Ibaraki Prefectural University of Health Sciences, Department of Radiological Sciences, Inasiki-gun, Ibaraki, Japan.
Oncol Rep. 2010 Jan;23(1):199-203.
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.
抑制热休克蛋白 90（Hsp90）是癌症治疗的一种有吸引力的方法。最近的研究表明，Hsp90 抑制剂 17AAG（17-烯丙基-17-去甲氧基格尔德霉素）增强了肿瘤的放射敏感性，而在正常细胞中则没有观察到这种现象。其中一项研究报告称，这种药物的作用仅在携带野生型 p53 基因的肿瘤细胞中观察到，从而证明 17AAG 通过 p53 依赖性肿瘤放射增敏作用。我们现在已经在来自同一供体的两种人类淋巴母细胞系中测试了 17AAG 的作用，即携带野生型 p53 基因的 TK6 细胞和携带突变型 p53 基因的 WTK1 细胞。在 10 和 100 nM 的浓度下测试了 17AAG 对各种参数的影响，包括细胞生长抑制、集落形成试验增强放射敏感性、细胞凋亡和染色体放射敏感性以及辐射诱导的 G2/M 检查点失活。当应用 100 nM 17AAG 时，这两种细胞系中的所有这些参数都以相似的方式增强，表明药物作用与 p53 无关。我们的结果表明，即使在携带突变型 p53 的肿瘤中，17AAG 也可能是放射治疗的有效增敏剂。
