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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Arsenic Trioxide Suppresses Angiogenesis in Non-small Cell Lung Cancer via the Nrf2-IL-33 Signaling Pathway

Author(s): Mingdong Wang, Jizhong Yin, Qianyu Han, Bing Li*, Xue-Wei Zhao* and Lei Xue*

Volume 24, Issue 15, 2024

Published on: 05 June, 2024

Page: [1142 - 1150] Pages: 9

DOI: 10.2174/0118715206288348240420174853

Price: $65

Abstract

Background: Non-Small Cell Lung Cancer (NSCLC) ranks as a leading cause of cancer-related mortality, necessitating the urgent search for cost-effective and efficient anti-NSCLC drugs. Our preliminary research has demonstrated that arsenic trioxide (ATO) significantly inhibits NSCLC angiogenesis, exerting anti-tumor effects. In conjunction with existing literature reports, the Nrf2-IL-33 pathway is emerging as a novel mechanism in NSCLC angiogenesis.

Objective: This study aimed to elucidate whether ATO can inhibit NSCLC angiogenesis through the Nrf2-IL-33 pathway.

Methods: Immunohistochemistry was employed to assess the expression of Nrf2, IL-33, and CD31 in tumor tissues from patients with NSCLC. DETA-NONOate was used as a nitric oxide (NO) donor to mimic high levels of NO in the tumor microenvironment. Western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay were utilized to evaluate the expression of Nrf2 and IL-33 in the NCI-H1299 cell line. Subcutaneous xenograft models were established in nude mice by implanting NCI-H1299 cells to assess the anti-tumor efficacy of ATO.

Results: High expression levels of Nrf2 and IL-33 were observed in tumor samples from patients with NSCLC, and Nrf2 expression positively correlated with microvascular density in NSCLC. In vitro, NO (released from 1mM DETA-NONOate) promoted activation of the Nrf2-IL-33 signaling pathway in NCI-H1299 cells, which was reversed by ATO. Additionally, both Nrf2 deficiency and ATO treatment significantly attenuated NOinduced IL-33 expression. In vivo, both ATO and the Nrf2 inhibitor ML385 demonstrated significant inhibitory effects on angiogenesis tumor growth.

Conclusion: Nrf2-IL-33 signaling is usually activated in NSCLC and positively correlates with tumor angiogenesis. ATO effectively disrupts the activation of the Nrf2-IL-33 pathway in NSCLC and thus inhibits angiogenesis, suggesting its potential as an anti-angiogenic agent for use in the treatment of NSCLC.

« Previous Next »
[1]
Xia, C.; Dong, X.; Li, H.; Cao, M.; Sun, D.; He, S.; Yang, F.; Yan, X.; Zhang, S.; Li, N.; Chen, W. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin. Med. J., 2022, 135(5), 584-590.
[http://dx.doi.org/10.1097/cm9.0000000000002108] [PMID: 35143424]
[2]
Asamura, H.; Nishimura, K.K.; Giroux, D.J.; Chansky, K.; Hoering, A.; Rusch, V.; Rami-Porta, R. IASLC Lung Cancer Staging Project: The new database to inform revisions in the ninth edition of the tnm classification of lung cancer. J. Thorac. Oncol., 2023, 18(5), 564-575.
[http://dx.doi.org/10.1016/j.jtho.2023.01.088] [PMID: 36773775]
[3]
Egbujor, M.C.; Tucci, P.; Buttari, B.; Nwobodo, D.C.; Marini, P.; Saso, L. Phenothiazines: Nrf2 activation and antioxidant effects. J. Biochem. Mol. Toxicol., 2024, 38(3), e23661.
[http://dx.doi.org/10.1002/jbt.23661] [PMID: 38369721]
[4]
He, F.; Antonucci, L.; Karin, M. NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis, 2020, 41(4), 405-416.
[http://dx.doi.org/10.1093/carcin/bgaa039] [PMID: 32347301]
[5]
Solis, L.M.; Behrens, C.; Dong, W.; Suraokar, M.; Ozburn, N.C.; Moran, C.A.; Corvalan, A.H.; Biswal, S.; Swisher, S.G.; Bekele, B.N.; Minna, J.D.; Stewart, D.J.; Wistuba, I.I. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin. Cancer Res., 2010, 16(14), 3743-3753.
[http://dx.doi.org/10.1158/1078-0432.Ccr-09-3352] [PMID: 20534738]
[6]
Fan, Z.; Wirth, A-K.; Chen, D.; Wruck, C.J.; Rauh, M.; Buchfelder, M.; Savaskan, N. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis, 2017, 6(8), e371.
[http://dx.doi.org/10.1038/oncsis.2017.65] [PMID: 28805788]
[7]
Dios-Barbeito, S.; González, R.; Cadenas, M.; García, L.F.; Victor, V.M.; Padillo, F.J.; Muntané, J. Impact of nitric oxide in liver cancer microenvironment. Nitric Oxide, 2022, 128, 1-11.
[http://dx.doi.org/10.1016/j.niox.2022.07.006] [PMID: 35940533]
[8]
Zhou, H.; Li, J.; Chen, Z.; Chen, Y.; Ye, S. Nitric oxide in occurrence, progress and therapy of lung Cancer: A systemic review and meta-analysis. BMC Cancer, 2021, 21(1), 678.
[http://dx.doi.org/10.1186/s12885-021-08430-2] [PMID: 34103000]
[9]
Luanpitpong, S.; Chanvorachote, P. Nitric oxide and aggressive behavior of lung cancer cells. Anticancer Res., 2015, 35(9), 4585-4592.
[PMID: 26254346]
[10]
Taniguchi, S.; Elhance, A.; Van Duzer, A.; Kumar, S.; Leitenberger, J.J.; Oshimori, N. Tumor-initiating cells establish an IL-33-TGF-β niche signaling loop to promote cancer progression. Science, 2020, 369(6501), eaay1813.
[http://dx.doi.org/10.1126/science.aay1813] [PMID: 32675345]
[11]
Choi, Y.S.; Choi, H.J.; Min, J.K.; Pyun, B.J.; Maeng, Y.S.; Park, H.; Kim, J.; Kim, Y.M.; Kwon, Y.G. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood, 2009, 114(14), 3117-3126.
[http://dx.doi.org/10.1182/blood-2009-02-203372] [PMID: 19661270]
[12]
Lo-Coco, F.; Avvisati, G.; Vignetti, M.; Thiede, C.; Orlando, S.M.; Iacobelli, S.; Ferrara, F.; Fazi, P.; Cicconi, L.; Di Bona, E.; Specchia, G.; Sica, S.; Divona, M.; Levis, A.; Fiedler, W.; Cerqui, E.; Breccia, M.; Fioritoni, G.; Salih, H.R.; Cazzola, M.; Melillo, L.; Carella, A.M.; Brandts, C.H.; Morra, E.; von Lilienfeld-Toal, M.; Hertenstein, B.; Wattad, M.; Lübbert, M.; Hänel, M.; Schmitz, N.; Link, H.; Kropp, M.G.; Rambaldi, A.; La Nasa, G.; Luppi, M.; Ciceri, F.; Finizio, O.; Venditti, A.; Fabbiano, F.; Döhner, K.; Sauer, M.; Ganser, A.; Amadori, S.; Mandelli, F.; Döhner, H.; Ehninger, G.; Schlenk, R.F.; Platzbecker, U. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med., 2013, 369(2), 111-121.
[http://dx.doi.org/10.1056/NEJMoa1300874] [PMID: 23841729]
[13]
Lin, C.C.; Hsu, C.; Hsu, C.H.; Hsu, W.L.; Cheng, A.L.; Yang, C.H. Arsenic trioxide in patients with hepatocellular carcinoma: A phase II trial. Invest. New Drugs, 2007, 25(1), 77-84.
[http://dx.doi.org/10.1007/s10637-006-9004-9] [PMID: 16937079]
[14]
Zhao, H.; Sun, G.; Kong, D.; Zhang, Y.; Shi, W.; Zhao, M.; Hong, L.; Qiao, Z. A phase II study of arsenic trioxide in patients with relapsed or refractory malignant lymphoma. Med. Oncol., 2015, 32(3), 79.
[http://dx.doi.org/10.1007/s12032-015-0526-x] [PMID: 25698531]
[15]
Mao, J.; Shi, X.; Hua, L.; Yang, M.; Shen, Y.; Ruan, Z.; Li, B.; Xi, X. Arsenic inhibits proliferation and induces autophagy of tumor cells in pleural effusion of patients with non-small cell lung cancer expressing egfr with or without mutations via PI3K/AKT/mTOR Pathway. Biomedicines, 2023, 11(6), 1721.
[http://dx.doi.org/10.3390/biomedicines11061721] [PMID: 37371816]
[16]
Xie, S.L.; Yang, M.H.; Chen, K.; Huang, H.; Zhao, X.W.; Zang, Y.S.; Li, B. Efficacy of arsenic trioxide in the treatment of malignant pleural effusion caused by pleural metastasis of lung cancer. Cell Biochem. Biophys., 2015, 71(3), 1325-1333.
[http://dx.doi.org/10.1007/s12013-014-0352-3] [PMID: 25413961]
[17]
Yang, M.H.; Chang, K.J.; Zheng, J.C.; Huang, H.; Sun, G.Y.; Zhao, X.W.; Li, B.; Xiu, Q.Y. Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation. Oncol. Lett., 2017, 14(3), 3103-3109.
[http://dx.doi.org/10.3892/ol.2017.6518] [PMID: 28928847]
[18]
Yang, M.H.; Zang, Y.S.; Huang, H.; Chen, K.; Li, B.; Sun, G.Y.; Zhao, X.W. Arsenic trioxide exerts anti-lung cancer activity by inhibiting angiogenesis. Curr. Cancer Drug Targets, 2014, 14(6), 557-566.
[http://dx.doi.org/10.2174/1568009614666140725090000] [PMID: 25088040]
[19]
Dong, S.; Li, Z.; Kong, J.; Wu, S.; Gao, J.; Sun, W. Arsenic trioxide inhibits angiogenesis of hepatocellular carcinoma after insufficient radiofrequency ablation via blocking paracrine angiopoietin-1 and angiopoietin-2. Int. J. Hyperthermia, 2022, 39(1), 888-896.
[http://dx.doi.org/10.1080/02656736.2022.2093995] [PMID: 35848416]
[20]
Yang, D.; Lv, Z.; Zhang, H.; Liu, B.; Jiang, H.; Tan, X.; Lu, J.; Baiyun, R.; Zhang, Z. Activation of the Nrf2 signaling pathway involving klf9 plays a critical role in allicin resisting against arsenic trioxide-induced hepatotoxicity in rats. Biol. Trace Elem. Res., 2017, 176(1), 192-200.
[http://dx.doi.org/10.1007/s12011-016-0821-1] [PMID: 27561292]
[21]
Bai, J.; Yao, X.; Jiang, L.; Qiu, T.; Liu, S.; Qi, B.; Zheng, Y.; Kong, Y.; Yang, G.; Chen, M.; Liu, X.; Sun, X. Taurine protects against As2O3-induced autophagy in pancreas of rat offsprings through Nrf2/Trx pathway. Biochimie, 2016, 123, 1-6.
[http://dx.doi.org/10.1016/j.biochi.2016.01.002] [PMID: 26775255]
[22]
Jögi, A.; Vaapil, M.; Johansson, M.; Påhlman, S. Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors. Ups. J. Med. Sci., 2012, 117(2), 217-224.
[http://dx.doi.org/10.3109/03009734.2012.659294] [PMID: 22376239]
[23]
Bonavida, B.; Garban, H. Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics. Redox Biol., 2015, 6, 486-494.
[http://dx.doi.org/10.1016/j.redox.2015.08.013] [PMID: 26432660]
[24]
Pervin, S.; Singh, R.; Chaudhuri, G. Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1. Proc. Natl. Acad. Sci., 2001, 98(6), 3583-3588.
[http://dx.doi.org/10.1073/pnas.041603998] [PMID: 11248121]
[25]
Chang, K.J.; Yang, M.H.; Zheng, J.C.; Li, B.; Nie, W. Arsenic trioxide inhibits cancer stem-like cells via down-regulation of Gli1 in lung cancer. Am. J. Transl. Res., 2016, 8(2), 1133-1143.
[PMID: 27158399]
[26]
Chang, K.J.; Yin, J.Z.; Huang, H.; Li, B.; Yang, M.H. Arsenic trioxide inhibits the growth of cancer stem cells derived from small cell lung cancer by downregulating stem cell maintenance factors and inducing apoptosis via the Hedgehog signaling blockade. Transl. Lung Cancer Res., 2020, 9(4), 1379-1396.
[http://dx.doi.org/10.21037/tlcr-20-467] [PMID: 32953511]
[27]
Yang, M.H.; Wang, Y-S.; Shi, X-Q.; Zhao, X. W; Li, B Arsenic trioxide restrains lung cancer growth and metastasis by blocking the calcineurin-nfat pathway by upregulating DSCR1. Curr. Cancer Drug Targets, 2022, 22(10), 854-864.
[http://dx.doi.org/10.2174/1568009622666220629154619] [PMID: 35770414]
[28]
Yin, J.Z.; Shi, X.Q.; Wang, M.D.; Du, H.; Zhao, X.W.; Li, B.; Yang, M.H. Arsenic trioxide elicits anti-tumor activity by inhibiting polarization of M2-like tumor-associated macrophages via Notch signaling pathway in lung adenocarcinoma. Int. Immunopharmacol., 2023, 117, 109899.
[http://dx.doi.org/10.1016/j.intimp.2023.109899] [PMID: 36827926]
[29]
Yang, M.H.; Chang, K.J.; Li, B.; Chen, W.S. Arsenic trioxide suppresses tumor growth through antiangiogenesis via notch signaling blockade in small-cell lung cancer. BioMed Res. Int., 2019, 2019, 4647252.
[http://dx.doi.org/10.1155/2019/4647252] [PMID: 31093499]
[30]
de Thé, H.; Chen, Z. Acute promyelocytic leukaemia: Novel insights into the mechanisms of cure. Nat. Rev. Cancer, 2010, 10(11), 775-783.
[http://dx.doi.org/10.1038/nrc2943] [PMID: 20966922]
[31]
Wang, X.; Jiang, F.; Mu, J.; Ye, X.; Si, L.; Ning, S.; Li, Z.; Li, Y. Arsenic trioxide attenuates the invasion potential of human liver cancer cells through the demethylation-activated microRNA-491. Toxicol. Lett., 2014, 227(2), 75-83.
[http://dx.doi.org/10.1016/j.toxlet.2014.03.016] [PMID: 24680928]
[32]
Tian, Z.; Tan, Y.; Lin, X.; Su, M.; Pan, L.; Lin, L.; Ou, G.; Chen, Y. Arsenic trioxide sensitizes pancreatic cancer cells to gemcitabine through downregulation of the TIMP1/PI3K/AKT/mTOR axis. Transl. Res., 2023, 255, 66-76.
[http://dx.doi.org/10.1016/j.trsl.2022.11.007] [PMID: 36400307]
[33]
Mirzaei, A.; Rashedi, S.; Akbari, M.R.; Khatami, F.; Aghamir, S.M.K. Combined anticancer effects of simvastatin and arsenic trioxide on prostate cancer cell lines via downregulation of the VEGF and OPN isoforms genes. J. Cell. Mol. Med., 2022, 26(9), 2728-2740.
[http://dx.doi.org/10.1111/jcmm.17286] [PMID: 35366048]
[34]
Zhang, J.; Ma, Y.; Zhang, Y.; Niu, S.; Chu, M.; Zhang, Z. Angiogenesis is inhibited by arsenic trioxide through downregulation of the CircHIPK3/miR-149-5p/FOXO1/VEGF functional module in rheumatoid arthritis. Front. Pharmacol., 2021, 12, 751667.
[http://dx.doi.org/10.3389/fphar.2021.751667] [PMID: 34776969]
[35]
Lew, Y.S.; Brown, S.L.; Griffin, R.J.; Song, C.W.; Kim, J.H. Arsenic trioxide causes selective necrosis in solid murine tumors by vascular shutdown. Cancer Res., 1999, 59(24), 6033-6037.
[PMID: 10626785]
[36]
Wu, S.; Lu, H.; Bai, Y. Nrf2 in cancers: A double‐edged sword. Cancer Med., 2019, 8(5), 2252-2267.
[http://dx.doi.org/10.1002/cam4.2101] [PMID: 30929309]
[37]
Sánchez-Ortega, M.; Carrera, A.C.; Garrido, A. Role of NRF2 in lung cancer. Cells, 2021, 10(8), 1879.
[http://dx.doi.org/10.3390/cells10081879] [PMID: 34440648]
[38]
Sha, W.; Zhao, B.; Wei, H.; Yang, Y.; Yin, H.; Gao, J.; Zhao, W.; Kong, W.; Ge, G.; Lei, T. Astragalus polysaccharide ameliorates vascular endothelial dysfunction by stimulating macrophage M2 polarization via potentiating Nrf2/HO-1 signaling pathway. Phytomedicine, 2023, 112, 154667.
[http://dx.doi.org/10.1016/j.phymed.2023.154667] [PMID: 36842218]
[39]
Zhang, X.; Xu, H. Azithromycin inhibits glioblastoma angiogenesis in mice via inducing mitochondrial dysfunction and oxidative stress. Cancer Chemother. Pharmacol., 2023, 92(4), 291-302.
[http://dx.doi.org/10.1007/s00280-023-04567-y] [PMID: 37486388]
[40]
Li, L.; Pan, H.; Wang, H.; Li, X.; Bu, X.; Wang, Q.; Gao, Y.; Wen, G.; Zhou, Y.; Cong, Z.; Yang, Y.; Tang, C.; Liu, Z. Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension. Sci. Rep., 2016, 6, 37338.
[http://dx.doi.org/10.1038/srep37338] [PMID: 27869147]
[41]
Chatterjee, A.; Azevedo-Martins, J.M.; Stachler, M.D. Interleukin-33 as a potential therapeutic target in gastric cancer patients: current insights. OncoTargets Ther., 2023, 16, 675-687.
[http://dx.doi.org/10.2147/ott.S389120] [PMID: 37583706]
[42]
Zhou, X.; Feng, Y.; Liu, S.; Li, C.; Teng, Y.; Li, X.; Lu, J. IL-33 promotes the growth of non-small cell lung cancer cells through regulating mir-128-3p/cdip1 signalling pathway. Cancer Manag. Res., 2021, 13, 2379-2388.
[http://dx.doi.org/10.2147/cmar.S276297] [PMID: 33737835]
[43]
Yang, M.; Feng, Y.; Yue, C.; Xu, B.; Chen, L.; Jiang, J.; Lu, B.; Zhu, Y. Lower expression level of IL-33 is associated with poor prognosis of pulmonary adenocarcinoma. PLoS One, 2018, 13(3), e0193428.
[http://dx.doi.org/10.1371/journal.pone.0193428] [PMID: 29499051]

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