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Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery

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...

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Autores principales: Wall, Thomas P., Crowley, Peter D., Sherwin, Aislinn, Foley, Andrew G., Buggy, Donal J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826872/
https://www.ncbi.nlm.nih.gov/pubmed/31546727
http://dx.doi.org/10.3390/cancers11101414
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author Wall, Thomas P.
Crowley, Peter D.
Sherwin, Aislinn
Foley, Andrew G.
Buggy, Donal J.
author_facet Wall, Thomas P.
Crowley, Peter D.
Sherwin, Aislinn
Foley, Andrew G.
Buggy, Donal J.
author_sort Wall, Thomas P.
collection PubMed
description 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’s 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.
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spelling pubmed-68268722019-11-18 Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery Wall, Thomas P. Crowley, Peter D. Sherwin, Aislinn Foley, Andrew G. Buggy, Donal J. Cancers (Basel) Article 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’s 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. MDPI 2019-09-22 /pmc/articles/PMC6826872/ /pubmed/31546727 http://dx.doi.org/10.3390/cancers11101414 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wall, Thomas P.
Crowley, Peter D.
Sherwin, Aislinn
Foley, Andrew G.
Buggy, Donal J.
Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
title Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
title_full Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
title_fullStr Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
title_full_unstemmed Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
title_short Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
title_sort effects of lidocaine and src inhibition on metastasis in a murine model of breast cancer surgery
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826872/
https://www.ncbi.nlm.nih.gov/pubmed/31546727
http://dx.doi.org/10.3390/cancers11101414
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