UCN-01, 7-hydroxyl-staurosporine, inhibits kinase activity of cyclin-dependent kinases and reduces the phosphorylation of the retinoblastoma susceptibility gene product in A549 human lung cancer cell line

Biochem Biophys Res Commun. 1996 Feb 27;219(3):778-83. doi: 10.1006/bbrc.1996.0310.

Abstract

UCN-01 (7-hydroxyl-staurosporine), which was initially developed as a selective protein kinase C inhibitor, has an anti-tumor effect on several human cancer cell lines in vivo. In this study, we examined whether this compound has an inhibitory effect on cell cyclin-dependent kinases (cdks) in vitro and in vivo using A549 human lung adenocarcinoma cell line. UCN-01 inhibited the retinoblastoma susceptibility gene product (pRB) kinase activity of three types of cdks (cdk 2, 4 and 6) with 50% inhibitory concentration values of 42, 32, and 58 nM, respectively, in vitro. Moreover, the amount of phosphorylated pRB was reduced by UCN-01 at a concentration of 100 nM in the living cells. Flow cytometric analysis showed that UCN-01 inhibited cell cycle progression at G1 to S transition in A549 cells at the concentration of 100 nM. These results suggest that inhibition of pRB phosphorylation by UCN-01 might lead to inhibition of the cell cycle and thereby contribute to antitumor activity of this compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Cell Cycle / drug effects*
  • Cell Line
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • DNA, Neoplasm / drug effects
  • DNA, Neoplasm / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Histones / metabolism
  • Humans
  • Lung Neoplasms
  • Phosphorylation
  • Protein Kinase C / antagonists & inhibitors
  • Retinoblastoma Protein / metabolism*
  • Staurosporine / analogs & derivatives
  • Tumor Cells, Cultured

Substances

  • Alkaloids
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Histones
  • Retinoblastoma Protein
  • 7-hydroxystaurosporine
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cyclin-Dependent Kinases
  • Staurosporine