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ISSN (Online): 1873-4286

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Research Article

Artesunate Inhibits the Growth of Insulinoma Cells via SLC7A11/ GPX4-mediated Ferroptosis

Author(s): Fengping Chen, Jiexia Lu, Biaolin Zheng, Nan Yi, Chunxiao Xie, Feiran Chen, Dafu Wei, Haixing Jiang* and Shanyu Qin*

Volume 30, Issue 3, 2024

Published on: 11 January, 2024

Page: [230 - 239] Pages: 10

DOI: 10.2174/0113816128289372240105041038

Price: $65

Abstract

Background: Artesunate (ART) has been recognized to induce ferroptosis in various tumor phenotypes, including neuroendocrine tumors. We aimed to investigate the effects of ART on insulinoma and the underlying mechanisms by focusing on the process of ferroptosis.

Methods: The CCK8 and colony formation assays were conducted to assess the effectiveness of ART. Lipid peroxidation, glutathione, and intracellular iron content were determined to validate the process of ferroptosis, while ferrostatin-1 (Fer-1) was employed as the inhibitor of ferroptosis. Subcutaneous tumor models were established and treated with ART. The ferroptosis-associated proteins were determined by western blot and immunohistochemistry assays. Pathological structures of the liver were examined by hematoxylin-eosin staining.

Results: ART suppressed the growth of insulinoma both in vitro and in vivo. Insulinoma cells treated by ART revealed signs of ferroptosis, including increased lipid peroxidation, diminished glutathione levels, and ascending intracellular iron. Notably, ART-treated insulinoma cells exhibited a decline in the expressions of catalytic component solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). These alterations were negated by Fer-1. Moreover, no hepatotoxicity was observed upon the therapeutic dose of ART.

Conclusion: Artesunate might regulate ferroptosis of insulinoma cells through the SLC7A11/GPX4 pathway.

« Previous
[1]
Hofland J, Kaltsas G, de Herder WW. Advances in the diagnosis and management of well-differentiated neuroendocrine neoplasms. Endocr Rev 2020; 41(2): 371-403.
[http://dx.doi.org/10.1210/endrev/bnz004] [PMID: 31555796]
[2]
Liu Q, Duan J, Zheng Y, Luo J, Cai X, Tan H. Rare malignant insulinoma with multiple liver metastases derived from ectopic pancreas: 3-year follow-up and literature review. OncoTargets Ther 2018; 11: 1813-9.
[http://dx.doi.org/10.2147/OTT.S154991] [PMID: 29662318]
[3]
Crinò SF, Partelli S, Napoleon B, et al. Study protocol for a multicenter randomized controlled trial to compare radiofrequency ablation with surgical resection for treatment of pancreatic insulinoma. Dig Liver Dis 2023; 55(9): 1187-93.
[http://dx.doi.org/10.1016/j.dld.2023.06.021] [PMID: 37407318]
[4]
Jilesen APJ, van Eijck CHJ, in’t Hof KH, van Dieren S, Gouma DJ, van Dijkum EJMN. Postoperative complications, in-hospital mortality and 5-year survival after surgical resection for patients with a pancreatic neuroendocrine tumor: A systematic review. World J Surg 2016; 40(3): 729-48.
[http://dx.doi.org/10.1007/s00268-015-3328-6] [PMID: 26661846]
[5]
El Sayed G, Frim L, Franklin J, et al. Endoscopic ultrasound-guided ethanol and radiofrequency ablation of pancreatic insulinomas: A systematic literature review. Therap Adv Gastroenterol 2021; 14: 17562848211042171.
[http://dx.doi.org/10.1177/17562848211042171] [PMID: 34819995]
[6]
Crinò SF, Napoleon B, Facciorusso A, et al. Endoscopic ultrasound-guided radiofrequency ablation versus surgical resection for treatment of pancreatic insulinoma. Clin Gastroenterol Hepatol 2023; 1542-3565.
[http://dx.doi.org/10.1016/j.cgh.2023.02.022]
[7]
Choi JH, Seo DW, Song TJ, et al. Endoscopic ultrasound-guided radiofrequency ablation for management of benign solid pancreatic tumors. Endoscopy 2018; 50(11): 1099-104.
[http://dx.doi.org/10.1055/a-0583-8387] [PMID: 29727904]
[8]
Marx M, Godat S, Caillol F, et al. Management of non-functional pancreatic neuroendocrine tumors by endoscopic ultrasound-guided radiofrequency ablation: Retrospective study in two tertiary centers. Dig Endosc 2022; 34(6): 1207-13.
[http://dx.doi.org/10.1111/den.14224] [PMID: 34963025]
[9]
Magi L, Marasco M, Rinzivillo M, Faggiano A, Panzuto F. Management of functional pancreatic neuroendocrine neoplasms. Curr Treat Options Oncol 2023; 24(7): 725-41.
[http://dx.doi.org/10.1007/s11864-023-01085-0] [PMID: 37103745]
[10]
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5): 1060-72.
[http://dx.doi.org/10.1016/j.cell.2012.03.042] [PMID: 22632970]
[11]
Yu P, Zhang J, Ding Y, et al. Dexmedetomidine post-conditioning alleviates myocardial ischemia-reperfusion injury in rats by ferroptosis inhibition via SLC7A11/GPX4 axis activation. Hum Cell 2022; 35(3): 836-48.
[http://dx.doi.org/10.1007/s13577-022-00682-9] [PMID: 35212945]
[12]
Jiang X, Stockwell BR, Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22(4): 266-82.
[http://dx.doi.org/10.1038/s41580-020-00324-8] [PMID: 33495651]
[13]
Gong Y, Wang N, Liu N, Dong H. Lipid peroxidation and GPX4 inhibition are common causes for myofibroblast differentiation and ferroptosis. DNA Cell Biol 2019; 38(7): 725-33.
[http://dx.doi.org/10.1089/dna.2018.4541] [PMID: 31140862]
[14]
Xu T, Ding W, Ji X, et al. Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med 2019; 23(8): 4900-12.
[http://dx.doi.org/10.1111/jcmm.14511] [PMID: 31232522]
[15]
Ye Z, Chen H, Ji S, et al. MEN1 promotes ferroptosis by inhibiting mTOR-SCD1 axis in pancreatic neuroendocrine tumors. Acta Biochim Biophys Sin 2022; 54(11): 1599-609.
[http://dx.doi.org/10.3724/abbs.2022162] [PMID: 36604142]
[16]
Ye M, Lu F, Chen J, et al. Orlistat induces ferroptosis in pancreatic neuroendocrine tumors by inactivating the MAPK pathway. J Cancer 2023; 14(8): 1458-69.
[http://dx.doi.org/10.7150/jca.83118] [PMID: 37283794]
[17]
Miotto G, Rossetto M, Di Paolo ML, et al. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol 2020; 28: 101328.
[http://dx.doi.org/10.1016/j.redox.2019.101328] [PMID: 31574461]
[18]
Augustin Y, Staines HM, Krishna S. Artemisinins as a novel anti- cancer therapy: Targeting a global cancer pandemic through drug repurposing. Pharmacol Ther 2020; 216: 107706.
[http://dx.doi.org/10.1016/j.pharmthera.2020.107706] [PMID: 33075360]
[19]
Efferth T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol 2017; 46: 65-83.
[http://dx.doi.org/10.1016/j.semcancer.2017.02.009] [PMID: 28254675]
[20]
Zhao F, Vakhrusheva O, Markowitsch SD, et al. Artesunate impairs growth in cisplatin-resistant bladder cancer cells by cell cycle arrest, apoptosis and autophagy induction. Cells 2020; 9(12): 2643.
[http://dx.doi.org/10.3390/cells9122643] [PMID: 33316936]
[21]
Song Q, Peng S, Che F, Zhu X. Artesunate induces ferroptosis via modulation of p38 and ERK signaling pathway in glioblastoma cells. J Pharmacol Sci 2022; 148(3): 300-6.
[http://dx.doi.org/10.1016/j.jphs.2022.01.007] [PMID: 35177209]
[22]
Yan G, Dawood M, Böckers M, et al. Multiple modes of cell death in neuroendocrine tumors induced by artesunate. Phytomedicine 2020; 79: 153332.
[http://dx.doi.org/10.1016/j.phymed.2020.153332] [PMID: 32957040]
[23]
Hu P, Ni C, Teng P. Effects of artesunate on the malignant biological behaviors of non-small cell lung cancer in human and its mechanism. Bioengineered 2022; 13(3): 6590-9.
[http://dx.doi.org/10.1080/21655979.2022.2042141] [PMID: 35361045]
[24]
Huang Z, Gan S, Zhuang X, et al. Artesunate inhibits the cell growth in colorectal cancer by promoting ros-dependent cell senescence and autophagy. Cells 2022; 11(16): 2472.
[http://dx.doi.org/10.3390/cells11162472] [PMID: 36010550]
[25]
Li Z, Dai H, Huang X, et al. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin 2021; 42(2): 301-10.
[http://dx.doi.org/10.1038/s41401-020-0478-3] [PMID: 32699265]
[26]
Markowitsch SD, Schupp P, Lauckner J, et al. Artesunate inhibits growth of sunitinib-resistant renal cell carcinoma cells through cell cycle arrest and induction of ferroptosis. Cancers 2020; 12(11): 3150.
[http://dx.doi.org/10.3390/cancers12113150] [PMID: 33121039]
[27]
Cao D, Chen D, Xia JN, et al. Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation. Biomed Pharmacother 2022; 155: 113705.
[http://dx.doi.org/10.1016/j.biopha.2022.113705] [PMID: 36271541]
[28]
Hänninen MM, Haapasalo J, Haapasalo H, et al. Expression of iron-related genes in human brain and brain tumors. BMC Neurosci 2009; 10(1): 36.
[http://dx.doi.org/10.1186/1471-2202-10-36] [PMID: 19386095]
[29]
Boult J, Roberts K, Brookes MJ, et al. Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res 2008; 14(2): 379-87.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-1054] [PMID: 18223212]
[30]
Calzolari A, Oliviero I, Deaglio S, et al. Transferrin receptor 2 is frequently expressed in human cancer cell lines. Blood Cells Mol Dis 2007; 39(1): 82-91.
[http://dx.doi.org/10.1016/j.bcmd.2007.02.003] [PMID: 17428703]
[31]
Huang X. Iron overload and its association with cancer risk in humans: Evidence for iron as a carcinogenic metal. Mutat Res 2003; 533(1-2): 153-71.
[http://dx.doi.org/10.1016/j.mrfmmm.2003.08.023] [PMID: 14643418]
[32]
Oh S, Kim BJ, Singh NP, Lai H, Sasaki T. Synthesis and anti- cancer activity of covalent conjugates of artemisinin and a transferrin-receptor targeting peptide. Cancer Lett 2009; 274(1): 33-9.
[http://dx.doi.org/10.1016/j.canlet.2008.08.031] [PMID: 18838215]
[33]
Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol 2017; 11: 254-62.
[http://dx.doi.org/10.1016/j.redox.2016.12.010] [PMID: 28012440]
[34]
Koskenkorva-Frank TS, Weiss G, Koppenol WH, Burckhardt S. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: Insights into the potential of various iron therapies to induce oxidative and nitrosative stress. Free Radic Biol Med 2013; 65: 1174-94.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.09.001] [PMID: 24036104]
[35]
Lane DJR, Merlot AM, Huang MLH, et al. Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease. Biochim Biophys Acta Mol Cell Res 2015; 1853(5): 1130-44.
[http://dx.doi.org/10.1016/j.bbamcr.2015.01.021] [PMID: 25661197]
[36]
Coffey R, Ganz T. Iron homeostasis: An anthropocentric perspective. J Biol Chem 2017; 292(31): 12727-34.
[http://dx.doi.org/10.1074/jbc.R117.781823] [PMID: 28615456]
[37]
Wu X, Li Y, Zhang S, Zhou X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics 2021; 11(7): 3052-9.
[http://dx.doi.org/10.7150/thno.54113] [PMID: 33537073]
[38]
Xie Y, Hou W, Song X, et al. Ferroptosis: Process and function. Cell Death Differ 2016; 23(3): 369-79.
[http://dx.doi.org/10.1038/cdd.2015.158] [PMID: 26794443]
[39]
Wei S, Liu L, Chen Z, et al. Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence. J Cell Mol Med 2020; 24(1): 276-84.
[http://dx.doi.org/10.1111/jcmm.14717] [PMID: 31746143]
[40]
Ilett KF, Ethell BT, Maggs JL, et al. Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos 2002; 30(9): 1005-12.
[http://dx.doi.org/10.1124/dmd.30.9.1005] [PMID: 12167566]
[41]
Song X, Zhu S, Chen P, et al. AMPK-Mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc– activity. Curr Biol 2018; 28(15): 2388-2399.e5.
[http://dx.doi.org/10.1016/j.cub.2018.05.094] [PMID: 30057310]
[42]
Elgendy SM, Alyammahi SK, Alhamad DW, Abdin SM, Omar HA. Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance. Crit Rev Oncol Hematol 2020; 155: 103095.
[http://dx.doi.org/10.1016/j.critrevonc.2020.103095] [PMID: 32927333]
[43]
Li Q, Peng F, Yan X, et al. Inhibition of SLC7A11-GPX4 signal pathway is involved in aconitine-induced ferroptosis in vivo and in vitro. J Ethnopharmacol 2023; 303: 116029.
[http://dx.doi.org/10.1016/j.jep.2022.116029] [PMID: 36503029]
[44]
Guo S, Zhao W, Zhang W, Li S, Teng G, Liu L. Vitamin D promotes ferroptosis in colorectal cancer stem cells via SLC7A11 downregulation. Oxid Med Cell Longev 2023; 2023: 1-16.
[http://dx.doi.org/10.1155/2023/4772134] [PMID: 36846715]
[45]
Guan X, Li Z, Zhu S, et al. Galangin attenuated cerebral ischemia-reperfusion injury by inhibition of ferroptosis through activating the SLC7A11/GPX4 axis in gerbils. Life Sci 2021; 264: 118660.
[http://dx.doi.org/10.1016/j.lfs.2020.118660] [PMID: 33127512]
[46]
Yuan Y, Zhai Y, Chen J, Xu X, Wang H. Kaempferol ameliorates oxygen-glucose deprivation/reoxygenation-induced neuronal ferroptosis by activating Nrf2/SLC7A11/GPX4 axis. Biomolecules 2021; 11(7): 923.
[http://dx.doi.org/10.3390/biom11070923] [PMID: 34206421]

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