T Piegeler1, M Schläpfer2, R O Dull3, D E Schwartz4, A Borgeat5, R D Minshall6, B Beck-Schimmer7. 1. 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. 2. 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. 3. Department of Anaesthesiology, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612, USA Department of Bioengineering, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612, USA. 4. Department of Anaesthesiology, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612, USA. 5. Department of Anaesthesiology, Balgrist Orthopaedic University Hospital Zurich, Forchstrasse 340, 8008 Zurich, Switzerland. 6. Department of Anaesthesiology, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612, USA Department of Pharmacology, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612, USA Department of Bioengineering, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612, USA. 7. 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 Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland beatrice.beckschimmer@uzh.ch.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: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. RESULTS: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). CONCLUSIONS: 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.
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