title: Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade.
abstract: 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.
authors: Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
authors: Tobias
authors: T
authors: Piegeler
authors: E Gina
authors: EG
authors: Votta-Velis
authors: Guoquan
authors: G
authors: Liu
authors: Aaron T
authors: AT
authors: Place
authors: David E
authors: DE
authors: Schwartz
authors: Beatrice
authors: B
authors: Beck-Schimmer
authors: Richard D
authors: RD
authors: Minshall
authors: Alain
authors: A
authors: Borgeat
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000577:Amides / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010766:Phosphorylation; D011343:Procaine / Q000031:analogs & derivatives / Q000494:pharmacology; D012189:Retrospective Studies; D000077212:Ropivacaine; D015398:Signal Transduction; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D026941:Sodium Channel Blockers; D018799:Intercellular Adhesion Molecule-1; D013779:Tetrodotoxin; D011343:Procaine; C004616:chloroprocaine; D014701:Veratridine; D000077212:Ropivacaine; D008012:Lidocaine; D019061:src-Family Kinases