Department of Anesthesiology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei Province, China.
Department of Anesthesiology, Jingzhou Central Hospital, Jingzhou, Hubei Province, China.
Fundam Clin Pharmacol. 2020 Oct;34(5):581-590. doi: 10.1111/fcp.12554. Epub 2020 Apr 6.
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.
尽管大量证据表明局部麻醉与肿瘤复发减少之间存在关联，但酰胺类局部麻醉药（特别是布比卡因）对血管生成（肿瘤进展和转移的标志）的作用尚未被揭示。在这项工作中，我们证明了布比卡因的抗血管生成活性及其在血管内皮细胞中的潜在机制。我们发现布比卡因通过抑制内皮细胞迁移而不影响细胞与基质的黏附来抑制毛细血管网络形成的早期阶段。布比卡因还抑制内皮细胞的生长和存活。机制分析表明，布比卡因通过降低复合物 I 和 II 的线粒体呼吸活性而不是 IV 或 V 来抑制线粒体呼吸，从而导致能量耗竭、氧化应激、Akt/mTOR 抑制和 AMPK 通路激活。抗氧化剂 NAC 对布比卡因作用的挽救证实，布比卡因通过氧化应激依赖性 Akt/mTOR 抑制和 AMPK 激活来抑制血管生成。我们的工作清楚地表明，布比卡因通过靶向线粒体来抑制血管生成。我们的发现与之前的工作一致，为局部麻醉药如何影响癌症患者的治疗结果提供了临床前证据。
