Inhibition of gastric cancer by local anesthetic bupivacaine through multiple mechanisms independent of sodium channel blockade

Background: Retrospective studies of patients undergoing cancer surgery suggest the use of local anesthesia may decrease tumor recurrence and improve survival. The mechanisms on the benefits of local anesthesia on cancer recurrence are complex and remain to be elucidated. Methods: This study investigated the effects of bupivacaine on various cellular activities of gastric cancer using proliferation, migration, apoptosis assay. The underlying mechanism was analyzed focusing on mitochondrial functions and the activities of Rho family members. Results: We show that bupivacaine at low concentrations (eg, 0.01 and 0.05 mM) inhibits migration whereas only at high concentrations (1 and 5 mM) inhibits growth and survival in two human gastric cancer cell lines. Bupivacaine also significantly augments 5-Fluorouracil in inhibiting growth and survival but not migration in gastric cancer cells. In addition, the mechanisms of bupivacaine's action on the growth and survival are different from those on the migration. We demonstrate that bupivacaine inhibits gastric cancer cell growth and survival through inhibiting mitochondrial respiratory complex I and II, leading to decreased mitochondrial oxidation and ATP production. In contrast, bupivacaine inhibits gastric cancer cell migration through decreasing RhoA and Rac1 activities without affecting their expression. Particularly, we demonstrate that bupivacaine inhibits gastric cancer cell migration via inhibiting RhoA/ROCK/MLC pathway. We further show that the action of bupivacaine on mitochondrial functions, RhoA, and Rac1 activities are independent of sodium channel blockade. Conclusions: Our work demonstrates that bupivacaine has direct anti-cancer activities with the dominant inhibitory effects on gastric cancer migration rather than growth and survival. Our findings also guide a proper understanding and provide underlying mechanisms on how local aesthesis could affect cancer patients.