Matrine induces the apoptosis of lung cancer cells through downregulation of inhibitor of apoptosis proteins and the Akt signaling pathway

Niu,Huiyan; Zhang,Yifei; Wu,Baogang; Zhang,Yi; Jiang,Hongfang; He,Ping

doi:10.3892/or.2014.3273

Matrine induces the apoptosis of lung cancer cells through downregulation of inhibitor of apoptosis proteins and the Akt signaling pathway

Authors:
- Huiyan Niu
- Yifei Zhang
- Baogang Wu
- Yi Zhang
- Hongfang Jiang
- Ping He
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Affiliations: Department of Geriatrics, Shengjing Hospital, China Medical University, Shenyang 110004, P.R. China
Published online on: June 20, 2014 https://doi.org/10.3892/or.2014.3273
Pages: 1087-1093

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Abstract

Lung cancer is the leading cause of cancer‑related mortality in humans. The prognosis for advanced lung cancer patients is extremely poor. Current standard care is rather ineffective for prolonging patient life while preserving satisfactory quality of life due to adverse side-effects. Matrine extracted from the traditional Chinese herbal plant Sophora flavescens was shown to induce cancer cell death in vitro. The aim of this study was to investigate the effect of matrine on the proliferation and apoptosis of lung cancer cells and the molecular basis of matrine-induced apoptosis. The results showed that matrine inhibited cell proliferation and induced apoptosis in lung cancer A549 and 95D cells in a dose- and time-dependent manner. The apoptotic effects of matrine on lung cancer cells appeared to act via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway and downregulation of the expression of the inhibitor of apoptosis protein (IAP) family proteins. Matrine exerts its cancer-killing effect via promoting apoptosis in lung cancer cells and may be a useful adjuvant therapeutic scheme for treating advanced lung cancer patients.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Molina JR, Yang P, Cassivi SD, Schild SE and Adjei AA: Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 83:584–594. 2008. View Article : Google Scholar : PubMed/NCBI
3	Zhang Y, Zhang H, Yu P, et al: Effects of matrine against the growth of human lung cancer and hepatoma cells as well as lung cancer cell migration. Cytotechnology. 59:191–200. 2009. View Article : Google Scholar : PubMed/NCBI
4	Efferth T, Konkimalla VB, Wang YF, et al: Prediction of broad spectrum resistance of tumors towards anticancer drugs. Clin Cancer Res. 14:2405–2412. 2008. View Article : Google Scholar : PubMed/NCBI
5	Dong J, Su SY, Wang MY and Zhan Z: Shenqi fuzheng, an injection concocted from Chinese medicinal herbs, combined with platinum-based chemotherapy for advanced non-small cell lung cancer: a systematic review. J Exp Clin Cancer Res. 29:1372010. View Article : Google Scholar : PubMed/NCBI
6	Liu XS, Jiang J, Jiao XY, Wu YE and Lin JH: Matrine-induced apoptosis in leukemia U937 cells: involvement of caspases activation and MAPK-independent pathways. Planta Med. 72:501–506. 2006. View Article : Google Scholar : PubMed/NCBI
7	Zhang HM and Li HQ: Anti-arrhythmic effects of sophoridine and oxysophoridine. Zhongguo Yao Li Xue Bao. 20:517–520. 1999.
8	Ai J, Gao HH, He SZ, Wang L, Luo DL and Yang BF: Effects of matrine, artemisinin, tetrandrine on cytosolic [Ca²⁺]i in guinea pig ventricular myocytes. Acta Pharmacol Sin. 22:512–515. 2001.PubMed/NCBI
9	Xu CQ, Dong DL, Du ZM, Chen QW, Gong DM and Yang BF: Comparison of the anti-arrhythmic effects of matrine and berbamine with amiodarone and RP58866. Yao Xue Xue Bao. 39:691–694. 2004.(In Chinese).
10	Hu ZL, Zhang JP, Yu XB, Lin W, Qian DH and Wan MB: Effect of matrine on lipopolysaccharides/D-galactosamine-induced hepatitis and tumor necrosis factor release from macrophages in vitro. Zhongguo Yao Li Xue Bao. 17:351–353. 1996.(In Chinese).
11	Liu J, Zhu M, Shi R and Yang M: Radix Sophorae flavescentis for chronic hepatitis B: a systematic review of randomized trials. Am J Chin Med. 31:337–354. 2003. View Article : Google Scholar
12	Long Y, Lin XT, Zeng KL and Zhang L: Efficacy of intramuscular matrine in the treatment of chronic hepatitis B. Hepatobiliary Pancreat Dis Int. 3:69–72. 2004.PubMed/NCBI
13	Gao HY, Li GY, Lou MM, Li XY, Wei XY and Wang JH: Hepato-protective effect of matrine salvianolic acid B salt on carbon tetrachloride-induced hepatic fibrosis. J Inflamm. 9:162012. View Article : Google Scholar : PubMed/NCBI
14	Liu JY, Hu JH, Zhu QG, Li FQ, Wang J and Sun HJ: Effect of matrine on the expression of substance P receptor and inflammatory cytokines production in human skin keratinocytes and fibroblasts. Int Immunopharmacol. 7:816–823. 2007. View Article : Google Scholar : PubMed/NCBI
15	Li H, Tan G, Jiang X, et al: Therapeutic effects of matrine on primary and metastatic breast cancer. Am J Chin Med. 38:1115–1130. 2010. View Article : Google Scholar : PubMed/NCBI
16	Li LQ, Li XL, Wang L, et al: Matrine inhibits breast cancer growth via miR-21/PTEN/Akt pathway in MCF-7 cells. Cell Physiol Biochem. 30:631–641. 2012. View Article : Google Scholar : PubMed/NCBI
17	Liu T, Song Y, Chen H, Pan S and Sun X: Matrine inhibits proliferation and induces apoptosis of pancreatic cancer cells in vitro and in vivo. Biol Pharm Bull. 33:1740–1745. 2010. View Article : Google Scholar : PubMed/NCBI
18	Luo C, Zhong HJ, Zhu LM, et al: Inhibition of matrine against gastric cancer cell line MNK45 growth and its anti-tumor mechanism. Mol Biol Rep. 39:5459–5464. 2012. View Article : Google Scholar : PubMed/NCBI
19	Yang CL, Liu SS, Ma YG, Liu YY, Xue YX and Huang B: The influence of intraoperative pleural perfusion with matrine-cisplatin or cisplatin on stromal cell-derived factor-1 in non-small cell lung cancer patients with subclinical pleural metastasis. Med Oncol. 29:574–581. 2012. View Article : Google Scholar : PubMed/NCBI
20	Zhang J, Li Y, Chen X, et al: Autophagy is involved in anticancer effects of matrine on SGC-7901 human gastric cancer cells. Oncol Rep. 26:115–124. 2011.PubMed/NCBI
21	Chui CH, Lau FY, Tang JC, et al: Activities of fresh juice of Scutellaria barbata and warmed water extract of Radix Sophorae Tonkinensis on anti-proliferation and apoptosis of human cancer cell lines. Int J Mol Med. 16:337–341. 2005.PubMed/NCBI
22	Hu MJ, Zeng H, Wu YL, et al: Synergistic effects of matrine and 5-fluorouracil on tumor growth of the implanted gastric cancer in nude mice. Chin J Dig Dis. 6:68–71. 2005. View Article : Google Scholar : PubMed/NCBI
23	Luo C, Zhu Y, Jiang T, et al: Matrine induced gastric cancer MKN45 cells apoptosis via increasing pro-apoptotic molecules of Bcl-2 family. Toxicology. 229:245–252. 2007. View Article : Google Scholar : PubMed/NCBI
24	Ma L, Wen S, Zhan Y, He Y, Liu X and Jiang J: Anticancer effects of the Chinese medicine matrine on murine hepatocellular carcinoma cells. Planta Med. 74:245–251. 2008. View Article : Google Scholar : PubMed/NCBI
25	Yu P, Liu Q, Liu K, Yagasaki K, Wu E and Zhang G: Matrine suppresses breast cancer cell proliferation and invasion via VEGF-Akt-NF-kappaB signaling. Cytotechnology. 59:219–229. 2009. View Article : Google Scholar : PubMed/NCBI
26	Dai ZJ, Gao J, Ji ZZ, et al: Matrine induces apoptosis in gastric carcinoma cells via alteration of Fas/FasL and activation of caspase-3. J Ethnopharmacol. 123:91–96. 2009. View Article : Google Scholar : PubMed/NCBI
27	Zhang S, Zhang Y, Zhuang Y, et al: Matrine induces apoptosis in human acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation. PLoS One. 7:e468532012. View Article : Google Scholar : PubMed/NCBI
28	Liang CZ, Zhang JK, Shi Z, Liu B, Shen CQ and Tao HM: Matrine induces caspase-dependent apoptosis in human osteosarcoma cells in vitro and in vivo through the upregulation of Bax and Fas/FasL and downregulation of Bcl-2. Cancer Chemother Pharmacol. 69:317–331. 2012. View Article : Google Scholar : PubMed/NCBI
29	Jiang H, Hou C, Zhang S, et al: Matrine upregulates the cell cycle protein E2F-1 and triggers apoptosis via the mitochondrial pathway in K562 cells. Eur J Pharmacol. 559:98–108. 2007. View Article : Google Scholar : PubMed/NCBI
30	Niu H, Li H, Xu C and He P: Expression profile of RhoGDI2 in lung cancers and role of RhoGDI2 in lung cancer metastasis. Oncol Rep. 24:465–471. 2010.PubMed/NCBI
31	Niu H, Wang J, Li H and He P: Rapamycin potentiates cytotoxicity by docetaxel possibly through downregulation of survivin in lung cancer cells. J Exp Clin Cancer Res. 30:282011. View Article : Google Scholar : PubMed/NCBI
32	Lu J, Luo Q, Cheng P, Liu X, Bai M and Tu M: The role of matrine and mitogen-ativated protein kinase/extracellular signal-regulated kinase signal transduction in the inhibition of the proliferation and migration of human umbilical veins endothelial cells induced by lung cancer cells. Zhongguo Fei Ai Za Zhi. 12:747–752. 2009.(In Chinese).
33	Chen Q, Liu L and Cao H: Effects of matrine on the growth inhibition, c-myc and hTERT protein expression in human adenocarcinoma lung cancer cell line A549. Zhongguo Fei Ai Za Zhi. 11:559–562. 2008.(In Chinese).
34	Nicholson KM and Anderson NG: The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 14:381–395. 2002. View Article : Google Scholar : PubMed/NCBI
35	Deveraux QL and Reed JC: IAP family proteins - suppressors of apoptosis. Genes Dev. 13:239–252. 1999. View Article : Google Scholar : PubMed/NCBI
36	Hu S and Yang X: Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO. J Biol Chem. 278:10055–10060. 2003. View Article : Google Scholar : PubMed/NCBI
37	Altieri DC: The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol Med. 7:542–547. 2001. View Article : Google Scholar : PubMed/NCBI
38	Marioni G, Bertolin A, Giacomelli L, et al: Expression of the apoptosis inhibitor protein survivin in primary laryngeal carcinoma and cervical lymph node metastasis. Anticancer Res. 26:3813–3817. 2006.PubMed/NCBI
39	Osaka E, Suzuki T, Osaka S, et al: Survivin as a prognostic factor for osteosarcoma patients. Acta Histochem Cytochem. 39:95–100. 2006. View Article : Google Scholar : PubMed/NCBI
40	Tran J, Rak J, Sheehan C, et al: Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Commun. 264:781–788. 1999. View Article : Google Scholar : PubMed/NCBI
41	Harfouche R, Hassessian HM, Guo Y, et al: Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. Microvasc Res. 64:135–147. 2002. View Article : Google Scholar : PubMed/NCBI
42	Als AB, Dyrskjot L, von der Maase H, et al: Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer. Clin Cancer Res. 13:4407–4414. 2007. View Article : Google Scholar : PubMed/NCBI
43	Hinnis AR, Luckett JC and Walker RA: Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients. Br J Cancer. 96:639–645. 2007. View Article : Google Scholar : PubMed/NCBI
44	Nakagawa Y, Abe S, Kurata M, et al: IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes. Am J Hematol. 81:824–831. 2006. View Article : Google Scholar
45	Watanuki-Miyauchi R, Kojima Y, Tsurumi H, et al: Expression of survivin and of antigen detected by a novel monoclonal antibody, T332, is associated with outcome of diffuse large B-cell lymphoma and its subtypes. Pathol Int. 55:324–330. 2005. View Article : Google Scholar
46	Schlette EJ, Medeiros LJ, Goy A, Lai R and Rassidakis GZ: Survivin expression predicts poorer prognosis in anaplastic large-cell lymphoma. J Clin Oncol. 22:1682–1688. 2004. View Article : Google Scholar : PubMed/NCBI
47	Adida C, Haioun C, Gaulard P, et al: Prognostic significance of survivin expression in diffuse large B-cell lymphomas. Blood. 96:1921–1925. 2000.PubMed/NCBI
48	Altieri DC: Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer. 8:61–70. 2008. View Article : Google Scholar : PubMed/NCBI
49	Wang Y, Zhang Z, Garbow JR, et al: Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs. Cancer Prev Res. 2:634–640. 2009. View Article : Google Scholar : PubMed/NCBI
50	Liu Y, Xu Y, Ji W, et al: Anti-tumor activities of matrine and oxymatrine: literature review. Tumour Biol. Feb 14–2014.(Epub ahead of print).
51	Linglu D, Yuxiang L, Yaqiong X, et al: Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice. Neurol Sci. Dec 14–2013.(Epub ahead of print).
52	Haiyan W, Yuxiang L, Linglu D, et al: Antinociceptive effects of matrine on neuropathic pain induced by chronic constriction injury. Pharm Biol. 51:844–850. 2013. View Article : Google Scholar : PubMed/NCBI