{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T06:42:30Z","timestamp":1793169750971,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,9,22]],"date-time":"2019-09-22T00:00:00Z","timestamp":1569110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"undefined  &lt;span style=&quot;color:gray;font-size:10px;&quot;&gt;undefined&lt;\/span&gt;","award":["European Society of Anaesthesiology Research Project Grant 2018, the College of Anaesthesiologists of Ireland Research Grant 2018, the British Journal of Anaesthesia International Grant 2016 and the AbbVie Research Grant of the College of Anaesthesiologis"],"award-info":[{"award-number":["European Society of Anaesthesiology Research Project Grant 2018, the College of Anaesthesiologists of Ireland Research Grant 2018, the British Journal of Anaesthesia International Grant 2016 and the AbbVie Research Grant of the College of Anaesthesiologis"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Breast cancer recurs in 20% of patients following intended curative resection. In vitro data indicates that amide local anaesthetics, including lidocaine, inhibit cancer cell metastasis by inhibiting the tyrosine kinase enzyme Src. In a murine breast cancer surgery model, systemic lidocaine reduces postoperative pulmonary metastases. We investigated whether the additional administration of bosutinib (a known Src inhibitor) influences lidocaine\u2019s observed beneficial effect in this in vivo model. Female BALB\/c mice (n = 95) were inoculated with 25,000 4T1 cells into the mammary fad pad and after 7 days the resulting tumours were excised under sevoflurane anaesthesia. Experimental animals were randomized to one of four treatments administered intravenously prior to excision: lidocaine, bosutinib, both lidocaine and bosutinib in combination, or saline. Animals were euthanized 14 days post-surgery and lung and liver metastatic colonies were evaluated. Post-mortem serum was analysed for MMP-2 and MMP-9, pro-metastatic enzymes whose expression is influenced by the Src pathway. Lidocaine reduced lung, but not liver metastatic colonies versus sevoflurane alone (p = 0.041), but bosutinib alone had no metastasis-inhibiting effect. When combined with lidocaine, bosutinib reversed the anti-metastatic effect observed with lidocaine on sevoflurane anaesthesia. Only lidocaine alone reduced MMP-2 versus sevoflurane (p = 0.044). Both bosutinib (p = 0.001) and bosutinib\/lidocaine combined (p = 0.001) reduced MMP-9 versus sevoflurane, whereas lidocaine alone did not. In a murine surgical breast cancer model, the anti-metastatic effects of lidocaine under sevoflurane anaesthesia are abolished by the Src inhibitor bosutinib, and lidocaine reduces serum MMP-2. These results suggest that lidocaine may act, at least partly, via an inhibitory effect on MMP-2 expression to reduce pulmonary metastasis, but whether this is due to an effect on Src or via another pathway remains unclear.<\/jats:p>","DOI":"10.3390\/cancers11101414","type":"journal-article","created":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T03:26:32Z","timestamp":1569209192000},"page":"1414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2315-1285","authenticated-orcid":false,"given":"Thomas P.","family":"Wall","sequence":"first","affiliation":[{"name":"Department of Anaesthesiology &amp; Perioperative Medicine, Mater University Hospital, School of Medicine, University College Dublin, D07 KH4C Dublin, Ireland"},{"name":"Conway Institute for Biomolecular and Biomedical Research, School of Medicine University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Crowley","sequence":"additional","affiliation":[{"name":"Conway Institute for Biomolecular and Biomedical Research, School of Medicine University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0062-2702","authenticated-orcid":false,"given":"Aislinn","family":"Sherwin","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology &amp; Perioperative Medicine, Mater University Hospital, School of Medicine, University College Dublin, D07 KH4C Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"Foley","sequence":"additional","affiliation":[{"name":"Berand Neuropharmacology Ltd., NovaUCD, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donal J.","family":"Buggy","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology &amp; Perioperative Medicine, Mater University Hospital, School of Medicine, University College Dublin, D07 KH4C Dublin, Ireland"},{"name":"Conway Institute for Biomolecular and Biomedical Research, School of Medicine University College Dublin, D04 V1W8 Dublin, Ireland"},{"name":"Outcomes Research, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/nrc1886","article-title":"Metastasis: A question of life or death","volume":"6","author":"Mehlen","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nrclinonc.2017.194","article-title":"Perioperative events influence cancer recurrence risk after surgery","volume":"15","author":"Hiller","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1080\/19336918.2015.1059563","article-title":"Metastasis of circulating tumor cells: favorable soil or suitable biomechanics, or both?","volume":"9","author":"Azevedo","year":"2015","journal-title":"Cell Adh. Migr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"i17","DOI":"10.1093\/bja\/aes421","article-title":"Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis?","volume":"109","author":"Heaney","year":"2012","journal-title":"Br. J. Anaesth."},{"key":"ref_6","first-page":"Cd009642","article-title":"Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults","volume":"6","author":"Weibel","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","first-page":"95","article-title":"Antitumor Effects of Lidocaine on Human Breast Cancer Cells: An In Vitro and In Vivo Experimental Trial","volume":"38","author":"Mathelin","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1097\/ALN.0000000000001528","article-title":"Lidocaine Induces Apoptosis and Suppresses Tumor Growth in Human Hepatocellular Carcinoma Cells In Vitro and in a Xenograft Model In Vivo","volume":"126","author":"Xing","year":"2017","journal-title":"Anesthesiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1093\/bja\/aev341","article-title":"Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFalpha-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase","volume":"115","author":"Piegeler","year":"2015","journal-title":"Br. J. Anaesth."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.bja.2017.12.043","article-title":"Effect of perioperative lidocaine on metastasis after sevoflurane or ketamine-xylazine anaesthesia for breast tumour resection in a murine model","volume":"121","author":"Johnson","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Freeman, J., Crowley, P.D., Foley, A.G., Gallagher, H.C., Iwasaki, M., Ma, D., and Buggy, D.J. (2019). Effect of Perioperative Lidocaine, Propofol and Steroids on Pulmonary Metastasis in a Murine Model of Breast Cancer Surgery. Cancers, 11.","DOI":"10.3390\/cancers11050613"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5599","DOI":"10.21873\/anticanres.12894","article-title":"Effect of Perioperative Lidocaine and Cisplatin on Metastasis in a Murine Model of Breast Cancer Surgery","volume":"38","author":"Freeman","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_13","first-page":"235","article-title":"The Amide Local Anesthetic Lidocaine in Cancer Surgery-Potential Antimetastatic Effects and Preservation of Immune Cell Function? A Narrative Review","volume":"4","author":"Piegeler","year":"2017","journal-title":"Front. Med. (Lausanne)"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.biopha.2018.04.106","article-title":"Inhibition of gastric cancer by local anesthetic bupivacaine through multiple mechanisms independent of sodium channel blockade","volume":"103","author":"Dan","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"i32","DOI":"10.1093\/bja\/aeu201","article-title":"Lidocaine and ropivacaine, but not bupivacaine, demethylate deoxyribonucleic acid in breast cancer cells in vitro","volume":"113","author":"Lirk","year":"2014","journal-title":"Br. J. Anaesth."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chang, Y.C., Hsu, Y.C., Liu, C.L., Huang, S.Y., Hu, M.C., and Cheng, S.P. (2014). Local anesthetics induce apoptosis in human thyroid cancer cells through the mitogen-activated protein kinase pathway. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089563"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1097\/CAD.0b013e32801265d7","article-title":"Src, chemoresistance and epithelial to mesenchymal transition: are they related?","volume":"18","author":"Shah","year":"2007","journal-title":"Anticancer Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"651","DOI":"10.2174\/187152007784111278","article-title":"SRC family nonreceptor tyrosine kinases as molecular targets for cancer therapy","volume":"7","author":"Johnson","year":"2007","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5287","DOI":"10.1200\/JCO.2009.23.5556","article-title":"Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer","volume":"27","author":"Roy","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","article-title":"Matrix metalloproteinases: Regulators of the tumor microenvironment","volume":"141","author":"Kessenbrock","year":"2010","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/jcp.20616","article-title":"Src oncogene activates MMP-2 expression via the ERK\/Sp1 pathway","volume":"207","author":"Kuo","year":"2006","journal-title":"J. Cell Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3892\/or.2014.3188","article-title":"Role of c-Src activity in the regulation of gastric cancer cell migration","volume":"32","author":"Yang","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1177\/1060028013503124","article-title":"Bosutinib: a second-generation tyrosine kinase inhibitor for chronic myelogenous leukemia","volume":"47","author":"Stansfield","year":"2013","journal-title":"Ann. Pharmacother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.21037\/atm.2018.10.26","article-title":"Dasatinib in breast cancer: Src-ing for response in all the wrong kinases","volume":"6","author":"Kennedy","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_25","first-page":"134","article-title":"Comparative Pharmacology of Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia","volume":"3","author":"Azanza","year":"2018","journal-title":"Int. J. Clin. Pharmacol. Pharmacother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s00441-012-1415-7","article-title":"Src-signaling interference impairs the dissemination of blood-borne tumor cells","volume":"349","author":"Siemann","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s40487-015-0010-y","article-title":"Bosutinib for Chronic Myeloid Leukemia","volume":"3","author":"Breccia","year":"2015","journal-title":"Rare Cancers Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1097\/ALN.0b013e3182661977","article-title":"Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade","volume":"117","author":"Piegeler","year":"2012","journal-title":"Anesthesiology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.phrs.2015.01.003","article-title":"Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors","volume":"94","author":"Roskoski","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.4103\/tme.tme_19_17","article-title":"Treatment with Src inhibitor Dasatinib results in elevated metastatic potential in the 4T1 murine mammary carcinoma model","volume":"1","author":"Hughes","year":"2018","journal-title":"Tumor Microenviron."},{"key":"ref_31","first-page":"6831","article-title":"Synergistic anti-tumor effects of dasatinib and dendritic cell vaccine on metastatic breast cancer in a mouse model","volume":"15","author":"Song","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_32","first-page":"1629","article-title":"Bosutinib reduces the efficacy of Dasatinib in triple-negative breast cancer cell lines","volume":"34","author":"Tarpley","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pulaski, B.A., and Ostrand-Rosenberg, S. (2001). Mouse 4T1 breast tumor model. Curr. Protoc. Immunol., Chapter 20, Unit 20.2.","DOI":"10.1002\/0471142735.im2002s39"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cleris, L., Daidone, M.G., Fina, E., and Cappelletti, V. (2019). The Detection and Morphological Analysis of Circulating Tumor and Host Cells in Breast Cancer Xenograft Models. Cells, 8.","DOI":"10.3390\/cells8070683"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kilkenny, C., Browne, W.J., Cuthill, I.C., Emerson, M., and Altman, D.G. (2010). Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000412"},{"key":"ref_36","unstructured":"The European Parliament and The Council of The European Union (2010). Directive 2010\/63\/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. Off. J. Eur. Union, 276, 33\u201379."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nmeth.1455","article-title":"Coding of facial expressions of pain in the laboratory mouse","volume":"7","author":"Langford","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_38","unstructured":"(2019, June 21). Volatile Anaesthesia and Perioperative Outcomes Related to Cancer (VAPOR-C): A Feasibility Study. Available online: https:\/\/www.anzctr.org.au\/Trial\/Registration\/TrialReview.aspx?id=373249."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/10\/1414\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:22:57Z","timestamp":1760188977000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/10\/1414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,22]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["cancers11101414"],"URL":"https:\/\/doi.org\/10.3390\/cancers11101414","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,22]]}}}