Machida H, Matsumoto Y, Shirai M, Kubota N.Geldanamycin, an
inhibitor of Hsp90, sensitizes human tumour cells to radiation.
Int J Radiat Biol. 2003 Dec;79(12):973-80.
Department of Radiological Sciences, Ibaraki Prefectural
University of Health Sciences, Ami-machi, Ibaraki 300-0394,
Japan.
PURPOSE: The effects of the heat shock protein 90 (Hsp90)
inhibitor geldanamycin 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 Geldanamycin for a further 8 h.
Radiation sensitivity was determined by clonogenic assays and
protein levels were examined by Western blotting. RESULTS:
Geldanamycin radiosensitized both cell lines, but
potentiated X-ray sensitivity more in SQ-5 than in DLD-1 cells.
It was found that Geldanamycin depleted EGFR and ErbB-2 in
DLD-1 cells and depleted only ErbB-2 in SQ-5 cells. Geldanamycin
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
Geldanamycin and X-ray irradiation. The findings suggest
that Geldanamycin enhances the radiation sensitivity of
human tumour cells by inhibiting the EGFR signal transduction
system and the Akt signalling pathway.
CONCLUSION: Targeting Hsp90 with Geldanamycin provides
a promising experimental strategy for radiosensitization of
carcinoma.
PMID: 14713575 |
