{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T01:29:01Z","timestamp":1788830941150,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T00:00:00Z","timestamp":1567123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2016R1A6A1A03012862"],"award-info":[{"award-number":["2016R1A6A1A03012862"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Breast cancer stem cells (BCSCs) are tumor-initiating cells that possess the capacity for self-renewal. Cancer stem cells (CSCs) are responsible for poor outcomes caused by therapeutic resistance. In our study, we found that sulconazole\u2014an antifungal medicine in the imidazole class\u2014inhibited cell proliferation, tumor growth, and CSC formation. This compound also reduced the frequency of cells expressing CSC markers (CD44high\/CD24low) as well as the expression of another CSC marker, aldehyde dehydrogenase (ALDH), and other self-renewal-related genes. Sulconazole inhibited mammosphere formation, reduced the protein level of nuclear NF-\u03baB, and reduced extracellular IL-8 levels in mammospheres. Knocking down NF-\u03baB expression using a p65-specific siRNA reduced CSC formation and secreted IL-8 levels in mammospheres. Sulconazole reduced nuclear NF-\u03baB protein levels and secreted IL-8 levels in mammospheres. These new findings show that sulconazole blocks the NF-\u03baB\/IL-8 signaling pathway and CSC formation. NF-\u03baB\/IL-8 signaling is important for CSC formation and may be an important therapeutic target for BCSC treatment.<\/jats:p>","DOI":"10.3390\/cells8091007","type":"journal-article","created":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T10:31:17Z","timestamp":1567161077000},"page":"1007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Disruption of the NF-\u03baB\/IL-8 Signaling Axis by Sulconazole Inhibits Human Breast Cancer Stem Cell Formation"],"prefix":"10.3390","volume":"8","author":[{"given":"Hack Sun","family":"Choi","sequence":"first","affiliation":[{"name":"School of Biomaterials Sciences and Technology, College of Applied Life Science, Jeju National University, Jeju 63243, Korea"},{"name":"Subtropical\/tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Hyang","family":"Kim","sequence":"additional","affiliation":[{"name":"Interdisciplinary Graduate Program in Advanced Convergence Technology &amp; Science, Jeju National University, Jeju 63243, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Lim","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Biomaterials Sciences and Technology, College of Applied Life Science, Jeju National University, Jeju 63243, Korea"},{"name":"Interdisciplinary Graduate Program in Advanced Convergence Technology &amp; Science, Jeju National University, Jeju 63243, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Sun","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Biomaterials Sciences and Technology, College of Applied Life Science, Jeju National University, Jeju 63243, Korea"},{"name":"Subtropical\/tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea"},{"name":"Interdisciplinary Graduate Program in Advanced Convergence Technology &amp; Science, Jeju National University, Jeju 63243, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3322\/caac.21262","article-title":"Global cancer statistics, 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.gene.2018.09.052","article-title":"Cancer stem cells: A brief review of the current status","volume":"681","author":"Kusoglu","year":"2019","journal-title":"Gene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nm0797-730","article-title":"Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell","volume":"3","author":"Bonnet","year":"1997","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10233","DOI":"10.1158\/0008-5472.CAN-06-1464","article-title":"Heparanase, hyaluronan, and CD44 in cancers: A breast carcinoma perspective","volume":"66","author":"Gotte","year":"2006","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.1038\/onc.2012.638","article-title":"Redox regulation in stem-like cancer cells by CD44 variant isoforms","volume":"32","author":"Nagano","year":"2013","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2925869","DOI":"10.1155\/2017\/2925869","article-title":"Targeting Signaling Pathways in Cancer Stem Cells for Cancer Treatment","volume":"2017","author":"Koury","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1182\/blood.V98.8.2301","article-title":"Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells","volume":"98","author":"Guzman","year":"2001","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"37340","DOI":"10.1038\/srep37340","article-title":"NF-kappaBeta-inducing kinase regulates stem cell phenotype in breast cancer","volume":"6","author":"Torres","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3389\/fonc.2018.00166","article-title":"Inhibition of NF-kappaB Signaling Reduces the Stemness Characteristics of Lung Cancer Stem Cells","volume":"8","author":"Zakaria","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6125","DOI":"10.1158\/1078-0432.CCR-10-2743","article-title":"Regulation of cancer stem cells by cytokine networks: Attacking cancer\u2019s inflammatory roots","volume":"17","author":"Korkaya","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Silva, E.M., Mariano, V.S., Pastrez, P.R.A., Pinto, M.C., Castro, A.G., Syrjanen, K.J., and Longatto-Filho, A. (2017). High systemic IL-6 is associated with worse prognosis in patients with non-small cell lung cancer. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181125"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1093722","DOI":"10.1080\/2162402X.2015.1093722","article-title":"Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis","volume":"5","author":"Lippitz","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3988","DOI":"10.1172\/JCI32533","article-title":"IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland","volume":"117","author":"Sansone","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/bcr3436","article-title":"Recent advances reveal IL-8 signaling as a potential key to targeting breast cancer stem cells","volume":"15","author":"Singh","year":"2013","journal-title":"Breast Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"494","DOI":"10.4062\/biomolther.2018.042","article-title":"Imidazole Antifungal Drugs Inhibit the Cell Proliferation and Invasion of Human Breast Cancer Cells","volume":"26","author":"Bae","year":"2018","journal-title":"Biomol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2165\/00003495-198835020-00004","article-title":"Sulconazole. A review of its antimicrobial activity and therapeutic use in superficial dermatomycoses","volume":"35","author":"Benfield","year":"1988","journal-title":"Drugs"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/cyto.a.20864","article-title":"Low-cost, high-throughput, automated counting of bacterial colonies","volume":"77","author":"Clarke","year":"2010","journal-title":"Cytom. Part A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12935-017-0392-z","article-title":"Screening of breast cancer stem cell inhibitors using a protein kinase inhibitor library","volume":"17","author":"Choi","year":"2017","journal-title":"Cancer Cell Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1002\/mc.22870","article-title":"Catechol derived from aronia juice through lactic acid bacteria fermentation inhibits breast cancer stem cell formation via modulation Stat3\/IL-6 signaling pathway","volume":"57","author":"Choi","year":"2018","journal-title":"Mol. Carcinog."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Choi, H.S., Kim, S.L., Kim, J.H., Deng, H.Y., Yun, B.S., and Lee, D.S. (2018). Triterpene Acid (3-O-p-Coumaroyltormentic Acid) Isolated From Aronia Extracts Inhibits Breast Cancer Stem Cell Formation through Downregulation of c-Myc Protein. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092528"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1124\/mol.104.008284","article-title":"Transcriptional regulation of mouse mu opioid receptor gene: Sp3 isoforms (M1, M2) function as repressors in neuronal cells to regulate the mu opioid receptor gene","volume":"67","author":"Choi","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9296439","DOI":"10.1155\/2019\/9296439","article-title":"Dihydrotanshinone-Induced NOX5 Activation Inhibits Breast Cancer Stem Cell through the ROS\/Stat3 Signaling Pathway","volume":"2019","author":"Kim","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.2147\/DDDT.S199182","article-title":"Caffeic acid phenethyl ester suppressed growth and metastasis of nasopharyngeal carcinoma cells by inactivating the NF-kappaB pathway","volume":"13","author":"Liang","year":"2019","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21332","article-title":"Cancer statistics, 2016","volume":"66","author":"Siegel","year":"2016","journal-title":"CA Cancer J. Clin."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.2741\/e478","article-title":"The role of cancer stem cells in relapse of solid tumors","volume":"4","author":"Yu","year":"2012","journal-title":"Front. Biosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"39","DOI":"10.21037\/sci.2018.10.05","article-title":"Breast cancer stem cells and the challenges of eradication: A review of novel therapies","volume":"5","author":"Saeg","year":"2018","journal-title":"Stem Cell Investig"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1186\/bcr1673","article-title":"Human breast cancer stem cell markers CD44 and CD24: Enriching for cells with functional properties in mice or in man?","volume":"9","author":"Fillmore","year":"2007","journal-title":"Breast Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1172\/JCI44745","article-title":"The JAK2\/STAT3 signaling pathway is required for growth of CD44(+)CD24(\u2212) stem cell-like breast cancer cells in human tumors","volume":"121","author":"Marotta","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"An, H., Kim, J.Y., Oh, E., Lee, N., Cho, Y., and Seo, J.H. (2015). Salinomycin Promotes Anoikis and Decreases the CD44+\/CD24\u2212 Stem-Like Population via Inhibition of STAT3 Activation in MDA-MB-231 Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141919"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Rinkenbaugh, A.L., and Baldwin, A.S. (2016). The NF-kappaB Pathway and Cancer Stem Cells. Cells, 5.","DOI":"10.3390\/cells5020016"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26167","DOI":"10.1074\/jbc.M113.477950","article-title":"Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappaB signaling in glioblastoma cancer stem cells regulates the Notch pathway","volume":"288","author":"Garner","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9090","DOI":"10.1073\/pnas.93.17.9090","article-title":"Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B","volume":"93","author":"Natarajan","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s10549-007-9798-y","article-title":"NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells","volume":"111","author":"Zhou","year":"2008","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.cyto.2018.03.020","article-title":"Cytokine-mediated therapeutic resistance in breast cancer","volume":"108","author":"Tan","year":"2018","journal-title":"Cytokine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1159\/000488166","article-title":"Upregulation of IL-11, an IL-6 Family Cytokine, Promotes Tumor Progression and Correlates with Poor Prognosis in Non-Small Cell Lung Cancer","volume":"45","author":"Zhao","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrclinonc.2018.8","article-title":"Targeting the IL-6\/JAK\/STAT3 signalling axis in cancer","volume":"15","author":"Johnson","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e94296","DOI":"10.1172\/jci.insight.94296","article-title":"Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer","volume":"2","author":"Dominguez","year":"2017","journal-title":"JCI Insight"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8247","DOI":"10.1038\/s41598-017-07495-z","article-title":"Characterisation of sterol biosynthesis and validation of 14alpha-demethylase as a drug target in Acanthamoeba","volume":"7","author":"Thomson","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/9\/1007\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:15:20Z","timestamp":1760188520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/9\/1007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,30]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["cells8091007"],"URL":"https:\/\/doi.org\/10.3390\/cells8091007","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,30]]}}}