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

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.

Local Anesthetics and Recurrence after Cancer Surgery-What’s New? A Narrative Review

“…The inhibiting effect of lidocaine on Src tyrosine protein kinase (Src) [ 101 , 102 , 103 ] indicates that systemically administered local anesthetics might potentially be able to inhibit cancer cell metastasis [ 26 , 96 , 104 , 105 ]. A recent study by Wall and colleagues in 2019 supported this hypothesis by measuring the metastatic burden in lung and liver as well as MMP-2 levels in dependency of the treatment with lidocaine and the Src-inhibitor bosutinib in a 4T1 mouse tumor model [ 106 ]. Bosutinib neutralized the protecting effect of lidocaine regarding lung metastasis and levels of MMP-2.…”

“…Bosutinib neutralized the protecting effect of lidocaine regarding lung metastasis and levels of MMP-2. However, the authors claimed that it remains unclear if the findings are due to a direct Src effect or another pathway [ 106 ].…”

<p>Anesthesia Options and the Recurrence of Cancer: What We Know so Far?</p>

“…The administration of intravenous lidocaine (1.5 mg/kg followed by infusion of 2 mg/kg) under sevoflurane anesthesia reduced postoperative lung metastasis by decreasing serum concentrations of the metalloproteinase (MMP)-2 in a murine surgical breast cancer model. 24,25 It was speculated that changes in MMP-2 resulted in a reduced ability of CTCs to form metastasis. 24 Local anesthetics also impair the movement of malignant cells in vitro.…”

“…24,25 It was speculated that changes in MMP-2 resulted in a reduced ability of CTCs to form metastasis. 24 Local anesthetics also impair the movement of malignant cells in vitro. 26,27 As an example, ropivacaine inhibited migration and invasion of esophageal and colorectal cancer cells.…”

Lidocaine suppresses the malignant behavior of gastric cancer cells via the c‑Met/c‑Src pathway

“…In vivo and in vitro studies have indicated the antitumor effects of lidocaine in gastric cancer (3)(4)(5). Mechanistically, lidocaine has been found to decrease Src activation (6)(7)(8). A recent study suggested that lidocaine can inhibit the proliferative and invasive capabilities of c-Met positive MKN45 cells (3).…”