Effect of low-dose local anesthetics on tyrosine kinase activity of growth factor receptors

局麻药通过直接作用于失活门抑制钠通道。首席研究员发现受体型酪氨酸激酶激活环自磷酸化位点周围的氨基酸序列与钠通道失活门周围的氨基酸序列惊人地相似，并开始研究局麻药对受体型酪氨酸激酶的影响。根据我们的假设，局部麻醉药，一种具有芳香环的胺，会通过静电、π-π堆叠、阳离子-π和C-H-π相互作用与芳香、酸性或碱性氨基酸相互作用，我们研究了利多卡因对受体型酪氨酸激酶的自磷酸化的影响，如表皮生长因子受体（EGFR）、胰岛素样生长因子受体（IGFR）或胰岛素受体。在体外纯化EGFR的初步研究中，低剂量利多卡因增加EGFR酪氨酸激酶活性，高剂量利多卡因降低其活性。然而，在体内研究中，超过400μM的利多卡因抑制了egf刺激的人角膜上皮细胞的增殖，并抑制了egf刺激的EGFR自磷酸化。这些结果表明利多卡因通过直接抑制EGFR的酪氨酸激酶活性来抑制角膜上皮细胞的增殖。利多卡因抑制胰岛素刺激的胰岛素受体自磷酸化，并使已被胰岛素磷酸化的酪氨酸残基去磷酸化。在乳腺癌细胞系MCF-7中，IGFR对细胞增殖起重要作用，400μM以上的利多卡因抑制MCF-7的细胞增殖。我们认为利多卡因可能使IGFR去磷酸化，从而抑制MCF-7的增殖，而IGFR自磷酸化位点周围的氨基酸序列与胰岛素受体周围的氨基酸序列相同

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