RRC ID 42067
Author Machida H, Matsumoto Y, Shirai M, Kubota N.
Title Geldanamycin, an inhibitor of Hsp90, sensitizes human tumour cells to radiation.
Journal Int. J. Radiat. Biol.
Abstract PURPOSE:The effects of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) were examined on the radiosensitivity and signal transduction pathways in human tumour cell lines.
MATERIALS AND METHODS:Two human cell lines, SQ-5 and DLD-1, derived from lung carcinoma and colon adenocarcinoma, respectively, were incubated for 16 h at 37 degrees C in medium containing 0.2 microM GA. The cells were then irradiated with X-rays and incubated with GA for a further 8 h. Radiation sensitivity was determined by clonogenic assays and protein levels were examined by Western blotting.
RESULTS:GA radiosensitized both cell lines, but potentiated X-ray sensitivity more in SQ-5 than in DLD-1 cells. It was found that GA depleted EGFR and ErbB-2 in DLD-1 cells and depleted only ErbB-2 in SQ-5 cells. GA also reduced the expression of Akt and phosphorylated Akt (pAkt) expression in SQ-5 cells. In addition, the ratio (%) of apoptotic cells and poly [ADP-ribose] polymerase cleavage increased in SQ-5 but not in DLD-1 cells after exposure to GA and X-ray irradiation. The findings suggest that GA enhances the radiation sensitivity of human tumour cells by inhibiting the EGFR signal transduction system and the Akt signalling pathway.
CONCLUSION:Targeting Hsp90 with GA provides a promising experimental strategy for radiosensitization of carcinoma.
Volume 79(12)
Pages 973-80
Published 2003-12
DOI 10.1080/09553000310001626135
PMID 14713575
MeSH Adenocarcinoma / metabolism* Adenocarcinoma / pathology Apoptosis / drug effects Apoptosis / radiation effects Benzoquinones Carcinoma, Squamous Cell / metabolism* Carcinoma, Squamous Cell / pathology Cell Line, Tumor / drug effects Cell Line, Tumor / metabolism Cell Line, Tumor / pathology Cell Line, Tumor / radiation effects Cell Survival / drug effects Cell Survival / radiation effects Colony-Forming Units Assay Dose-Response Relationship, Drug Dose-Response Relationship, Radiation ErbB Receptors / metabolism* HSP90 Heat-Shock Proteins / antagonists & inhibitors* Humans Lactams, Macrocyclic Protein-Serine-Threonine Kinases* Proto-Oncogene Proteins / metabolism* Proto-Oncogene Proteins c-akt Quinones / pharmacology* Radiation Dosage Radiation Tolerance / drug effects* Radiation-Sensitizing Agents / pharmacology* Signal Transduction / drug effects Signal Transduction / radiation effects X-Rays
IF 2.266
Times Cited 51
Human and Animal Cells