| Research Abstract |
Local anesthetics inhibit sodium channel through the direct effect on the inactivation gate. Head investigator revealed that amino-acid sequences around the autophosphorylation site at the activation loop of receptor-type tyrosine kinase surprisingly resemble to those around the inactivation gate of sodium channel, and started to investigate the effect of local anesthetics on the receptor-type tyrosine kinases. Under our hypothesis that local anesthetic, an amine having aromatic ring, would interact with aromatic, acidic, or basic amino acids through electrostatic, π-πstacking, cation-π, and C-H-π interactions, we studied the effect of lidocaine on autophosphorylation of receptor-type tyrosine kineses, such as epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), or insulin receptor.
In the preliminary in vitro study using purified EGFR, low-dose lidocaine increased tyrosine kinase activity of EGFR, and high-dose lidocaine decreased it. In the in vivo study, however, over 400μM of lidocaine suppressed EGF-stimulated proliferation of human corneal epithelial cells, and inhibited EGF-stimulated autophosphorylation of EGFR. These results suggested that lidocaine suppresses corneal epithelial cell proliferation with direct inhibition of tyrosine kinase activity of EGFR. Lidocaine inhibited insulin-stimulated autophosphorylation of insulin receptor, and also dephosphorylated tyrosine residues already phosphorylated by insulin. In the breast cancer cell line, MCF-7, in which IGFR plays an important role for cell proliferation, over 400μM of lidocaine suppressed cell proliferation of MCF-7. We suggest that lidocaine might dephosphorylate IGFR, of which amino acid sequences around autophosphorylation site are the same as those around insulin receptor, and then suppressed MCF-7 proliferation
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