{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:39:29Z","timestamp":1788885569462,"version":"build-2803163510"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:00:00Z","timestamp":1715299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Vandetanib is a small-molecule tyrosine kinase inhibitor. It exerts its therapeutic effects primarily in a range of lung cancers by inhibiting the vascular endothelial growth factor receptor 2. However, it remains unclear whether vandetanib has therapeutic benefits in other lung diseases, particularly asthma. The present study investigated the pioneering use of vandetanib in the treatment of asthma.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold><jats:italic>In vivo<\/jats:italic> experiments including establishment of an asthma model, measurement of airway resistance measurement and histological analysis were used primarily to confirm the anticontractile and anti-inflammatory effects of vandetanib, while <jats:italic>in vitro<\/jats:italic> experiments, including measurement of muscle tension and whole-cell patch-clamp recording, were used to explore the underlying molecular mechanism.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold><jats:italic>In vivo<\/jats:italic> experiments in an asthmatic mouse model showed that vandetanib could significantly alleviate systemic inflammation and a range of airway pathological changes including hypersensitivity, hypersecretion and remodeling. Subsequent <jats:italic>in vitro<\/jats:italic> experiments showed that vandetanib was able to relax the precontracted rings of the mouse trachea via calcium mobilization which was regulated by specific ion channels including VDLCC, NSCC, NCX and K<jats:sup>+<\/jats:sup> channels.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> Taken together, our study demonstrated that vandetanib has both anticontractile and anti-inflammatory properties in the treatment of asthma, which also suggests the feasibility of using vandetanib in the treatment of asthma by reducing abnormal airway contraction and systemic inflammation.<\/jats:p>","DOI":"10.3389\/fphar.2024.1345070","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T05:09:27Z","timestamp":1715317767000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Vandetanib as a prospective anti-inflammatory and anti-contractile agent in asthma"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiaoyue","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.3390\/cancers12082104","article-title":"Novel targeted therapies for metastatic thyroid cancer-A comprehensive review","volume":"12","author":"Al-Jundi","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.hoc.2018.05.012","article-title":"First-Generation and second-generation Bruton tyrosine kinase inhibitors in waldenstrom macroglobulinemia","volume":"32","author":"Argyropoulos","year":"2018","journal-title":"Hematol. Oncol. Clin. North Am."},{"key":"B3","doi-asserted-by":"publisher","first-page":"240","DOI":"10.3390\/jpm11040240","article-title":"Systems approaches to treatment response to imatinib in severe asthma: a pilot study","volume":"11","author":"Baek","year":"2021","journal-title":"J. Pers. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1124\/pr.116.012518","article-title":"Kinases as novel therapeutic targets in asthma and chronic obstructive pulmonary disease","volume":"68","author":"Barnes","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1007\/s10787-021-00798-8","article-title":"Bevacizumab regulates inflammatory cytokines and inhibits VEGFR2 signaling pathway in an ovalbumin-induced rat model of airway hypersensitivity","volume":"29","author":"Bolandi","year":"2021","journal-title":"Inflammopharmacology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1586\/1744666X.1.2.263","article-title":"Overview of novel therapeutic targets for asthma and chronic obstructive pulmonary disease","volume":"1","author":"Braido","year":"2005","journal-title":"Expert Rev. Clin. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1111\/j.1476-5381.2010.01054.x","article-title":"KB-R7943, an inhibitor of the reverse Na+\/Ca2+ exchanger, blocks N-methyl-D-aspartate receptor and inhibits mitochondrial complex I","volume":"162","author":"Brustovetsky","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","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":"B9","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.jaip.2017.04.027","article-title":"Management of severe asthma before referral to the severe asthma specialist","volume":"5","author":"Carr","year":"2017","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"B10","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3389\/fmed.2020.00098","article-title":"Needs for systems approaches to better treat individuals with severe asthma: predicting phenotypes and responses to treatments","volume":"7","author":"Colas","year":"2020","journal-title":"Front. Med. (Lausanne)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s12943-018-0782-4","article-title":"Mechanisms of receptor tyrosine kinase activation in cancer","volume":"17","author":"Du","year":"2018","journal-title":"Mol. Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1113\/JP282367","article-title":"Chronic stress facilitates bursting electrical activity in pituitary corticotrophs","volume":"600","author":"Duncan","year":"2021","journal-title":"J. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"CD012912","DOI":"10.1002\/14651858.CD012912.pub2","article-title":"Nifedipine for primary dysmenorrhoea","volume":"12","author":"Earl","year":"2021","journal-title":"Cochrane Database Syst. Rev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"761910","DOI":"10.3389\/fphys.2021.761910","article-title":"KCNQ1 potassium channel expressed in human sperm is involved in sperm motility, acrosome reaction, protein tyrosine phosphorylation, and ion homeostasis during capacitation","volume":"12","author":"Gao","year":"2021","journal-title":"Front. Physiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1167\/iovs.62.14.25","article-title":"Role of the phospholipase C pathway and calcium mobilization in oxytocin-induced contraction of lacrimal gland myoepithelial cells","volume":"62","author":"Garriz","year":"2021","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.2741\/3660","article-title":"TRPC channels in smooth muscle cells","volume":"15","author":"Gonzalez-Cobos","year":"2010","journal-title":"Front. Biosci. Landmark Ed."},{"key":"B17","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1007\/s12325-013-0069-5","article-title":"Vandetanib in advanced medullary thyroid cancer: review of adverse event management strategies","volume":"30","author":"Grande","year":"2013","journal-title":"Adv. Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1097\/ACI.0b013e32834ecb4f","article-title":"The potential use of tyrosine kinase inhibitors in severe asthma","volume":"12","author":"Guntur","year":"2012","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"G43","DOI":"10.1152\/ajpgi.1999.276.1.G43","article-title":"Cholestatic effects of the K+ channel blockers Ba2+ and TEA occur through different pathways in the rat liver","volume":"276","author":"Hill","year":"1999","journal-title":"Am. J. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"28485","DOI":"10.1073\/pnas.2003111117","article-title":"The odorant receptor OR2W3 on airway smooth muscle evokes bronchodilation via a cooperative chemosensory tradeoff between TMEM16A and CFTR","volume":"117","author":"Huang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/micc.12421","article-title":"K<sub>V<\/sub> channels and the regulation of vascular smooth muscle tone","volume":"25","author":"Jackson","year":"2018","journal-title":"Microcirculation"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2045894020956592","DOI":"10.1177\/2045894020956592","article-title":"Revisiting the mechanism of hypoxic pulmonary vasoconstriction using isolated perfused\/ventilated mouse lung","volume":"10","author":"Jain","year":"2020","journal-title":"Pulm. Circ."},{"key":"B23","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.phrs.2013.01.008","article-title":"Ion channel remodeling in vascular smooth muscle during hypertension: implications for novel therapeutic approaches","volume":"70","author":"Joseph","year":"2013","journal-title":"Pharmacol. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1542\/peds.2013-2273","article-title":"Dexamethasone for acute asthma exacerbations in children: a meta-analysis","volume":"133","author":"Keeney","year":"2014","journal-title":"Pediatrics"},{"key":"B25","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s12272-020-01232-3","article-title":"Small molecule tyrosine kinase inhibitors in glioblastoma","volume":"43","author":"Kim","year":"2020","journal-title":"Arch. Pharm. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1186\/s12931-019-1245-1","article-title":"Upregulation of MUC5AC by VEGF in human primary bronchial epithelial cells: implications for asthma","volume":"20","author":"Kim","year":"2019","journal-title":"Respir. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"111897","DOI":"10.1016\/j.yexcr.2020.111897","article-title":"Effects of dexamethasone on VEGF-induced MUC5AC expression in human primary bronchial epithelial cells: implications for asthma","volume":"389","author":"Kim","year":"2020","journal-title":"Exp. Cell Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1016\/j.jaci.2021.11.026","article-title":"Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma","volume":"149","author":"Lechner","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s10020-023-00748-w","article-title":"PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model","volume":"29","author":"Li","year":"2023","journal-title":"Mol. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.ejmech.2018.03.062","article-title":"The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: a mini-review","volume":"151","author":"Liang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1007\/s11596-020-2293-y","article-title":"A selective TRPC3 inhibitor Pyr3 attenuates myocardial ischemia\/reperfusion injury in mice","volume":"40","author":"Lu","year":"2020","journal-title":"Curr. Med. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/nri2765","article-title":"The SYK tyrosine kinase: a crucial player in diverse biological functions","volume":"10","author":"Mocsai","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1358\/dot.2010.46.9.1516989","article-title":"Vandetanib: an overview of its clinical development in NSCLC and other tumors","volume":"46","author":"Morabito","year":"2010","journal-title":"Drugs Today (Barc)"},{"key":"B34","doi-asserted-by":"publisher","first-page":"55","DOI":"10.2174\/1568009620666201009130008","article-title":"Tyrosine kinase inhibitors (TKIs) in lung cancer treatment: a comprehensive analysis","volume":"21","author":"Murugesan","year":"2021","journal-title":"Curr. Cancer Drug Targets"},{"key":"B35","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1183\/09059180.00007609","article-title":"Investigational therapeutics targeting the IL-4\/IL-13\/STAT-6 pathway for the treatment of asthma","volume":"19","author":"Oh","year":"2010","journal-title":"Eur. Respir. Rev."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.1002\/cphy.c200031","article-title":"The cardiac Na(+) -Ca(2+) exchanger: from structure to function","volume":"12","author":"Ottolia","year":"2021","journal-title":"Compr. Physiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1200\/JCO.2011.37.4231","article-title":"Expression of tumor-derived vascular endothelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung","volume":"30","author":"Pajares","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1007\/s10753-023-01892-5","article-title":"Duloxetine HCl alleviates asthma symptoms by regulating PI3K\/AKT\/mTOR and Nrf2\/HO-1 signaling pathways","volume":"46","author":"Peng","year":"2023","journal-title":"Inflammation"},{"key":"B39","doi-asserted-by":"publisher","first-page":"102154","DOI":"10.1016\/j.ceca.2019.102154","article-title":"On the special role of NCX in astrocytes: translating Na(+)-transients into intracellular Ca(2+) signals","volume":"86","author":"Rose","year":"2020","journal-title":"Cell Calcium"},{"key":"B40","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1007\/s13238-012-2076-8","article-title":"The BK channel: a vital link between cellular calcium and electrical signaling","volume":"3","author":"Rothberg","year":"2012","journal-title":"Protein Cell"},{"key":"B41","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1111\/1440-1681.12217","article-title":"Bitter tastants induce relaxation of rat thoracic aorta precontracted with high K(+)","volume":"41","author":"Sai","year":"2014","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"560361","DOI":"10.3389\/fphar.2020.560361","article-title":"Anti-contractile and anti-inflammatory effects of diacerein on isolated mouse airways smooth muscle and mouse asthma model","volume":"11","author":"Shi","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1540\/jsmr.39.231","article-title":"Nonselective cation channels activated by the stimulation of muscarinic receptors in mammalian gastric smooth muscle","volume":"39","author":"So","year":"2003","journal-title":"J. Smooth Muscle Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1097\/COC.0000000000000845","article-title":"A pilot study of preoperative vandetanib on markers of proliferation and apoptosis in breast cancer","volume":"44","author":"Spanheimer","year":"2021","journal-title":"Am. J. Clin. Oncol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1111\/1440-1681.13062","article-title":"Azithromycin inhibits muscarinic 2 receptor-activated and voltage-activated Ca(2+) permeant ion channels and Ca(2+) sensitization, relaxing airway smooth muscle contraction","volume":"46","author":"Wang","year":"2019","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1111\/cas.14801","article-title":"VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers","volume":"112","author":"Watanabe","year":"2021","journal-title":"Cancer Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"503","DOI":"10.3389\/fped.2019.00503","article-title":"Oral dexamethasone vs. Oral prednisone for children with acute asthma exacerbations: a systematic review and meta-analysis","volume":"7","author":"Wei","year":"2019","journal-title":"Front. Pediatr."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.3389\/fphys.2018.01785","article-title":"Potential arrhythmogenic role of TRPC channels and store-operated calcium entry mechanism in mouse ventricular myocytes","volume":"9","author":"Wen","year":"2018","journal-title":"Front. Physiol."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20190534","article-title":"Coptisine, a protoberberine alkaloid, relaxes mouse airway smooth muscle via blockade of VDLCCs and NSCCs","volume":"40","author":"Wen","year":"2020","journal-title":"Biosci. Rep."},{"key":"B50","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1124\/jpet.113.208223","article-title":"Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis","volume":"349","author":"Wollin","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B51","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.coph.2005.01.009","article-title":"Inhibitors of the tyrosine kinase signaling cascade for asthma","volume":"5","author":"Wong","year":"2005","journal-title":"Curr. Opin. Pharmacol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.bbapap.2003.11.013","article-title":"Tyrosine kinase inhibitors: a new approach for asthma","volume":"1697","author":"Wong","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"B53","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s13045-016-0313-y","article-title":"Second-generation inhibitors of Bruton tyrosine kinase","volume":"9","author":"Wu","year":"2016","journal-title":"J. Hematol. Oncol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1002\/jcp.22231","article-title":"Extracellular high K+ stimulates vesicular glutamate release from astrocytes by activating voltage-dependent calcium channels","volume":"225","author":"Yaguchi","year":"2010","journal-title":"J. Cell Physiol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"153","DOI":"10.7888\/juoeh.41.153","article-title":"Treatment of non-small cell lung cancer with EGFR-mutations","volume":"41","author":"Yoneda","year":"2019","journal-title":"J. UOEH"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1345070\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T05:09:30Z","timestamp":1715317770000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1345070\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,10]]},"references-count":55,"alternative-id":["10.3389\/fphar.2024.1345070"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1345070","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,10]]},"article-number":"1345070"}}