{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T11:27:32Z","timestamp":1768822052438,"version":"3.49.0"},"reference-count":30,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T00:00:00Z","timestamp":1721260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["24K18523"],"award-info":[{"award-number":["24K18523"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) is a cancer with a poor prognosis due to difficulties in diagnosis and limited treatment options, highlighting the urgent need for new targeted therapies. In a clinical setting, we found that leukotriene levels in bile were higher than in serum. Immunohistochemical analysis of surgically resected samples also revealed that CysLT receptor 1 (CysLTR1) was more highly expressed in CCA than in normal bile duct tissue, prompting us to investigate leukotriene as a potential therapeutic target in CCA. In vitro studies using CCA cell lines expressing CysLTR1 showed that leukotriene D4, a major ligand of CysLTR1, promoted cell proliferation, with increased phosphorylation of AKT and extracellular signal-regulated kinase 1\/2 (ERK1\/2). Additionally, treatment with two clinically available anti-allergic drugs\u2014zileuton, an inhibitor of CysLT formation, and montelukast, a CysLTR1 inhibitor\u2014had inhibitory effects on cell proliferation and migratory capacity, accompanied by the reduced phosphorylation of AKT and ERK1\/2. Furthermore, the simultaneous administration of both drugs synergistically enhanced the inhibitory effect on cell proliferation. Our study suggests that use of these drugs may represent a novel approach to treat CCA through drug repositioning.<\/jats:p>","DOI":"10.3390\/molecules29143379","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T14:59:50Z","timestamp":1721314790000},"page":"3379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Potential of Anti-Leukotriene Drugs as New Therapeutic Agents for Inhibiting Cholangiocarcinoma Progression"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3927-222X","authenticated-orcid":false,"given":"Yusuke","family":"Kito","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenta","family":"Kachi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"},{"name":"Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi 507-8522, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4167-2781","authenticated-orcid":false,"given":"Michihiro","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9510-2568","authenticated-orcid":false,"given":"Yasuki","family":"Hori","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7733-7854","authenticated-orcid":false,"given":"Akihisa","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3983-593X","authenticated-orcid":false,"given":"Hidenori","family":"Sahashi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadashi","family":"Toyohara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayoko","family":"Kuno","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihisa","family":"Adachi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Urakabe","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9491-0723","authenticated-orcid":false,"given":"Hiromi","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1073274817729245","DOI":"10.1177\/1073274817729245","article-title":"Epidemiology of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma","volume":"24","author":"Massarweh","year":"2017","journal-title":"Cancer Control"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Expert Consensus Document: Cholangiocarcinoma: Current Knowledge and Future Perspectives Consensus Statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)","volume":"13","author":"Banales","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sasaki, T., Takeda, T., Okamoto, T., Ozaka, M., and Sasahira, N. (2021). Chemotherapy for Biliary Tract Cancer in 2021. J. Clin. Med. Res., 10.","DOI":"10.3390\/jcm10143108"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Becht, R., and Wasilewicz, M.P. (2023). New Options for Systemic Therapies in Intrahepatic Cholangiocarcinoma (ICCA). Medicina, 59.","DOI":"10.3390\/medicina59061174"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1111\/jphp.13273","article-title":"Drug Repositioning: A Brief Overview","volume":"72","author":"Jourdan","year":"2020","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1111\/cas.14318","article-title":"Drug Repositioning in Cancer: The Current Situation in Japan","volume":"111","author":"Masuda","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"886","DOI":"10.3332\/ecancer.2018.886","article-title":"ReDO_DB: The Repurposing Drugs in Oncology Database","volume":"12","author":"Pantziarka","year":"2018","journal-title":"Ecancermedicalscience"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1002\/pros.22505","article-title":"Therapeutic Targeting of Angiotensin II Receptor Type 1 to Regulate Androgen Receptor in Prostate Cancer","volume":"72","author":"Takahashi","year":"2012","journal-title":"Prostate"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1007\/s00432-014-1873-2","article-title":"The Inhibition of Renin-Angiotensin System in Advanced Pancreatic Cancer: An Exploratory Analysis in 349 Patients","volume":"141","author":"Nakai","year":"2015","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1080\/0284186X.2020.1769185","article-title":"Desloratadine and Loratadine Stand out among Common H1-Antihistamines for Association with Improved Breast Cancer Survival","volume":"59","author":"Fritz","year":"2020","journal-title":"Acta Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"23979","DOI":"10.1038\/srep23979","article-title":"Cysteinyl Leukotriene Receptor Antagonists Decrease Cancer Risk in Asthma Patients","volume":"6","author":"Tsai","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1136\/gutjnl-2015-310442","article-title":"Reduced Risk of Pancreatic Cancer Associated with Asthma and Nasal Allergies","volume":"66","author":"Zock","year":"2017","journal-title":"Gut"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tsai, M.-J., Chang, W.-A., Chuang, C.-H., Wu, K.-L., Cheng, C.-H., Sheu, C.-C., Hsu, Y.-L., and Hung, J.-Y. (2021). Cysteinyl Leukotriene Pathway and Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010120"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kachi, K., Kato, H., Naiki-Ito, A., Komura, M., Nagano-Matsuo, A., Naitoh, I., Hayashi, K., Kataoka, H., Inaguma, S., and Takahashi, S. (2021). Anti-Allergic Drug Suppressed Pancreatic Carcinogenesis via Down-Regulation of Cellular Proliferation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147444"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.ejca.2009.12.022","article-title":"Low Expression of CysLT1R and High Expression of CysLT2R Mediate Good Prognosis in Colorectal Cancer","volume":"46","author":"Magnusson","year":"2010","journal-title":"Eur. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1158\/0008-5472.732.65.3","article-title":"A Novel Localization of the G-Protein-Coupled CysLT1 Receptor in the Nucleus of Colorectal Adenocarcinoma Cells","volume":"65","author":"Nielsen","year":"2005","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3156","DOI":"10.3390\/cancers3033156","article-title":"Upregulation of Leukotriene Receptors in Gastric Cancer","volume":"3","author":"Venerito","year":"2011","journal-title":"Cancers"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/ijc.25648","article-title":"Cysteinyl Leukotriene Receptor Expression Pattern Affects Migration of Breast Cancer Cells and Survival of Breast Cancer Patients","volume":"129","author":"Magnusson","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1100\/tsw.2007.200","article-title":"The Role of Leukotriene Receptor Signaling in Inflammation and Cancer","volume":"7","author":"Massoumi","year":"2007","journal-title":"Sci. World J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/S0006-291X(03)00187-6","article-title":"Regulation of Leukotriene-Dependent Induction of Cyclooxygenase-2 and Bcl-2","volume":"302","author":"Ohd","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41397-017-0006-0","article-title":"The Phosphatidylinositide 3-Kinase (PI3K) Signaling Pathway Is a Determinant of Zileuton Response in Adults with Asthma","volume":"18","author":"Dahlin","year":"2018","journal-title":"Pharmacogenom. J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tsai, M.-J., Chang, W.-A., Tsai, P.-H., Wu, C.-Y., Ho, Y.-W., Yen, M.-C., Lin, Y.-S., Kuo, P.-L., and Hsu, Y.-L. (2017). Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071353"},{"key":"ref_23","first-page":"99","article-title":"Overexpression of Cysteinyl LT1 Receptor in Prostate Cancer and CysLT1R Antagonist Inhibits Prostate Cancer Cell Growth through Apoptosis","volume":"18","author":"Matsuyama","year":"2007","journal-title":"Oncol. Rep."},{"key":"ref_24","first-page":"245","article-title":"Cysteinyl-Leukotriene1 Receptor Is a Potent Target for the Prevention and Treatment of Human Urological Cancer","volume":"3","author":"Matsuyama","year":"2010","journal-title":"Mol. Med. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7019","DOI":"10.2147\/OTT.S178942","article-title":"Zileuton Suppresses Cholangiocarcinoma Cell Proliferation and Migration through Inhibition of the Akt Signaling Pathway","volume":"11","author":"Khophai","year":"2018","journal-title":"Onco. Targets. Ther."},{"key":"ref_26","first-page":"4199","article-title":"Chemoprevention by Lipoxygenase and Leukotriene Pathway Inhibitors of Vinyl Carbamate-Induced Lung Tumors in Mice","volume":"62","author":"Gunning","year":"2002","journal-title":"Cancer Res."},{"key":"ref_27","first-page":"833","article-title":"Leukotriene Receptor Antagonists Inhibit Mitogenic Activity in Triple Negative Breast Cancer Cells","volume":"19","author":"Suknuntha","year":"2018","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3525","DOI":"10.1096\/fj.07-103457","article-title":"Expression of Enzymes and Receptors of the Leukotriene Pathway in Human Neuroblastoma Promotes Tumor Survival and Provides a Target for Therapy","volume":"22","author":"Rasmuson","year":"2008","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9190","DOI":"10.1158\/0008-5472.CAN-07-0771","article-title":"An Increased Expression of Cysteinyl Leukotriene 2 Receptor in Colorectal Adenocarcinomas Correlates with High Differentiation","volume":"67","author":"Magnusson","year":"2007","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Slater, K., Heeran, A.B., Garcia-Mulero, S., Kalirai, H., Sanz-Pamplona, R., Rahman, A., Al-Attar, N., Helmi, M., O\u2019Connell, F., and Bosch, R. (2020). High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells. Cancers, 12.","DOI":"10.1101\/2020.08.23.261545"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/14\/3379\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:19:11Z","timestamp":1760109551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/14\/3379"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,18]]},"references-count":30,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["molecules29143379"],"URL":"https:\/\/doi.org\/10.3390\/molecules29143379","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,18]]}}}