Treatment of human glioblastoma cells with the staurosporine derivative CGP 41251 inhibits CDC2 and CDK2 kinase activity and increases radiation sensitivity

Martin Begemann, Sharafadeen A. Kashimawo, Daniel F. Heitjan, Peter B. Schiff, Jeffrey N. Bruce, I. Bernard Weinstein

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

CGP 31251, a staurosporine derivative, is a potent inhibitor of protein kinase C (PKC). In recent studies we found that this compound causes growth inhibition and induces apoptosis in human glioblastoma cell lines and also inhibits the growth of xenografts of a human astrocytoma. In this study we investigate its effects on cell cycle control. Treatment of glioblastoma or gliosarcoma cells with CGP 41251 lend to a time and dose dependent increase of the percentage of cells in the G2-M phase of the cell cycle. This correlated with a decrease of CDC2- and CDK2-associated histone H1 kinase activities as well as a decrease in the cellular level of the CDC2 protein. The decrease of CDC2- associated histone H1 kinase activity was detected within 5 hours, and there was complete inhibition after 24 hours. Assays of mixtures of cell extracts obtained from cultures treated with CGP 41251, the inactive analog CGP 42700, or untreated cultures indicated that this decrease was due to a decrease in the CDC2 kinase itself rather than the accumulation of an inhibitor of this kinase. In vitro assays in which CGP 41251 was added directly to the in vitro assay system revealed marked inhibition of both CDC2- and CDK2-associated kinase activity at about 1 μM. Thus CGP 41251 inhibits CDC2- and CDK2- associated kinase activities both in vivo and in vitro. Its biologic effects may, therefore, not be due simply to inhibition of PKC. Since cells in the G2-M phase of the cell cycle are relatively more sensitive to killing by γ- radiation than cells in other phases of the cell cycle, we carried out radiosensitization studies. We found that CGP 41251 was a radiation sensitizer in two glioblastoma cell lines. Therefore, this compound may be useful in the treatment of glioblastomas, possibly in combination with radiation therapy.

Original languageEnglish (US)
Pages (from-to)2275-2282
Number of pages8
JournalAnticancer Research
Volume18
Issue number4 A
StatePublished - Jul 1 1998

Fingerprint

4'-N-benzoylstaurosporine
Staurosporine
Radiation Tolerance
Glioblastoma
Phosphotransferases
Cell Cycle
G2 Phase
Cell Division
Protein Kinase C
Gliosarcoma
Radiation-Sensitizing Agents
Cell Line
Astrocytoma
Growth
Cell Cycle Checkpoints
Cell Extracts
Heterografts
Radiotherapy
Radiation
Apoptosis

Keywords

  • CDC2
  • CDK2
  • Cell cycle
  • CGP 41251
  • Protein kinase C
  • Radiosensitization

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Treatment of human glioblastoma cells with the staurosporine derivative CGP 41251 inhibits CDC2 and CDK2 kinase activity and increases radiation sensitivity. / Begemann, Martin; Kashimawo, Sharafadeen A.; Heitjan, Daniel F.; Schiff, Peter B.; Bruce, Jeffrey N.; Weinstein, I. Bernard.

In: Anticancer Research, Vol. 18, No. 4 A, 01.07.1998, p. 2275-2282.

Research output: Contribution to journalArticle

Begemann, Martin ; Kashimawo, Sharafadeen A. ; Heitjan, Daniel F. ; Schiff, Peter B. ; Bruce, Jeffrey N. ; Weinstein, I. Bernard. / Treatment of human glioblastoma cells with the staurosporine derivative CGP 41251 inhibits CDC2 and CDK2 kinase activity and increases radiation sensitivity. In: Anticancer Research. 1998 ; Vol. 18, No. 4 A. pp. 2275-2282.
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