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Vemurafenib (PLX4032), a specific inhibitor of BRAFV600E kinase, exhibits antitumor activity in patients with BRAFV600E-mutated thyroid cancer. However, the clinical benefit of PLX4032 is often limited by short-term response and acquired resistance via heterogeneous feedback mechanisms. Disulfiram (DSF), an alcohol-aversion drug, shows potent antitumor efficacy in a copper (Cu)-dependent way. However, its antitumor activity in thyroid cancer and its effect on cellular response to BRAF kinase inhibitors remain unclear. Antitumor effects of DSF\/Cu on BRAFV600E-mutated thyroid cancer cells and its effect on the response of these cells to BRAF kinase inhibitor PLX4032 were systematically assessed by a series of in vitro and in vivo functional experiments. The molecular mechanism underlying the sensitizing effect of DSF\/Cu on PLX4032 was explored by Western blot and flow cytometry assays. DSF\/Cu exhibited stronger inhibitory effects on the proliferation and colony formation of BRAFV600E-mutated thyroid cancer cells than DSF treatment alone. Further studies revealed that DSF\/Cu killed thyroid cancer cells by ROS-dependent suppression of MAPK\/ERK and PI3K\/AKT signaling pathways. Our data also showed that DSF\/Cu strikingly increased the response of BRAFV600E-mutated thyroid cancer cells to PLX4032. Mechanistically, DSF\/Cu sensitizes BRAF-mutant thyroid cancer cells to PLX4032 by inhibiting HER3 and AKT in an ROS-dependent way and subsequently relieving feedback activation of MAPK\/ERK and PI3K\/AKT pathways. This study not only implies potential clinical use of DSF\/Cu in cancer therapy but also provides a new therapeutic strategy for BRAFV600E-mutated thyroid cancers.<\/jats:p>","DOI":"10.3390\/ijms24043418","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T01:59:43Z","timestamp":1675907983000},"page":"3418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Disulfiram\/Cu Kills and Sensitizes BRAF-Mutant Thyroid Cancer Cells to BRAF Kinase Inhibitor by ROS-Dependently Relieving Feedback Activation of MAPK\/ERK and PI3K\/AKT Pathways"],"prefix":"10.3390","volume":"24","author":[{"given":"Jingyi","family":"Xie","sequence":"first","affiliation":[{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinru","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuelei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxin","family":"Cao","sequence":"additional","affiliation":[{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiju","family":"Ji","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingwei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Hou","sequence":"additional","affiliation":[{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/nrendo.2016.110","article-title":"The changing incidence of thyroid cancer","volume":"12","author":"Kitahara","year":"2016","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1089\/thy.2021.0662","article-title":"Thyroid Cancer Incidence and Mortality Trends in the United States: 2000\u20132018","volume":"32","author":"Megwalu","year":"2022","journal-title":"Thyroid"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1001\/jama.2017.2719","article-title":"Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974\u20132013","volume":"317","author":"Lim","year":"2017","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/nrc3431","article-title":"Molecular pathogenesis and mechanisms of thyroid cancer","volume":"13","author":"Xing","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.otc.2008.07.001","article-title":"Recent advances in molecular biology of thyroid cancer and their clinical implications","volume":"41","author":"Xing","year":"2008","journal-title":"Otolaryngol. Clin. North Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1677\/erc.1.0978","article-title":"BRAF mutation in thyroid cancer","volume":"12","author":"Xing","year":"2005","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1210\/er.2007-0007","article-title":"BRAF mutation in papillary thyroid cancer: Pathogenic role, molecular bases, and clinical implications","volume":"28","author":"Xing","year":"2007","journal-title":"Endocr. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1001\/jama.2013.3190","article-title":"Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer","volume":"309","author":"Xing","year":"2013","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1200\/JCO.2014.56.8253","article-title":"Association between BRAF V600E mutation and recurrence of papillary thyroid cancer","volume":"33","author":"Xing","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1210\/jc.2011-3106","article-title":"A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome","volume":"97","author":"Guerra","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/sj.bjc.6603520","article-title":"Targeting BRAF in thyroid cancer","volume":"96","author":"Espinosa","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.critrevonc.2014.08.007","article-title":"The evolving field of kinase inhibitors in thyroid cancer","volume":"93","author":"Marotta","year":"2015","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103353","DOI":"10.1016\/j.critrevonc.2021.103353","article-title":"Kinase-inhibitors for iodine-refractory differentiated thyroid cancer: Still far from a structured therapeutic algorithm","volume":"162","author":"Marotta","year":"2021","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14903","DOI":"10.1073\/pnas.1008990107","article-title":"The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner","volume":"107","author":"Joseph","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1158\/2159-8290.CD-12-0531","article-title":"Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas","volume":"3","author":"Dominguez","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/S1470-2045(16)30166-8","article-title":"Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: A non-randomised, multicentre, open-label, phase 2 trial","volume":"17","author":"Brose","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1158\/1541-7786.MCR-07-2001","article-title":"BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells","volume":"6","author":"Sala","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nature10868","article-title":"Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR","volume":"483","author":"Prahallad","year":"2012","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature08833","article-title":"RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth","volume":"464","author":"Hatzivassiliou","year":"2010","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nature08902","article-title":"RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF","volume":"464","author":"Poulikakos","year":"2010","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.trecan.2020.05.009","article-title":"Clinical Development of BRAF plus MEK Inhibitor Combinations","volume":"6","author":"Subbiah","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.drudis.2011.12.010","article-title":"Nonprofit drugs as the salvation of the world\u2019s healthcare systems: The case of Antabuse (disulfiram)","volume":"17","author":"Cvek","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0006-2952(00)00586-4","article-title":"Determination of in vivo adducts of disulfiram with mitochondrial aldehyde dehydrogenase","volume":"61","author":"Shen","year":"2001","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6070","DOI":"10.1158\/1078-0432.CCR-09-1035","article-title":"High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth","volume":"15","author":"Iljin","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10425","DOI":"10.1158\/0008-5472.CAN-06-2126","article-title":"Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity","volume":"66","author":"Chen","year":"2006","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/1479-5876-12-163","article-title":"Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition","volume":"12","author":"Zha","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1002\/ijc.21534","article-title":"Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram","volume":"118","author":"Lovborg","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/bjc.2011.126","article-title":"Disulfiram modulated ROS-MAPK and NFkappaB pathways and targeted breast cancer cells with cancer stem cell-like properties","volume":"104","author":"Yip","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/j.molonc.2015.02.007","article-title":"Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer","volume":"9","author":"Allensworth","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nature25016","article-title":"Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4","volume":"552","author":"Skrott","year":"2017","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.canlet.2016.03.042","article-title":"Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals","volume":"387","author":"Prasad","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.drup.2004.01.004","article-title":"ROS stress in cancer cells and therapeutic implications","volume":"7","author":"Pelicano","year":"2004","journal-title":"Drug Resist. Updat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2006.10.029","article-title":"Dual role of hydrogen peroxide in cancer: Possible relevance to cancer chemoprevention and therapy","volume":"252","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzyme Regul."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1158\/1535-7163.MCT-10-0799","article-title":"BRAFV600E: Implications for carcinogenesis and molecular therapy","volume":"10","author":"Sheils","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105463","DOI":"10.1016\/j.phrs.2021.105463","article-title":"Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update","volume":"165","author":"Roskoski","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1210\/er.2019-00007","article-title":"Targeted Therapy for Advanced Thyroid Cancer: Kinase Inhibitors and Beyond","volume":"40","author":"Cabanillas","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.annonc.2021.12.014","article-title":"Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: Updated analysis from the phase II ROAR basket study","volume":"33","author":"Subbiah","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1056\/NEJMoa1103782","article-title":"Improved survival with vemurafenib in melanoma with BRAF V600E mutation","volume":"364","author":"Chapman","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1093\/annonc\/mdx339","article-title":"Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: Final overall survival results of the randomized BRIM-3 study","volume":"28","author":"Chapman","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1056\/NEJMoa1112302","article-title":"Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib","volume":"366","author":"Sosman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.phrs.2018.08.013","article-title":"Targeting oncogenic Raf protein-serine\/threonine kinases in human cancers","volume":"135","author":"Roskoski","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1056\/NEJMoa1502309","article-title":"Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations","volume":"373","author":"Hyman","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.canlet.2017.09.008","article-title":"MITF suppression improves the sensitivity of melanoma cells to a BRAF inhibitor","volume":"409","author":"Aida","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41419-022-04550-0","article-title":"Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib","volume":"13","author":"Hu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1158\/1535-7163.MCT-13-0212","article-title":"Synergistic combination of novel tubulin inhibitor ABI-274 and vemurafenib overcome vemurafenib acquired resistance in BRAFV600E melanoma","volume":"13","author":"Wang","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrd3461","article-title":"Mining for therapeutic gold","volume":"10","author":"Collins","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.semcancer.2020.01.008","article-title":"Repurposing drugs in oncology: From candidate selection to clinical adoption","volume":"68","author":"Pantziarka","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Ying, H., Qin, A., Cheng, T.S., Pavlos, N.J., Rea, S., Dai, K., and Zheng, M.H. (2015). Disulfiram attenuates osteoclast differentiation in vitro: A potential antiresorptive agent. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125696"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1089\/thy.2021.0246","article-title":"Disulfiram Exerts Antiadipogenic, Anti-Inflammatory, and Antifibrotic Therapeutic Effects in an In Vitro Model of Graves\u2019 Orbitopathy","volume":"32","author":"Wang","year":"2022","journal-title":"Thyroid"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.drudis.2020.04.003","article-title":"The combination of disulfiram and copper for cancer treatment","volume":"25","author":"Li","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/CMR.0b013e328334131d","article-title":"Disulfiram induces copper-dependent stimulation of reactive oxygen species and activation of the extrinsic apoptotic pathway in melanoma","volume":"20","author":"Morrison","year":"2010","journal-title":"Melanoma Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Chiba, T., Suzuki, E., Yuki, K., Zen, Y., Oshima, M., Miyagi, S., Saraya, A., Koide, S., Motoyama, T., and Ogasawara, S. (2014). Disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ROS-p38 MAPK pathway-dependent and -independent manners. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0084807"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/S0021-9258(19)70048-9","article-title":"Analyses of catalytic intermediates of hog thyroid peroxidase during its iodinating reaction","volume":"256","author":"Ohtaki","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.mce.2011.05.047","article-title":"Cell biology of H2O2 generation in the thyroid: Investigation of the control of dual oxidases (DUOX) activity in intact ex vivo thyroid tissue and cell lines","volume":"343","author":"Massart","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1056\/NEJMoa012752","article-title":"Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism","volume":"347","author":"Moreno","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Li, Y., Chen, F., Chen, J., Chan, S., He, Y., Liu, W., and Zhang, G. (2020). Disulfiram\/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS\/MAPK and Ferroptosis Pathways. Cancers, 12.","DOI":"10.3390\/cancers12010138"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"E962","DOI":"10.1210\/jc.2013-3147","article-title":"PRIMA-1, a mutant p53 reactivator, restores the sensitivity of TP53 mutant-type thyroid cancer cells to the histone methylation inhibitor 3-Deazaneplanocin A","volume":"99","author":"Cui","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1186\/s12951-021-01034-9","article-title":"Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment","volume":"19","author":"Wang","year":"2021","journal-title":"J. Nanobiotechnol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1089\/thy.2018.0312","article-title":"TBX1 Functions as a Tumor Suppressor in Thyroid Cancer Through Inhibiting the Activities of the PI3K\/AKT and MAPK\/ERK Pathways","volume":"29","author":"Wang","year":"2019","journal-title":"Thyroid"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3418\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:28:35Z","timestamp":1760120915000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,8]]},"references-count":63,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043418"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043418","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,8]]}}}