Reference - Detail
|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.|
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.
|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|
|WOS Category||NUCLEAR SCIENCE & TECHNOLOGY RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING BIOLOGY|
|Human and Animal Cells|