Duan SZ, Xia YC, Zhu RY and Chen YB: JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor. Oncotarget. 6:14329–14343. 2015. View Article : Google Scholar : PubMed/NCBI
15	Liu Y, Xu Y, Ji W, Li X, Sun B, Gao Q and Su C: Anti-tumor activities of matrine and oxymatrine: Literature review. Tumour Biol. 35:5111–5119. 2014. View Article : Google Scholar : PubMed/NCBI
16	Zhang LP, Jiang JK, Tam JW, Zhang Y, Liu XS, Xu XR, Liu BZ and He YJ: Effects of matrine on proliferation and differentiation in K-562 cells. Leuk Res. 25:793–800. 2001. View Article : Google Scholar : PubMed/NCBI
17	Lu X, Zhu Z, Jiang L, Sun X, Jia Z, Qian S, Li J and Ma L: Matrine increases NKG2D ligand ULBP2 in K562 cells via inhibiting JAK/STAT3 pathway: A potential mechanism underlying the immunotherapy of matrine in leukemia. Am J Transl Res. 7:1838–1849. 2015.PubMed/NCBI
18	Lin W, Zhang JP, Hu ZL and Qian DH: Inhibitory effect of matrine on lipopolysacchride-induced tumor necrosis factor and interleukin-6 production from rat Kupffer cells. Yao Xue Xue Bao. 32:93–96. 1997.(In Chinese). PubMed/NCBI
19	Zhang Y, Wang S, Li Y, Xiao Z, Hu Z and Zhang J: Sophocarpine and matrine inhibit the production of TNF-alpha and IL-6 in murine macrophages and prevent cachexia-related symptoms induced by colon26 adenocarcinoma in mice. Int Immunopharmacol. 8:1767–1772. 2008. View Article : Google Scholar : PubMed/NCBI
20	Liu X, Ye F, Xiong H, Hu DN, Limb GA, Xie T, Peng L, Zhang P, Wei Y, Zhang W, et al: IL-1β induces IL-6 production in retinal Müller cells predominantly through the activation of P38 MAPK/NF-κB signaling pathway. Exp Cell Res. 331:223–231. 2015. View Article : Google Scholar : PubMed/NCBI
21	Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, et al: Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 21:560–562. 2015. View Article : Google Scholar : PubMed/NCBI
22	Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, Xu C, Rhee K, Chen T, Zhang H, et al: Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 534:129–132. 2016. View Article : Google Scholar : PubMed/NCBI
23	Nan J, Du Y, Chen X, Bai Q, Wang Y, Zhang X, Zhu N, Zhang J, Hou J, Wang Q and Yang J: TPCA-1 is a direct dual inhibitor of STAT3 and NF-κB and regresses mutant EGFR-associated human non-small cell lung cancers. Mol Cancer Ther. 13:617–629. 2014. View Article : Google Scholar : PubMed/NCBI
24	Ma L, Zhu Z, Jiang L, Sun X, Lu X, Zhou M, Qian S and Jianyong L: Matrine suppresses cell growth of human chronic myeloid leukemia cells via its inhibition of the interleukin-6/Janus activated kinase/signal transducer and activator of transcription 3 signaling cohort. Leuk Lymphoma. 56:2923–2930. 2015. View Article : Google Scholar : PubMed/NCBI