Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade

Anesthesiology. 2012 Sep;117(3):548-59. doi: 10.1097/ALN.0b013e3182661977.


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-α in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1 nM-100 μM). 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 μM) 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-α 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 μM ropivacaine and 21% by 1 μM 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-α-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology
  • Amides / pharmacology
  • Anesthetics, Local / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lidocaine / pharmacology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Neoplasm Metastasis / prevention & control
  • Phosphorylation
  • Procaine / analogs & derivatives
  • Procaine / pharmacology
  • Retrospective Studies
  • Ropivacaine
  • Signal Transduction
  • Sodium Channel Blockers / pharmacology*
  • Tetrodotoxin / pharmacology
  • Veratridine / pharmacology
  • src-Family Kinases / physiology*


  • Amides
  • Anesthetics, Local
  • Sodium Channel Blockers
  • Intercellular Adhesion Molecule-1
  • Tetrodotoxin
  • Procaine
  • chloroprocaine
  • Veratridine
  • Ropivacaine
  • Lidocaine
  • src-Family Kinases