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Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
Thomas P Wall1,2, Peter D Crowley3, Aislinn Sherwin4
1Department of Anaesthesiology & Perioperative Medicine, Mater University Hospital, School of Medicine, University College Dublin, D07 KH4C Dublin, Ireland. tom.p.wall@gmail.com.
Abstract:
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.
Insights
Lidocaine reduced breast cancer metastasis in mice, but this effect was blocked by the Src inhibitor bosutinib. Lidocaine also lowered MMP-2 levels, suggesting a potential pathway for reducing metastasis.
Area of Science:
- Oncology
- Anesthesiology
- Pharmacology
Background:
- Breast cancer recurrence after surgery affects 20% of patients.
- Local anesthetics like lidocaine may inhibit cancer metastasis by targeting the Src tyrosine kinase enzyme.
- Systemic lidocaine has shown potential in reducing postoperative metastases in preclinical models.
Purpose of the Study:
- To investigate the effect of combining lidocaine with bosutinib, a Src inhibitor, on breast cancer metastasis in a murine model.
- To determine if bosutinib influences the anti-metastatic effects of lidocaine during sevoflurane anesthesia.
- To analyze the impact on pro-metastatic enzymes MMP-2 and MMP-9.
Main Methods:
- Female BALB/c mice with 4T1 tumors underwent surgical excision under sevoflurane anesthesia.
- Mice received intravenous treatments: lidocaine, bosutinib, combination therapy, or saline.
- Metastatic colonies in lungs and liver were evaluated 14 days post-surgery.
- Serum levels of MMP-2 and MMP-9 were analyzed.
Main Results:
- Lidocaine alone significantly reduced lung metastases compared to saline (p=0.041) but not liver metastases.
- Bosutinib alone had no significant effect on metastasis.
- Co-administration of bosutinib abolished lidocaine's anti-metastatic effect.
- Lidocaine alone reduced serum MMP-2 (p=0.044), while bosutinib and combination therapy reduced MMP-9.
Conclusions:
- The anti-metastatic effect of lidocaine in this breast cancer model is negated by the Src inhibitor bosutinib.
- Lidocaine's ability to reduce pulmonary metastasis may involve, at least partially, the inhibition of MMP-2.
- The precise mechanism of lidocaine's action, whether solely via Src or other pathways, requires further investigation.
