Piegeler T, Schläpfer M, Dull R O, Schwartz D E, Borgeat A, Minshall R D, Beck-Schimmer B
Institute of Anaesthesiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland Department of Anaesthesiology, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612, USA.
Institute of Anaesthesiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Br J Anaesth. 2015 Nov;115(5):784-91. doi: 10.1093/bja/aev341.
Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells.
NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml(-1)) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed.
Ropivacaine (1 nM-100 μM) and lidocaine (1-100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10(-6) M for lidocaine; IC50=1.52×10(-10) M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM).
At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasis.
基质金属蛋白酶（MMP）和癌细胞侵袭对于实体瘤转移至关重要。由炎性细胞因子触发的重要信号事件，如肿瘤坏死因子α（TNFα），包括Akt和粘着斑激酶（FAK）的Src激酶依赖性激活以及小窝蛋白-1的磷酸化。基于我们之前的研究，即酰胺型局部麻醉药可阻断恶性细胞中TNFα诱导的Src激活，我们推测局部麻醉药也可能抑制Akt、FAK和小窝蛋白-1的激活和/或磷酸化，从而减弱MMP的释放和恶性细胞的侵袭。
将NCI-H838肺腺癌细胞分别在不存在/存在TNFα（20 ng/ml）的情况下，用罗哌卡因或利多卡因（1 nM - 100 μM）孵育20分钟或4小时。通过蛋白质免疫印迹法评估Akt、FAK和小窝蛋白-1的激活/磷酸化，并通过酶联免疫吸附测定法测定MMP-9的分泌。还评估了肿瘤细胞迁移（电损伤愈合试验）和侵袭。
罗哌卡因（1 nM - 100 μM）和利多卡因（1 - 100 μM）显著降低了NCI-H838细胞中TNFα诱导的Akt、FAK和小窝蛋白-1的激活/磷酸化。利多卡因和罗哌卡因均显著减弱了TNFα触发的MMP-9分泌（利多卡因的半数最大抑制浓度[IC50]=3.29×10(-6) M；罗哌卡因的IC50=1.52×10(-10) M）。TNFα诱导的侵袭增加被利多卡因（10 μM）和罗哌卡因（1 μM）完全阻断。
在临床相关浓度下，罗哌卡因和利多卡因均通过减弱Src依赖性炎性信号事件来阻断肿瘤细胞侵袭和MMP-9分泌。尽管这些发现完全是在体外确定的，但它们为局部麻醉药可能减少转移的潜在机制提供了重要见解。
