酰胺类局麻药的抗转移作用：抑制肺腺癌细胞迁移和炎症性Src 信号转导，不依赖于钠通道阻滞。
Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade.
机构信息
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
出版信息
Anesthesiology. 2012 Sep;117(3):548-59. doi: 10.1097/ALN.0b013e3182661977.
BACKGROUND
Retrospective analysis of patients undergoing cancer surgery suggests the use of regional anesthesia may reduce cancer recurrence and improve survival. Amide-linked local anesthetics have antiinflammatory properties, although the mechanism of action in this regard is unclear. As inflammatory processes involving Src tyrosine protein kinase and intercellular adhesion molecule-1 are important in tumor growth and metastasis, we hypothesized that amide-linked local anesthetics may inhibit inflammatory Src-signaling involved in migration of adenocarcinoma cells.
METHODS
NCI-H838 lung cancer cells were incubated with tumor necrosis factor-α in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1 nM-100 μM). Cell migration and total cell lysate Src-activation and intercellular adhesion molecule-1 phosphorylation were assessed. The role of voltage-gated sodium-channels in the mechanism of local anesthetic effects was also evaluated.
RESULTS
Ropivacaine treatment (100 μM) of H838 cells for 20 min decreased basal Src activity by 62% (P=0.003), and both ropivacaine and lidocaine coadministered with tumor necrosis factor-α statistically significantly decreased Src-activation and intercellular adhesion molecule-1 phosphorylation, whereas chloroprocaine had no such effect. Migration of these cells at 4 h was inhibited by 26% (P=0.005) in presence of 1 μM ropivacaine and 21% by 1 μM lidocaine (P=0.004). These effects of ropivacaine and lidocaine were independent of voltage-gated sodium-channel inhibition.
CONCLUSIONS
This study indicates that amide-, but not ester-linked, local anesthetics may provide beneficial antimetastatic effects. The observed inhibition of NCI-H838 cell migration by lidocaine and ropivacaine was associated with the inhibition of tumor necrosis factor-α-induced Src-activation and intercellular adhesion molecule-1 phosphorylation, providing the first evidence of a molecular mechanism that appears to be independent of their known role as sodium-channel blockers.
背景
对接受癌症手术的患者进行回顾性分析表明，使用区域麻醉可能会降低癌症复发率并提高生存率。酰胺类局部麻醉剂具有抗炎特性，尽管其在这方面的作用机制尚不清楚。由于涉及Src 酪氨酸蛋白激酶和细胞间黏附分子-1 的炎症过程在肿瘤生长和转移中很重要，我们假设酰胺类局部麻醉剂可能会抑制与腺癌细胞迁移相关的炎症 Src 信号传导。
方法
将 NCI-H838 肺癌细胞在肿瘤坏死因子-α存在/不存在的情况下与罗哌卡因、利多卡因或氯普鲁卡因孵育（1 nM-100 μM）。评估细胞迁移和总细胞裂解物Src 激活和细胞间黏附分子-1 磷酸化。还评估了电压门控钠通道在局部麻醉剂作用机制中的作用。
结果
罗哌卡因（100 μM）处理 H838 细胞 20 分钟可使基础 Src 活性降低 62%（P=0.003），并且罗哌卡因和利多卡因与肿瘤坏死因子-α共同给药可显著降低 Src 激活和细胞间黏附分子-1 磷酸化，而氯普鲁卡因则没有这种作用。在存在 1 μM 罗哌卡因的情况下，这些细胞的迁移在 4 小时时被抑制了 26%（P=0.005），在存在 1 μM 利多卡因的情况下被抑制了 21%（P=0.004）。罗哌卡因和利多卡因的这些作用与电压门控钠通道抑制无关。
结论
这项研究表明，酰胺类而非酯类局部麻醉剂可能具有有益的抗转移作用。观察到的利多卡因和罗哌卡因抑制 NCI-H838 细胞迁移与抑制肿瘤坏死因子-α诱导的 Src 激活和细胞间黏附分子-1 磷酸化有关，为一种分子机制提供了首次证据，该机制似乎独立于它们作为钠通道阻滞剂的已知作用。
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