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.

Potential Impact of Local Anesthetics Inducing Granulocyte Arrest and Altering Immune Functions on Perioperative Outcome

“…The amide type LAs bupivacaine and lidocaine are on the WHO's list of essential drugs 9,10 and may also have antitumor effects for several tumor entities. 11,12 Furthermore, a recent study by Tohme et al observed that neutrophil extracellular traps (NETs), which are chromatin DNA released by PMNs, were implicated in colorectal carcinoma liver metastasis after surgical stress. 13 Galos et al could observe reduced NETosis in women treated with intravenous lidocaine during breast cancer surgery which might result in lower recurrence rates.…”

Repositioning Lidocaine as an Anticancer Drug: The Role Beyond Anesthesia

“…This study suggested that by administering topically within the oral cavity, lidocaine cold suppress the proliferation of human tongue cancer cells ( Sakaguchi et al, 2006 ). A recent study also confirmed the suppressing effects of lidocaine to the cell migration, growth, and survival of esophageal carcinoma at >100 μM, which was mediated by inhibiting mitochondrial respiration ( Zhu et al, 2020 ).…”

“…There is also research showing that under clinically relevant concentrations (0.1–200 μM), lidocaine exhibited anticancer efficacies. The plasma concentration of local anesthetics is at low μ M, ranged from 2.5–10 μM, suggesting a suitable administrative method, such as local infiltration or administering topically, should be taken into account when used for killing cancer cells ( Li R. et al, 2018 ; Zhu et al, 2020 ). More efforts, including the pharmacokinetics profile in vivo, are needed to verify its campatibal dose/concentration in certain treatments that are achievable in clinical practice.…”

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

“…Although early small retrospective clinical trials have shown that local anesthetics play a beneficial role in reducing tumor metastasis and recurrence in cancer patients, prospective, large-scale, and randomized clinical trials are needed to investigate the effect of regional anesthesia on long-term outcomes after cancer surgery [37]. This will confirm the significance of anesthetics for cancer patients and guide clinical practice.…”