Indirubin-3'-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

Oncogene. 2007 Sep 27;26(44):6372-85. doi: 10.1038/sj.onc.1210473. Epub 2007 May 28.


Indirubin-3'-monoxime is a derivative of the bis-indole alkaloid indirubin, an active ingredient of a traditional Chinese medical preparation that exhibits anti-inflammatory and anti-leukemic activities. Indirubin-3'-monoxime is mainly recognized as an inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3. It inhibits proliferation of cultured cells, mainly through arresting the cells in the G1/S or G2/M phase of the cell cycle. Here, we report that indirubin-3'-monoxime is able to inhibit proliferation of NIH/3T3 cells by specifically inhibiting autophosphorylation of fibroblast growth factor receptor 1 (FGFR1), blocking in this way the receptor-mediated cell signaling. Indirubin-3'-monoxime inhibits the activity of FGFR1 at a concentration lower than that required for inhibition of phosphorylation of CDK2 and retinoblastoma protein and cell proliferation stimulated by fetal calf serum. The ability of indirubin-3'-monoxime to inhibit FGFR1 signaling was similar to that of the FGFR1 inhibitor SU5402. In addition, we found that indirubin-3'-monoxime activates long-term p38 mitogen-activated protein kinase activity, which stimulates extracellular signal-regulated kinase 1/2 in a way unrelated to the activity of FGFR1. Furthermore, we show that indirubin-3'-monoxime can inhibit proliferation of the myeloid leukemia cell line KG-1a through inhibition of the activity of the FGFR1 tyrosine kinase. The data presented here demonstrate previously unknown activities of indirubin-3'-monoxime that may have clinical implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 2 / metabolism
  • Endocytosis
  • ErbB Receptors / metabolism
  • Fibroblast Growth Factor 1 / metabolism
  • Humans
  • Indoles / pharmacology*
  • K562 Cells / drug effects
  • K562 Cells / metabolism
  • Leukemia, Myeloid / drug therapy
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • NIH 3T3 Cells / drug effects
  • NIH 3T3 Cells / metabolism
  • Oximes / pharmacology*
  • Phosphorylation
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Retinoblastoma Protein / metabolism
  • Signal Transduction / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Indoles
  • Oximes
  • Retinoblastoma Protein
  • indirubin-3'-monoxime
  • Fibroblast Growth Factor 1
  • EGFR protein, human
  • ErbB Receptors
  • Receptor, Fibroblast Growth Factor, Type 1
  • Cyclin-Dependent Kinase 2
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases