Local anesthetics suppress proliferation in several cancer cells. The mechanism of the suppression, however, is unknown. Our previous study shows that lidocaine, at the level of tissue concentration under topical or local administration, has a direct inhibitory effect on the activity of epidermal growth factor receptor (EGFR), which is a potential target for antiproliferation in cancer cells. Therefore, we hypothesized that lidocaine would suppress the proliferation of cancer cells through the inhibition of EGFR activity. We investigated the effects of lidocaine (40-4000 microM) on proliferation of a human tongue cancer cell line, CAL27, which has a high level of EGFR expression, and also examined the effect of lidocaine on epidermal growth factor (EGF)-stimulated autophosphorylation of EGFR in CAL27 cells. A clinical concentration of lidocaine (400 microM) suppressed both serum-induced and EGF-induced proliferation of CAL27 cells and inhibited EGF-stimulated tyrosine kinase activity of EGFR without cytotoxicity. A larger concentration of lidocaine (4000 microM) showed cytotoxicity with an antiproliferative effect. We suggest that the inhibition of EGF-stimulated EGFR activity is one of the mechanisms of the antiproliferative effect of lidocaine on CAL27 cells. Lidocaine administered topically within the oral cavity for cancer pain relief may suppress the proliferation of human tongue cancer cells.
Background Acute lung injury (ALI) is characterized by neutrophilic inflammation and increased lung permeability. Thiosulfate is a stable metabolite of hydrogen sulfide, a gaseous mediator that exerts anti-inflammatory effects. While sodium thiosulfate (STS) has been used as an antidote, the effect of STS in ALI is unknown. We assessed the effects of STS in mice lung and vascular endothelial cells subjected to acute inflammation. Methods Lung injury was assessed in mice challenged with intratracheal lipopolysaccharide or subjected to cecal ligation and puncture with or without STS. Effects of STS on endothelial permeability, and the production of inflammatory cytokines and reactive oxygen species were examined in cultured endothelial cells incubated with lipopolysaccharide or tumor necrosis factor alpha (TNFα). Levels of sulfide and sulfane sulfur were measured using novel fluorescence probes. Results STS inhibited lipopolysaccharide-induced production of cytokines (Interleukin-6 (pg/ml); 313±164, lipopolysaccharide; 79±27, lipopolysaccharide + STS (n=10)), lung permeability, histological lung injury, and nuclear factor-κB activation in the lung. STS also prevented upregulation of Interleukin-6 in the mouse lung subjected to cecal ligation and puncture. In endothelial cells, STS increased intracellular levels of sulfide and sulfane sulfur, inhibited lipopolysaccharide or TNFα-induced production of cytokines and reactive oxygen species. The beneficial effects of STS were associated with attenuation of the lipopolysaccharide-induced nuclear factor-κB activation through the inhibition of TNF receptor-associated factor 6 ubiquitination. Conclusions STS exerts robust anti-inflammatory effects in mice lung and vascular endothelium. Our results suggest a therapeutic potential of STS in ALI.
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