期刊
ANESTHESIOLOGY
卷 117, 期 3, 页码 548-559出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/ALN.0b013e3182661977
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资金
- National Institutes of Health, Bethesda, Maryland [HL60678, HL71626]
- Lung Society, Zurich, Switzerland
- Swiss Society of Anesthesiology and Resuscitation, Bern, Switzerland
Background: Retrospective analysis of patients undergoing cancer surgery suggests the use of regional anesthesia may reduce cancer recurrence and improve survival. Amide-linked local anesthetics have antiinflammatory properties, although the mechanism of action in this regard is unclear. As inflammatory processes involving Src tyrosine protein kinase and intercellular adhesion molecule-1 are important in tumor growth and metastasis, we hypothesized that amide-linked local anesthetics may inhibit inflammatory Src-signaling involved in migration of adenocarcinoma cells. Methods: NCI-H838 lung cancer cells were incubated with tumor necrosis factor-alpha in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1 nM-100 mu M). Cell migration and total cell lysate Src-activation and intercellular adhesion molecule-1 phosphorylation were assessed. The role of voltage-gated sodium-channels in the mechanism of local anesthetic effects was also evaluated. Results: Ropivacaine treatment (100 mu M) of H838 cells for 20 min decreased basal Src activity by 62% (P = 0.003), and both ropivacaine and lidocaine coadministered with tumor necrosis factor-alpha statistically significantly decreased Src-activation and intercellular adhesion molecule-1 phosphorylation, whereas chloroprocaine had no such effect. Migration of these cells at 4 h was inhibited by 26% (P = 0.005) in presence of 1 mu M ropivacaine and 21% by 1 mu M lidocaine (P = 0.004). These effects of ropivacaine and lidocaine were independent of voltage-gated sodium-channel inhibition. Conclusions: This study indicates that amide-, but not ester-linked, local anesthetics may provide beneficial antimetastatic effects. The observed inhibition of NCI-H838 cell migration by lidocaine and ropivacaine was associated with the inhibition of tumor necrosis factor-alpha induced Src-activation and intercellular adhesion molecule-1 phosphorylation, providing the first evidence of a molecular mechanism that appears to be independent of their known role as sodium-channel blockers.
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