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2003 Fiscal Year Final Research Report Summary

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

Research Project

Project/Area Number 14571459
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Anesthesiology/Resuscitation studies
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

HIROSE Munetaka  Kyoto Prefectural University of Medicine, Anesthesiology, Instructor, 医学研究科, 助手 (50275228)

Project Period (FY) 2002 – 2003
KeywordsTyrosine kinase / Lidocaine / Phosphorylation / Dephosphorylation / Corneal epithelial cell / Breast cancer cell / Epidermal growth factor receptor / Insulin-like growth factor receptor
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

  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] 平田昌史: "リドカインのヒト角膜上皮細胞増殖抑制作用の機序について"日本ペインクリニック学会誌. 9. 265 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Munetaka Hirose: "Mechanism of suppression of insulin signaling with lignocaine"British Journal of Phamacology. 136. 76-80 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 廣瀬宗孝: "鏡視下術後の鎮痛"ペインクリニック. 24. 32-38 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Munetaka Hirose: "Suppression of Insulin Signalling by a Synthetic Peptide KIFMK Suggests the Cytoplasrnio Linker between DIII-S6 and DIV-S1 as a Local Anaesthetic Binding Site on the Sodium Channel."British Journal of Phamacology. (印刷中). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Masashi Hirata: "Lidocaine inhibits tyrosine kinase activity of the epidermal growth factor receptor and suppreses proliferation of corneal epithelial cells."Anesthesiology. (印刷中). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Munetaka Hirose et al.: "Mechanism of suppression of insulin signaling with lignocaine"British Journal of Pharmacology. 136. 76-80 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Munetaka Hirose et al.: "Suppression of Insulin Signalling by a Synthetic Peptide KIFMK Suggests the Cytoplasmic Linker between DIII-56 and DIV-S1 as a Local Anaesthetic Binding Site on the Sodium Channel."British Journal of Pharmacology. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masashi Hirata et al.: "Lidocaine inhibits tyrosine kinase activity of the epidermal growth factor receptor and suppresses proliferation of corneal epithelial cells."Anesthesiology. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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