p53 independent radio-sensitization of human lymphoblastoid cell lines by Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin
p53 independent radio-sensitization of human lymphoblastoid cell lines by Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin
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DOI：
10.3892/or_00000623
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发表时间：
2010-01-01
期刊：
影响因子：
4.2
通讯作者：
Okayasu, Ryuichi
中科院分区：
文献类型：
--
作者：
Fujii, Yoshihiro;Kato, Takamitsu;Okayasu, Ryuichi
抑制热休克蛋白90（HSP 90）是肿瘤治疗的一种有吸引力的方式。最近的研究表明，热休克蛋白90抑制剂，17-烯丙基氨基-17-去甲氧基格尔德霉素（17-allylamino-17-demethoxygeldanamycin，17-AAG），增强肿瘤的放射敏感性，而这在正常细胞中没有观察到。其中一项研究报告称，该药物的作用仅在携带野生型p53基因的肿瘤细胞中观察到，因此证明了17 AAG的p53依赖性肿瘤放射增敏作用。我们现在已经测试了17 AAG对来自同一供体的两种人淋巴母细胞样细胞系（具有野生型p53基因的TK 6细胞和具有突变的p53基因的WTK 1细胞）的作用。在10和100 nM的浓度下测试17 AAG对各种参数的影响，包括细胞的生长抑制、通过集落形成测定的放射敏感性增强、细胞凋亡和染色体放射敏感性以及放射诱导的G2/M检查点的消除。当应用100 nM 17 AAG时，所有这些参数在两种细胞系中以相似的方式增强，表明药物作用是p53非依赖性的。我们的结果表明，17 AAG可能是放射治疗的所有有效增敏剂，甚至是具有突变的p53的油瘤。
Inhibition of heat shock protein 90 (HSP90) is all 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 oil 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 radiosensitivity 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 ail effective sensitizer for radiotherapy, even oil tumors with mutated p53.