p53 independent radio-sensitization of human lymphoblastoid cell lines by Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin.
Inhibition of heat shock protein 90 (Hsp90) is an attractive modality for cancer therapy. Recent studies presented that an Hsp90 inhibitor, 17AAG (17-allylamino-17-demethoxygeldanamycin), enhanced tumor radio-sensitivity, while this was not observed in normal cells. One of the studies reported that the effect of this drug was only observed in tumor cells carrying the wild-type p53 gene, thus demonstrating p53-dependent tumor radio-sensitization by 17AAG. We have now tested the effects of 17AAG on two human lymphoblastoid cell lines from the same donor, TK6 cells with the wild-type p53 gene and WTK1 cells with the mutated p53 gene. The effects of 17AAG were tested at concentrations of 10 and 100 nM on various parameters, including growth inhibition of the cells, enhancement of radio-sensitivity by colony formation assay, apoptosis and chromosomal radio-sensitivity and abrogation of radiation induced G2/M checkpoint. When 100 nM 17AAG was applied, all of these parameters were enhanced in a similar fashion in both cell lines, indicating that the drug effect is p53-independent. Our results suggest that 17AAG is likely to be an effective sensitizer for radiotherapy, even on tumors with mutated p53.
Fujii
Yoshihiro
Y
Ibaraki Prefectural University of Health Sciences, Department of Radiological Sciences, Inasiki-gun, Ibaraki, Japan.
Kato
Takamitsu
T
Kubota
Nobuo
N
Fujimori
Akira
A
Niwa
Ohtsura
O
Okayasu
Ryuichi
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004307:Dose-Response Relationship, Radiation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008214:Lymphocytes / Q000378:metabolism; D009154:Mutation; D011836:Radiation Tolerance; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C112765:tanespimycin