The anti-cancer role of local anesthetics has garnered attention in recent years because increasing evidence show that local anesthetics reduce the risk of tumor metastasis and recurrence. Angiogenesis, the formation of new blood vessels, is fundamental for tumor growth and metastasis. The role of local anesthetics on tumor angiogenesis still remains unknown. Using human lung tumor-associated endothelial cell (HLT-EC) and angiogenesis models, our work shows that ropivacaine at the clinically relevant concentration is active against multiple biological functions of HLT-EC but not lung tumor cells. Ropivacaine inhibits HLT-EC capillary network formation, growth and survival. The anti-angiogenic activity of ropivacaine is further confirmed in in vivo angiogenesis mouse model. Mechanistically, we show that ropivacaine inhibits HLT-EC mitochondrial respiration via specifically targeting mitochondrial respiratory complex II. As a consequence of mitochondrial respiration inhibition, we observe the energy depletion, oxidative stress and damage in HLT-EC after ropivacaine exposure. Additionally, an antioxidant agent completely reverses the inhibitory effects of ropivacaine, suggesting that oxidative stress is required for the action of ropivacaine in HLT-EC. Interestingly, mitochondrial dysfunction and oxidative stress induced by ropivacaine is sodium channel-independent. Our work demonstrates the potent inhibitory effects of ropivacaine in lung tumor angiogenesis by inducing mitochondrial dysfunction. These findings provide significant insight into the potential mechanisms by which local anaesthetics may negatively affect tumor reoccurrence and metastasis.

中文翻译：

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罗哌卡因通过不依赖钠通道的线粒体功能障碍和氧化应激抑制肿瘤血管生成。

近年来，局部麻醉药的抗癌作用受到关注，因为越来越多的证据表明，局部麻醉药降低了肿瘤转移和复发的风险。血管生成是新血管的形成，是肿瘤生长和转移的基础。局麻药在肿瘤血管生成中的作用仍然未知。使用人肺肿瘤相关内皮细胞（HLT-EC）和血管生成模型，我们的工作表明，具有临床相关浓度的罗哌卡因对HLT-EC的多种生物学功能具有活性，但对肺肿瘤细胞没有活性。罗哌卡因可抑制HLT-EC毛细血管网的形成，生长和存活。罗哌卡因的抗血管生成活性在体内血管生成小鼠模型中得到进一步证实。机械上，我们显示罗哌卡因通过特异性靶向线粒体呼吸复合物II抑制HLT-EC线粒体呼吸。由于线粒体呼吸抑制，我们观察到罗哌卡因暴露后HLT-EC中的能量消耗，氧化应激和损伤。此外，抗氧化剂可以完全逆转罗哌卡因的抑制作用，这表明罗哌卡因在HLT-EC中的作用需要氧化应激。有趣的是，罗哌卡因引起的线粒体功能障碍和氧化应激与钠通道无关。我们的工作证明了罗哌卡因通过诱导线粒体功能障碍，在肺部肿瘤血管生成中具有强大的抑制作用。