Bupivacaine inhibits angiogenesis through oxidative stress‐dependent inhibition of Akt/mTOR and activation of AMPK

Abstract Although substantial evidence shows the link of local anesthesia and decreased tumor recurrence, the role of amide‐linked local anesthetics, particularly bupivacaine, on angiogenesis (a hallmark of tumor progression and metastasis) has not been revealed. In this work, we demonstrate the anti‐angiogenic activity of bupivacaine and its underlying mechanism in endothelial cells. We show that bupivacaine inhibits early stage of capillary network formation via suppressing endothelial cell migration without affecting adhesion to matrix. Bupivacaine also inhibits endothelial cell growth and survival. Mechanism analysis indicates that bupivacaine inhibits mitochondrial respiration via decreasing mitochondrial respiratory activity of complex I and II but not IV or V, resulting in energy depletion, oxidative stress, inhibition of Akt/mTOR, and activation of AMPK pathway. The rescue of an antioxidant NAC on the effects of bupivacaine confirms that bupivacaine inhibits angiogenesis through oxidative stress‐dependent inhibition of Akt/mTOR and activation of AMPK. Our work clearly demonstrates the inhibitory effects of bupivacaine on angiogenesis via targeting mitochondria. Our findings are in line with the previous work providing the preclinical evidence on how local anesthetics could influence the outcome of cancer patients.