Induction of radiation resistance by a heat shock protein inhibitor, KNK437, in human glioblastoma cells

Int J Radiat Biol. 2006 Aug;82(8):569-75. doi: 10.1080/09553000600876645.

Abstract

Purpose: We examined the effects of a heat shock protein (hsp) inhibitor, N-formyl-3, 4-methylenedioxy-gamma-butyrolactam (KNK437), on the radiosensitivity of human glioblastoma cells (A-172).

Materials and methods: Effects of KNK437 on radiosensitivity and cell cycle regulation were examined using colony formation assays, flow cytometry analysis and Western blot analysis. KNK437 was added to the culture medium 1 h before X-ray irradiation at 50, 100 or 300 microM final concentration.

Results: KNK437 induced the resistance of A-172 cells and human squamous cell carcinoma cells (SAS) to X-rays. Flow cytometry analysis showed that KNK437 alone efficiently induced A-172 cells to enter G2/M phase. Though A-172 cells irradiated with X-rays at 6 Gy showed no clear change in the cell cycle, the irradiated cells were induced to enter G2/M phase when they had been pre-treated with KNK437. By Western blot analysis, p53, 14-3-3sigma and cell division cycle 2 (cdc2) proteins that function in G2 arrest were observed to be persistently accumulated or phosphorylated in KNK437-treated cells, regardless of X-ray irradiation.

Conclusions: These results show that KNK437 causes cells to be resistant to radiation, and that this might be correlated with maintenance of G2 arrest in the cell cycle regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzhydryl Compounds / administration & dosage*
  • Cell Cycle / drug effects*
  • Cell Cycle / radiation effects*
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Dose-Response Relationship, Radiation
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Pyrrolidinones / administration & dosage*
  • Radiation Tolerance / drug effects*

Substances

  • Benzhydryl Compounds
  • Heat-Shock Proteins
  • KNK 437
  • Pyrrolidinones