Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Simvastatin Enhanced Anti-tumor Effects of Bevacizumab against Lung Adenocarcinoma A549 Cells via Abating HIF-1α-Wnt/β-Catenin Signaling Pathway

Author(s): Xin Tu, Jian Zhang, Wei Yuan, Xia Wu, Zhi Xu and Cuo Qing*

Volume 23, Issue 19, 2023

Published on: 07 September, 2023

Page: [2083 - 2094] Pages: 12

DOI: 10.2174/1871520623666230816090914

Price: $65

Abstract

Background: Bevacizumab increased hypoxia-inducible factor (HIF-1α) expression attenuates its antitumor effect. Simvastatin can reduce the expression of HIF-1α to exert a tumor-suppressive effect in many in vitro experiments. Therefore, this study aimed to determine whether simvastatin could strengthen the anti-tumor activity of bevacizumab in lung adenocarcinoma.

Objective: To determine whether simvastatin could strengthen the anti-tumor activity of bevacizumab in lung adenocarcinoma.

Methods: The changes in the biological behavior of A549 cells treated with different drugs were determined through colony forming assay, Cell Counting Assay-8 (CCK-8), transwell assay, wound healing assay, and flow cytometry. The expressions of pathway-related factors HIF-1α and β-Catenin were determined via qRT-PCR and western blotting. The expressions of proliferation-related proteins, invasion-related proteins, and apoptosis-related proteins were detected by western blotting. In addition, a xenograft non-small cell lung cancer model in nude mice was used to explore in vivo tumor growth.

Results: We found that simvastatin combined with bevacizumab synergistically suppressed the proliferation, migration, and invasion of A549 cells while promoting their apoptosis. As demonstrated by qRT-PCR and western blotting experiments, the bevacizumab group displayed a higher expression of pathway-related factors HIF-1α and β-Catenin than the control groups, however simvastatin group showed the opposite trend. Its combination with bevacizumab induced elevation of HIF-1α and β-catenin expressions. During in vivo experiments, simvastatin inhibited tumor growth, and in comparison, the inhibitory effects of its combination with bevacizumab were stronger.

Conclusion: Based on our findings, simvastatin may affect the biological responses of bevacizumab on A549 cells by restraining the HIF-1α-Wnt/β-catenin signaling pathway, thus representing a novel and effective combination therapy that can be potentially applied in a clinical therapy for lung adenocarcinoma.

« Previous Next »
Graphical Abstract

[1]
Chen, W.; Zheng, R.; Baade, P.D.; Zhang, S.; Zeng, H.; Bray, F.; Jemal, A.; Yu, X.Q.; He, J. Cancer statistics in China, 2015. CA Cancer J. Clin., 2016, 66(2), 115-132.
[http://dx.doi.org/10.3322/caac.21338] [PMID: 26808342]
[2]
Chen, Z.; Fillmore, C.M.; Hammerman, P.S.; Kim, C.F.; Wong, K.K. Non-small-cell lung cancers: A heterogeneous set of diseases. Nat. Rev. Cancer, 2014, 14(8), 535-546.
[http://dx.doi.org/10.1038/nrc3775] [PMID: 25056707]
[3]
Schwartzberg, L.; Korytowsky, B.; Penrod, J.R.; Zhang, Y.; Le, T.K.; Batenchuk, C.; Krug, L. Real-world clinical impact of immune checkpoint inhibitors in patients with advanced/metastatic non–small cell lung cancer after platinum chemotherapy. Clin. Lung Cancer, 2019, 20(4), 287-296.e4.
[http://dx.doi.org/10.1016/j.cllc.2019.04.004] [PMID: 31130450]
[4]
Chen, J.H.; Yang, J.L.; Chou, C.Y.; Wang, J.Y.; Hung, C.C. Indirect comparison of efficacy and safety between immune checkpoint inhibitors and antiangiogenic therapy in advanced non–small-cell lung cancer. Sci. Rep., 2018, 8(1), 9686.
[http://dx.doi.org/10.1038/s41598-018-27994-x] [PMID: 29946182]
[5]
Reck, M.; Garassino, M.C.; Imbimbo, M.; Shepherd, F.A.; Socinski, M.A.; Shih, J.Y.; Tsao, A.; Lee, P.; Winfree, K.B.; Sashegyi, A.; Cheng, R.; Varea, R.; Levy, B.; Garon, E. Antiangiogenic therapy for patients with aggressive or refractory advanced non-small cell lung cancer in the second-line setting. Lung Cancer, 2018, 120, 62-69.
[http://dx.doi.org/10.1016/j.lungcan.2018.03.025] [PMID: 29748017]
[6]
Alevizakos, M.; Kaltsas, S.; Syrigos, K.N. The VEGF pathway in lung cancer. Cancer Chemother. Pharmacol., 2013, 72(6), 1169-1181.
[http://dx.doi.org/10.1007/s00280-013-2298-3] [PMID: 24085262]
[7]
Blagosklonny, M.V. Antiangiogenic therapy and tumor progression. Cancer Cell, 2004, 5(1), 13-17.
[http://dx.doi.org/10.1016/S1535-6108(03)00336-2] [PMID: 14749122]
[8]
De Francesco, E.M.; Sims, A.H.; Maggiolini, M.; Sotgia, F.; Lisanti, M.P.; Clarke, R.B. GPER mediates the angiocrine actions induced by IGF1 through the HIF-1α/VEGF pathway in the breast tumor microenvironment. Breast Cancer Res., 2017, 19(1), 129.
[http://dx.doi.org/10.1186/s13058-017-0923-5] [PMID: 29212519]
[9]
Rapisarda, A.; Melillo, G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat. Rev. Clin. Oncol., 2012, 9(7), 378-390.
[http://dx.doi.org/10.1038/nrclinonc.2012.64] [PMID: 22525710]
[10]
Mazumdar, J.; O’Brien, W.T.; Johnson, R.S.; LaManna, J.C.; Chavez, J.C.; Klein, P.S.; Simon, M.C. O2 regulates stem cells through Wnt/β-catenin signalling. Nat. Cell Biol., 2010, 12(10), 1007-1013.
[http://dx.doi.org/10.1038/ncb2102] [PMID: 20852629]
[11]
Lv, Z.; Liu, R.D.; Chen, X.Q.; Wang, B.; Li, L.F.; Guo, Y.S.; Chen, X.J.; Ren, X.Q. HIF 1α promotes the stemness of oesophageal squamous cell carcinoma by activating the Wnt/β catenin pathway. Oncol. Rep., 2019, 42(2), 726-734.
[http://dx.doi.org/10.3892/or.2019.7203] [PMID: 31233197]
[12]
Wang, X.; Yu, Z.; Wang, C.; Cheng, W.; Tian, X.; Huo, X.; Wang, Y.; Sun, C.; Feng, L.; Xing, J.; Lan, Y.; Sun, D.; Hou, Q.; Zhang, B.; Ma, X.; Zhang, B. Alantolactone, a natural sesquiterpene lactone, has potent antitumor activity against glioblastoma by targeting IKKβ kinase activity and interrupting NF-κB/COX-2-mediated signaling cascades. J. Exp. Clin. Cancer Res., 2017, 36(1), 93.
[http://dx.doi.org/10.1186/s13046-017-0563-8] [PMID: 28701209]
[13]
McIntyre, A.; Harris, A.L. Metabolic and hypoxic adaptation to anti‐angiogenic therapy: A target for induced essentiality. EMBO Mol. Med., 2015, 7(4), 368-379.
[http://dx.doi.org/10.15252/emmm.201404271] [PMID: 25700172]
[14]
Vasudev, N.S.; Goh, V.; Juttla, J.K.; Thompson, V.L.; Larkin, J.M.G.; Gore, M.; Nathan, P.D.; Reynolds, A.R. Changes in tumour vessel density upon treatment with anti-angiogenic agents: Relationship with response and resistance to therapy. Br. J. Cancer, 2013, 109(5), 1230-1242.
[http://dx.doi.org/10.1038/bjc.2013.429] [PMID: 23922108]
[15]
Huang, W.; Zhang, C.; Cui, M.; Niu, J.; Ding, W. Inhibition of bevacizumab-induced epithelial-mesenchymal transition by BATF2 overexpression involves the suppression of Wnt/β-catenin signaling in glioblastoma cells. Anticancer Res., 2017, 37(8), 4285-4294.
[http://dx.doi.org/10.21873/anticanres.11821] [PMID: 28739720]
[16]
Xie, W.; Zhao, H.; Wang, F.; Wang, Y.; He, Y.; Wang, T.; Zhang, K.; Yang, H.; Zhou, Z.; Shi, H.; Wang, J.; Huang, G. A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway. J. Exp. Clin. Cancer Res., 2021, 40(1), 30.
[http://dx.doi.org/10.1186/s13046-020-01800-x] [PMID: 33436039]
[17]
Shepherd, J.; Cobbe, S.M.; Ford, I.; Isles, C.G.; Lorimer, A.R.; Macfarlane, P.W.; McKillop, J.H.; Packard, C.J. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N. Engl. J. Med., 1995, 333(20), 1301-1308.
[http://dx.doi.org/10.1056/NEJM199511163332001] [PMID: 7566020]
[18]
Fujikake, K.; Kajiyama, H.; Yoshihara, M.; Nishino, K.; Yoshikawa, N.; Utsumi, F.; Suzuki, S.; Niimi, K.; Sakata, J.; Mitsui, H.; Shibata, K.; Senga, T.; Kikkawa, F. A novel mechanism of neovascularization in peritoneal dissemination via cancer-associated mesothelial cells affected by TGF-β derived from ovarian cancer. Oncol. Rep., 2017, 39(1), 193-200.
[http://dx.doi.org/10.3892/or.2017.6104] [PMID: 29192324]
[19]
Murai, T. Cholesterol lowering: Role in cancer prevention and treatment. Biol. Chem., 2015, 396(1), 1-11.
[http://dx.doi.org/10.1515/hsz-2014-0194] [PMID: 25205720]
[20]
Lee, Y.; Lee, K.H.; Lee, G.K.; Lee, S.H.; Lim, K.Y.; Joo, J.; Go, Y.J.; Lee, J.S.; Han, J.Y. Randomized phase ii study of afatinib plus simvastatin versus afatinib alone in previously treated patients with advanced nonadenocarcinomatous non-small cell lung cancer. Cancer Res. Treat., 2017, 49(4), 1001-1011.
[http://dx.doi.org/10.4143/crt.2016.546] [PMID: 28111428]
[21]
Feng, J.; Dai, W.; Mao, Y.; Wu, L.; Li, J.; Chen, K.; Yu, Q.; Kong, R.; Li, S.; Zhang, J.; Ji, J.; Wu, J.; Mo, W.; Xu, X.; Guo, C. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis. J. Exp. Clin. Cancer Res., 2020, 39(1), 24.
[http://dx.doi.org/10.1186/s13046-020-1528-x] [PMID: 32000827]
[22]
Chou, T.C.; Martin, N. CompuSyn software. CompuSyn for drug combinations: PC software and user’s guide: A computer program for quantitation of synergism and antagonism in drug combinations, and the determination of IC50 and ED50 and LD50 values. ComboSyn Inc., Paramus, NJ. 2005. Available from: https://www.combosyn.com
[23]
Chou, T.C.; Talalay, P. Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur. J. Biochem., 1981, 115(1), 207-216.
[http://dx.doi.org/10.1111/j.1432-1033.1981.tb06218.x] [PMID: 7227366]
[24]
Welti, J.; Loges, S.; Dimmeler, S.; Carmeliet, P. Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J. Clin. Invest., 2013, 123(8), 3190-3200.
[http://dx.doi.org/10.1172/JCI70212] [PMID: 23908119]
[25]
Kerbel, R.; Folkman, J. Clinical translation of angiogenesis inhibitors. Nat. Rev. Cancer, 2002, 2(10), 727-739.
[http://dx.doi.org/10.1038/nrc905] [PMID: 12360276]
[26]
Lu, X.; Kang, Y. Hypoxia and hypoxia-inducible factors: Master regulators of metastasis. Clin. Cancer Res., 2010, 16(24), 5928-5935.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-1360] [PMID: 20962028]
[27]
Ai, Z.; Lu, Y.; Qiu, S.; Fan, Z. Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism. Cancer Lett., 2016, 373(1), 36-44.
[http://dx.doi.org/10.1016/j.canlet.2016.01.009] [PMID: 26801746]
[28]
Tong, D.; Liu, Q.; Liu, G.; Yuan, W.; Wang, L.; Guo, Y.; Lan, W.; Zhang, D.; Dong, S.; Wang, Y.; Xiao, H.; Mu, J.; Mao, C.; Wong, J.; Jiang, J. The HIF/PHF8/AR axis promotes prostate cancer progression. Oncogenesis, 2016, 5(12), e283.
[http://dx.doi.org/10.1038/oncsis.2016.74] [PMID: 27991916]
[29]
Zhang, Y.; Bian, Y.; Wang, Y.; Wang, Y.; Duan, X.; Han, Y.; Zhang, L.; Wang, F.; Gu, Z.; Qin, Z. HIF‐1α is necessary for activation and tumour‐promotion effect of cancer‐associated fibroblasts in lung cancer. J. Cell. Mol. Med., 2021, 25(12), 5457-5469.
[http://dx.doi.org/10.1111/jcmm.16556] [PMID: 33943003]
[30]
Valenta, T.; Hausmann, G.; Basler, K. The many faces and functions of β-catenin. EMBO J., 2012, 31(12), 2714-2736.
[http://dx.doi.org/10.1038/emboj.2012.150] [PMID: 22617422]
[31]
Pastushenko, I.; Brisebarre, A.; Sifrim, A.; Fioramonti, M.; Revenco, T.; Boumahdi, S.; Van Keymeulen, A.; Brown, D.; Moers, V.; Lemaire, S.; De Clercq, S.; Minguijón, E.; Balsat, C.; Sokolow, Y.; Dubois, C.; De Cock, F.; Scozzaro, S.; Sopena, F.; Lanas, A.; D’Haene, N.; Salmon, I.; Marine, J.C.; Voet, T.; Sotiropoulou, P.A.; Blanpain, C. Identification of the tumour transition states occurring during EMT. Nature, 2018, 556(7702), 463-468.
[http://dx.doi.org/10.1038/s41586-018-0040-3] [PMID: 29670281]
[32]
Brabletz, T.; Kalluri, R.; Nieto, M.A.; Weinberg, R.A. EMT in cancer. Nat. Rev. Cancer, 2018, 18(2), 128-134.
[http://dx.doi.org/10.1038/nrc.2017.118] [PMID: 29326430]
[33]
Nusse, R.; Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 2017, 169(6), 985-999.
[http://dx.doi.org/10.1016/j.cell.2017.05.016] [PMID: 28575679]
[34]
Han, P.; Li, J.; Zhang, B.; Lv, J.; Li, Y.; Gu, X.; Yu, Z.; Jia, Y.; Bai, X.; Li, L.; Liu, Y.; Cui, B. The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/β-catenin signaling. Mol. Cancer, 2017, 16(1), 9.
[http://dx.doi.org/10.1186/s12943-017-0583-1] [PMID: 28086904]
[35]
Teng, Y.; Wang, X.; Wang, Y.; Ma, D. Wnt/β-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochem. Biophys. Res. Commun., 2010, 392(3), 373-379.
[http://dx.doi.org/10.1016/j.bbrc.2010.01.028] [PMID: 20074550]
[36]
Niehrs, C. The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol., 2012, 13(12), 767-779.
[http://dx.doi.org/10.1038/nrm3470] [PMID: 23151663]
[37]
Zhou, Y.Y.; Zhu, G.Q.; Wang, Y.; Zheng, J.N.; Ruan, L.Y.; Cheng, Z.; Hu, B.; Fu, S.W.; Zheng, M.H. Systematic review with network meta-analysis: Statins and risk of hepatocellular carcinoma. Oncotarget, 2016, 7(16), 21753-21762.
[http://dx.doi.org/10.18632/oncotarget.7832] [PMID: 26943041]
[38]
Ishikawa, S.; Hayashi, H.; Kinoshita, K.; Abe, M.; Kuroki, H.; Tokunaga, R.; Tomiyasu, S.; Tanaka, H.; Sugita, H.; Arita, T.; Yagi, Y.; Watanabe, M.; Hirota, M.; Baba, H. Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer. Int. J. Cancer, 2014, 135(11), 2528-2536.
[http://dx.doi.org/10.1002/ijc.28672] [PMID: 24346863]
[39]
Cardwell, C.R.; Mc Menamin, Ú.; Hughes, C.M.; Murray, L.J. Statin use and survival from lung cancer: A population-based cohort study. Cancer Epidemiol. Biomarkers Prev., 2015, 24(5), 833-841.
[http://dx.doi.org/10.1158/1055-9965.EPI-15-0052] [PMID: 25934831]
[40]
Yu, X.; Pan, Y.; Ma, H.; Li, W. Simvastatin inhibits proliferation and induces apoptosis in human lung cancer cells. Oncol. Res., 2013, 20(8), 351-357.
[http://dx.doi.org/10.3727/096504013X13657689382897] [PMID: 23924855]
[41]
Han, J.Y.; Lee, S.H.; Yoo, N.J.; Hyung, L.S.; Moon, Y.J.; Yun, T.; Kim, H.T.; Lee, J.S. A randomized phase II study of gefitinib plus simvastatin Versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin. Cancer Res., 2011, 17(6), 1553-1560.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2525] [PMID: 21411446]
[42]
Rauca, V.F.; Licarete, E.; Luput, L.; Sesarman, A.; Patras, L.; Bulzu, P.; Rakosy-Tican, E.; Banciu, M. Combination therapy of simvastatin and 5, 6-dimethylxanthenone-4-acetic acid synergistically suppresses the aggressiveness of B16.F10 melanoma cells. PLoS One, 2018, 13(8), e0202827.
[http://dx.doi.org/10.1371/journal.pone.0202827] [PMID: 30138430]
[43]
Wang, J.C.; Li, X.X.; Sun, X.; Li, G.Y.; Sun, J.L.; Ye, Y.P.; Cong, L.L.; Li, W.M.; Lu, S.Y.; Feng, J.; Liu, P.J. Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF ‐1α‐induced pro‐angiogenic factor. Cancer Sci., 2018, 109(5), 1627-1637.
[http://dx.doi.org/10.1111/cas.13570] [PMID: 29532562]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy