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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Celastrus orbiculatus Extract Inhibits the Invasion and Migration of Human Gastric Cancer Cells in the Hypoxia Microenvironment

Author(s): Guangqing Feng, Zewen Chu, Haibo Wang, Yanqing Liu* and Fangshi Zhu*

Volume 22, Issue 18, 2022

Published on: 18 July, 2022

Page: [3125 - 3135] Pages: 11

DOI: 10.2174/1871520622666220421092831

Price: $65

Abstract

Background: Gastric cancer is a common global disease. So far, the best choice for diagnosis and treatment of gastric cancer includes surgical resection, chemotherapy, and other targeted drug therapies; however, the overall survival rate of patients with gastric cancer is still very low. The hypoxic microenvironment facilitates tumor cells to develop tolerance to chemotherapy and radiotherapy and promotes the early invasion and metastasis of various tumors. Celastrus Orbiculatus extract (COE) has shown inhibitory activities against a variety of tumor cells. In this study, we found that COE could inhibit the invasion and migration of gastric cancer cells by inhibiting epithelial-mesenchymal transformation (EMT) in the hypoxia microenvironment.

Methods: CoCl2 was first diluted to various concentrations and then used to treat MKN28 and AGS cells. The MTT (thiazolyl blue) assay was used to evaluate cell proliferation. The transwell assay was used to measure the invasion and migration abilities of the cells. Wound healing assays were used to detect the healing ability of the cells. Western blotting was used to assess the effects of COE on the expression of EMT and matrix metalloproteinase (MMP) signaling pathway-related proteins.

Results: We found that gastric cancer cells showed stronger proliferation, invasion, and metastasis in the hypoxia microenvironment. COE inhibited the migration and invasion of AGS and MKN28 cells in both hypoxic and normoxic environments. Additionally, COE decreased the expression of EMT and MMP signaling pathway-related proteins in gastric cancer cells.

Conclusion: Therefore, it can be concluded that COE suppresses the migration and invasion of gastric cancer cells by inhibiting EMT and MMP in the hypoxia microenvironment.

Keywords: Celastrus orbiculatus, HIF-1α, hypoxia, EMT, MMP, matrix metalloproteinase.

Graphical Abstract

[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN esti-mates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Das, M. Neoadjuvant chemotherapy: Survival benefit in gastric cancer. Lancet Oncol., 2017, 18(6), e307.
[http://dx.doi.org/10.1016/S1470-2045(17)30321-2] [PMID: 28483410]
[3]
Chang, A.Y.; Foo, K.F.; Koo, W.H.; Ong, S.; So, J.; Tan, D.; Lim, K.H. Phase II study of neo-adjuvant chemotherapy for locally advanced gastric cancer. BMJ Open Gastroenterol., 2016, 3(1), e000095.
[http://dx.doi.org/10.1136/bmjgast-2016-000095] [PMID: 27648294]
[4]
Liu, Y.; Wang, D.; Lei, M.; Gao, J.; Cui, Y.; Jin, X.; Yu, Q.; Jiang, Y.; Guo, Y.; Liu, Y.; Cai, L.; Chen, X. GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway. Aging (Albany NY), 2021, 13(4), 5858-5874.
[http://dx.doi.org/10.18632/aging.202510] [PMID: 33591943]
[5]
Hayashi, Y.; Yokota, A.; Harada, H.; Huang, G. Hypoxia/pseudohypoxia-Med.iated activation of hypoxia-inducible factor-1α in cancer. Cancer Sci., 2019, 110(5), 1510-1517.
[http://dx.doi.org/10.1111/cas.13990] [PMID: 30844107]
[6]
Peitzsch, C.; Perrin, R.; Hill, R.P.; Dubrovska, A.; Kurth, I. Hypoxia as a biomarker for radioresistant cancer stem cells. Int. J. Radiat. Biol., 2014, 90(8), 636-652.
[http://dx.doi.org/10.3109/09553002.2014.916841] [PMID: 24844374]
[7]
Balamurugan, K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int. J. Cancer, 2016, 138(5), 1058-1066.
[http://dx.doi.org/10.1002/ijc.29519] [PMID: 25784597]
[8]
Wigerup, C.; Påhlman, S.; Bexell, D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol. Ther., 2016, 164, 152-169.
[http://dx.doi.org/10.1016/j.pharmthera.2016.04.009] [PMID: 27139518]
[9]
Qian, Y.Y.; Li, W.Y.; Yan, Y.; Zhao, X.Y.; Yang, T.; Fang, C.C.; Hou, J.J.; Liu, Y.Q. Celastrus orbiculatus extracts inhibit human hepato-cellular carcinoma growth by targeting mtor signaling pathways. Chin. J. Integr. Med., 2019, 25(11), 845-852.
[http://dx.doi.org/10.1007/s11655-019-3035-5] [PMID: 31127506]
[10]
Zhu, Y.; Liu, L.; Hu, L.; Dong, W.; Zhang, M.; Liu, Y.; Li, P. Effect of Celastrus orbiculatus in inhibiting Helicobacter pylori induced in-flammatory response by regulating epithelial mesenchymal transition and targeting miR-21/PDCD4 signaling pathway in gastric epithelial cells. BMC Complement. Altern. Med., 2019, 19(1), 91.
[http://dx.doi.org/10.1186/s12906-019-2504-x] [PMID: 31035975]
[11]
Zhu, Y.D.; Liu, Y.Q.; Qian, Y.Y.; Zhang, H.; Li, G.Q.; Yang, L. Extracts of Celastrus orbiculatus exhibit anti-proliferative and anti-invasive effects on human gastric adenocarcinoma cells. Chin. J. Integr. Med., 2014. Epub ahead of print
[http://dx.doi.org/10.1007/s11655-014-1951-y] [PMID: 25382615]
[12]
Lamb, R.; Harrison, H.; Hulit, J.; Smith, D.L.; Lisanti, M.P.; Sotgia, F. Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget, 2014, 5(22), 11029-11037.
[http://dx.doi.org/10.18632/oncotarget.2789] [PMID: 25415228]
[13]
Siegelin, M.D.; Dohi, T.; Raskett, C.M.; Orlowski, G.M.; Powers, C.M.; Gilbert, C.A.; Ross, A.H.; Plescia, J.; Altieri, D.C. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J. Clin. Invest., 2011, 121(4), 1349-1360.
[http://dx.doi.org/10.1172/JCI44855] [PMID: 21364280]
[14]
Wang, W.; Zhou, Y.; Yao, Q.; Liu, W.; Xiang, L.; Ni, T.; Dai, X.; Liu, Y. Celastrus Orbiculatus extract potentiates the sensitivity of cispla-tin via caspase-depenent apoptosis in gastric cancer. Anticancer. Agents Med. Chem., 2018, 18(15), 2206-2211.
[http://dx.doi.org/10.2174/1871520618666180911110124] [PMID: 30205802]
[15]
Zhang, H.; Qian, Y.; Liu, Y.; Li, G.; Cui, P.; Zhu, Y.; Ma, H.; Ji, X.; Guo, S.; Tadashi, H. Celastrus orbiculatus extract induces mitochon-drial-mediated apoptosis in human hepatocellular carcinoma cells. J. Tradit. Chin. Med., 2012, 32(4), 621-626.
[http://dx.doi.org/10.1016/S0254-6272(13)60081-3] [PMID: 23427399]
[16]
Zhou, F.; Du, J.; Wang, J. Albendazole inhibits HIF-1α-dependent glycolysis and VEGF expression in non-small cell lung cancer cells. Mol. Cell. Biochem., 2017, 428(1-2), 171-178.
[http://dx.doi.org/10.1007/s11010-016-2927-3] [PMID: 28063005]
[17]
Lee, D.H.; Cheul Oh, S.; Giles, A.J.; Jung, J.; Gilbert, M.R.; Park, D.M. Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells. Oncotarget, 2017, 8(25), 40233-40245.
[http://dx.doi.org/10.18632/oncotarget.16714] [PMID: 28410215]
[18]
Noman, M.Z.; Messai, Y.; Muret, J.; Hasmim, M.; Chouaib, S. Crosstalk between CTC, immune system and hypoxic tumor microenvi-ronment. Cancer Microenviron., 2014, 7(3), 153-160.
[http://dx.doi.org/10.1007/s12307-014-0157-3] [PMID: 25337680]
[19]
Gao, T.; Li, J.Z.; Lu, Y.; Zhang, C.Y.; Li, Q.; Mao, J.; Li, L.H. The mechanism between epithelial mesenchymal transition in breast cancer and hypoxia microenvironment. Biomed. Pharmacother., 2016, 80, 393-405.
[http://dx.doi.org/10.1016/j.biopha.2016.02.044] [PMID: 27133080]
[20]
Kim, E.J.; Kwon, K.A.; Lee, Y.E.; Kim, J.H.; Kim, S.H.; Kim, J.H. Korean Red Ginseng extract reduces hypoxia-induced epithelial-mesenchymal transition by repressing NF-κB and ERK1/2 pathways in colon cancer. J. Ginseng Res., 2018, 42(3), 288-297.
[http://dx.doi.org/10.1016/j.jgr.2017.03.008] [PMID: 29983610]
[21]
Yang, S.W.; Zhang, Z.G.; Hao, Y.X.; Zhao, Y.L.; Qian, F.; Shi, Y.; Li, P.A.; Liu, C.Y.; Yu, P.W. HIF-1α induces the epithelial-mesenchymal transition in gastric cancer stem cells through the Snail pathway. Oncotarget, 2017, 8(6), 9535-9545.
[http://dx.doi.org/10.18632/oncotarget.14484] [PMID: 28076840]
[22]
Liu, N.; Wang, Y.; Zhou, Y.; Pang, H.; Zhou, J.; Qian, P.; Liu, L.; Zhang, H. Krüppel-like factor 8 involved in hypoxia promotes the inva-sion and metastasis of gastric cancer via epithelial to mesenchymal transition. Oncol. Rep., 2014, 32(6), 2397-2404.
[http://dx.doi.org/10.3892/or.2014.3495] [PMID: 25333643]
[23]
Romano, E.; Vllahu, M.; Bizzarro, V.; Belvedere, R.; Esposito, R.; Petrella, A.; Tosco, A. TFF1 promotes EMT-like changes through an auto-induction mechanism. Int. J. Mol. Sci., 2018, 19(7), 2018.
[http://dx.doi.org/10.3390/ijms19072018] [PMID: 29997345]
[24]
Kannan, A.; Krishnan, A.; Ali, M.; Subramaniam, S.; Halagowder, D.; Sivasithamparam, N.D. Caveolin-1 promotes gastric cancer progres-sion by up-regulating epithelial to mesenchymal transition by crosstalk of signalling mechanisms under hypoxic condition. Eur. J. Cancer, 2014, 50(1), 204-215.
[http://dx.doi.org/10.1016/j.ejca.2013.08.016] [PMID: 24070739]
[25]
Zhang, W.J.; Chen, C.; Zhou, Z.H.; Gao, S.T.; Tee, T.J.; Yang, L.Q.; Xu, Y.Y.; Pang, T.H.; Xu, X.Y.; Sun, Q.; Feng, M.; Wang, H.; Lu, C.L.; Wu, G.Z.; Wu, S.; Guan, W.X.; Xu, G.F. Hypoxia-inducible factor-1 alpha correlates with tumor-associated macrophages infiltration, influences survival of gastric cancer patients. J. Cancer, 2017, 8(10), 1818-1825.
[http://dx.doi.org/10.7150/jca.19057] [PMID: 28819379]
[26]
Qin, W.; Li, C.; Zheng, W.; Guo, Q.; Zhang, Y.; Kang, M.; Zhang, B.; Yang, B.; Li, B.; Yang, H.; Wu, Y. Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells. Oncotarget, 2015, 6(37), 39839-39854.
[http://dx.doi.org/10.18632/oncotarget.5674] [PMID: 26497999]
[27]
Yu, P.; Fan, S.; Huang, L.; Yang, L.; Du, Y. MIR210 as a potential molecular target to block invasion and metastasis of gastric cancer. Med. Hypotheses, 2015, 84(3), 209-212.
[http://dx.doi.org/10.1016/j.mehy.2014.12.024] [PMID: 25618442]
[28]
Akanji, M.A.; Rotimi, D.; Adeyemi, O.S. Hypoxia-inducible factors as an alternative source of treatment strategy for cancer. Oxid. Med. Cell. Longev., 2019, 2019, 8547846.
[http://dx.doi.org/10.1155/2019/8547846] [PMID: 31485300]
[29]
Kiyozumi, Y.; Iwatsuki, M.; Kurashige, J.; Ogata, Y.; Yamashita, K.; Koga, Y.; Toihata, T.; Hiyoshi, Y.; Ishimoto, T.; Baba, Y.; Miyamoto, Y.; Yoshida, N.; Yanagihara, K.; Mimori, K.; Baba, H. PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer. Int. J. Cancer, 2018, 143(5), 1202-1211.
[http://dx.doi.org/10.1002/ijc.31410] [PMID: 29603227]
[30]
Han, Y.L.; Chen, L.; Qin, R.; Wang, G.Q.; Lin, X.H.; Dai, G.H. Lysyl oxidase and hypoxia-inducible factor 1α: Biomarkers of gastric can-cer. World J. Gastroenterol., 2019, 25(15), 1828-1839.
[http://dx.doi.org/10.3748/wjg.v25.i15.1828] [PMID: 31057297]
[31]
Palucka, A.K.; Coussens, L.M. The basis of oncoimmunology. Cell, 2016, 164(6), 1233-1247.
[http://dx.doi.org/10.1016/j.cell.2016.01.049] [PMID: 26967289]
[32]
Deng, R.; Mo, F.; Chang, B.; Zhang, Q.; Ran, H.; Yang, S.; Zhu, Z.; Hu, L.; Su, Q. Glucose-derived AGEs enhance human gastric cancer metastasis through RAGE/ERK/Sp1/MMP2 cascade. Oncotarget, 2017, 8(61), 104216-104226.
[http://dx.doi.org/10.18632/oncotarget.22185] [PMID: 29262634]
[33]
Shen, Y.G.; Feng, W.; Xu, Y.J.; Jiao, N.N.; Sun, D.Q.; Qu, W.D.; Tang, Q.; Xiong, W.; Tang, Y.; Xia, Y.; Cai, Q.Y.; Liu, D.X.; Zhang, X.; Xu, G.; Liang, G.Y. Effects of RNA silencing of matrix metalloproteinase-2 on the growth of esophageal carcinoma cells in vivo. Oncol. Lett., 2017, 13(3), 1119-1124.
[http://dx.doi.org/10.3892/ol.2016.5542] [PMID: 28454222]
[34]
Hadler-Olsen, E.; Solli, A.I.; Hafstad, A.; Winberg, J.O.; Uhlin-Hansen, L. Intracellular MMP-2 activity in skeletal muscle is associated with type II fibers. J. Cell. Physiol., 2015, 230(1), 160-169.
[http://dx.doi.org/10.1002/jcp.24694] [PMID: 24905939]
[35]
Peduk, S.; Tatar, C.; Dincer, M.; Ozer, B.; Kocakusak, A.; Citlak, G.; Akinci, M.; Tuzun, I.S. The Role of Serum CK18, TIMP1, and MMP-9 levels in predicting r0 resection in patients with gastric cancer. Dis. Markers, 2018, 2018, 5604702.
[http://dx.doi.org/10.1155/2018/5604702] [PMID: 29651326]
[36]
Biswas, S.K.; Allavena, P.; Mantovani, A. Tumor-associated macrophages: Functional diversity, clinical significance, and open questions. Semin. Immunopathol., 2013, 35(5), 585-600.
[http://dx.doi.org/10.1007/s00281-013-0367-7] [PMID: 23657835]
[37]
Hassanalilou, T.; Ghavamzadeh, S.; Khalili, L. Curcumin and gastric cancer: A review on mechanisms of action. J. Gastrointest. Cancer, 2019, 50(2), 185-192.
[http://dx.doi.org/10.1007/s12029-018-00186-6] [PMID: 30725357]
[38]
Zhang, H.X.; Kang, Y.; Li, N.; Wang, H.F.; Bao, Y.R.; Li, Y.W.; Li, X.Z.; Jiang, Z.; Chen, G. Triterpenoids from Liquidambar Fructus induced cell apoptosis via a PI3K-AKT related signal pathway in SMMC7721 cancer cells. Phytochemistry, 2020, 171, 112228.
[http://dx.doi.org/10.1016/j.phytochem.2019.112228] [PMID: 31911265]
[39]
Noel, P.; Von Hoff, D.D.; Saluja, A.K.; Velagapudi, M.; Borazanci, E.; Han, H. Triptolide and its derivatives as cancer therapies. Trends Pharmacol. Sci., 2019, 40(5), 327-341.
[http://dx.doi.org/10.1016/j.tips.2019.03.002] [PMID: 30975442]
[40]
Hou, D.; Xiong, J.; Li, Y.; Peng, Y.; Xiong, L. Efficacy and safety of Xiaoaiping injection for liver cancer: A protocol for systematic re-view and meta-analysis. Medicine (Baltimore), 2020, 99(35), e21993.
[http://dx.doi.org/10.1097/MD.0000000000021993] [PMID: 32871951]
[41]
Wang, H.; Tao, L.; Ni, T.; Gu, H.; Jin, F.; Dai, X.; Feng, J.; Ding, Y.; Xiao, W.; Guo, S.; Hisamitsu, T.; Qian, Y.; Liu, Y. Anticancer efficacy of the ethyl acetate extract from the traditional Chinese Medicine herb Celastrus orbiculatus against human gastric cancer. J. Ethnopharmacol., 2017, 205, 147-157.
[http://dx.doi.org/10.1016/j.jep.2017.04.030] [PMID: 28476678]
[42]
Jue, C.; Min, Z.; Zhisheng, Z.; Lin, C.; Yayun, Q.; Xuanyi, W.; Feng, J.; Haibo, W.; Youyang, S.; Tadashi, H.; Shintaro, I.; Shiyu, G.; Yan-qing, L. COE inhibits vasculogenic mimicry in hepatocellular carcinoma via suppressing Notch1 signaling. J. Ethnopharmacol., 2017, 208, 165-173.
[http://dx.doi.org/10.1016/j.jep.2017.07.007] [PMID: 28694103]
[43]
Jiang, W.; Shan, T.Z.; Xu, J.J.; Chen, W.J.; Miao, L.; Lv, M.Y.; Tao, L.; Liu, Y.Q. Cytotoxic abietane and kaurane diterpenoids from Celas-trus orbiculatus. J. Nat. Med., 2019, 73(4), 841-846.
[http://dx.doi.org/10.1007/s11418-019-01326-3] [PMID: 31197550]
[44]
Chu, Z.; Shi, X.; Chen, G.; He, X.; Qian, Y.; Wang, H.; Tao, L.; Liu, Y.; Jiang, W.; Chen, J. COE inhibits vasculogenic mimicry by targeting epha2 in hepatocellular carcinoma, a research based on proteomics analysis. Front. Pharmacol., 2021, 12, 619732.
[http://dx.doi.org/10.3389/fphar.2021.619732] [PMID: 33867982]
[45]
Chu, Z.; Wang, H.; Ni, T.; Tao, L.; Xiang, L.; Zhou, Z.; Qian, Y.; Sunagawa, M.; Liu, Y. 28-Hydroxy-3-oxoolean-12-en-29-oic acid, a triterpene acid from Celastrus Orbiculatus extract, inhibits the migration and invasion of human gastric cancer cells in vitro. Molecules, 2019, 24(19), 3513.
[http://dx.doi.org/10.3390/molecules24193513] [PMID: 31569766]
[46]
Yang, L.; Liu, Y.; Wang, M.; Qian, Y.; Dai, X.; Zhu, Y.; Chen, J.; Guo, S.; Hisamitsu, T. Celastrus orbiculatus extract triggers apoptosis and autophagy via PI3K/Akt/mTOR inhibition in human colorectal cancer cells. Oncol. Lett., 2016, 12(5), 3771-3778.
[http://dx.doi.org/10.3892/ol.2016.5213] [PMID: 27895729]
[47]
Zhu, Y.; Liu, Y.; Qian, Y.; Dai, X.; Yang, L.; Chen, J.; Guo, S.; Hisamitsu, T. Antimetastatic effects of Celastrus orbiculatus on human gastric adenocarcinoma by inhibiting epithelial-mesenchymal transition and NF-κB/snail signaling pathway. Integr. Cancer Ther., 2015, 14(3), 271-281.
[http://dx.doi.org/10.117S7/1534735415572880] [PMID: 25722220]

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