Differential effects and mechanisms of local anesthetics on esophageal carcinoma cell migration, growth, survival and chemosensitivity

Abstract

Background: Retrospective analysis and pre-clinical studies suggest that local anesthetics have anti-tumoral effects. However, the association between cancer recurrence and the use of local anesthesia is inconclusive and most reports are based on single local anesthetic results. Methods: The biological effects (growth, migration and survival) of four common local anesthetics on esophageal carcinoma cells were compared. Biochemical assays on molecules involved in cell migration and proliferation were analyzed. Results: Ropivacaine and bupivacaine significantly inhibited esophageal carcinoma cell migration, at clinically relevant micromolar concentrations. Mepivacaine and lidocaine showed less potent cell migration inhibition than ropivacaine or bupivacaine. All four local anesthetics inhibited cell proliferation. Of note, the effective concentration of anti-proliferative activities requires higher doses. At millimolar concentrations of these local anesthetics, cell apoptosis was moderately affected. Drug combination analysis demonstrated that two of four local anesthetics augmented chemotherapeutic drugs in inhibiting migration. However, all four local anesthetics significantly augmented chemotherapeutic drugs in inhibiting growth and inducing apoptosis. The anti-growth and anti-survival effects of four local anesthetics were attributed to mitochondrial dysfunction and oxidative damage. The anti-migratory effect of local anesthetics is likely through decreasing Rac1 activity. Conclusions: Our work demonstrates the differential effects and proposes the mechanisms of local anesthetics on esophageal carcinoma cell migration, growth, survival and chemosensitivity.