Loss of G2/M arrest correlates with radiosensitization in two human sarcoma cell lines with mutant p53
Loss of G2/M arrest correlates with radiosensitization in two human sarcoma cell lines with mutant p53
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DOI：
10.1002/ijc.1002
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发表时间：
2001-04-20
影响因子：
6.4
通讯作者：
Taubert, H
中科院分区：
文献类型：
--
作者：
Bache, M;Pigorsch, S;Taubert, H
我们研究了在两种p53突变的人肉瘤细胞系（US8-93和LMS6-93）中使用咖啡因对放射敏感性的调节。在两种细胞系中，强辐照诱导的G2/M阻滞与低凋亡率相结合。用咖啡因孵育导致低百分比的S和G2/M细胞，与G1积累有关。在较高的咖啡因浓度下，我们检测到2 mM处的IC50较低的克隆存活率。在两种细胞系中，咖啡因孵育完全阻止了辐射诱导的G2/M阻滞。这与放射致敏有关，但与诱导细胞凋亡没有直接关系。放射致敏效应随辐照剂量的增加而增强。但与LMS6-93相比，它在细胞系US8-93中表现较强。US8-93较高的放射致敏性与预防强辐照诱导的G2/M反应和较高的初始DNA损伤相关。Western杂交结果揭示了咖啡因引起的放射致敏不依赖于p53的机制。我们的研究结果表明，G2/M调节的调节可能会影响p53功能缺陷的肿瘤细胞的一个共同检查点。此外，我们的研究结果表明，咖啡因的增强作用依赖于G2/M阻滞细胞数量的大幅减少和照射后DNA损伤修复的抑制。(C) 2001 Wiley-Liss, Inc。
We have examined the modulation of radiosensitivity by using caffeine in two human sarcoma cell lines both with a p53 mutation (US8-93 and LMS6-93). In both cell lines a strong irradiation-induced G2/M arrest was coupled with a low rate of apoptosis. Incubation with caffeine resulted in a low percentage of S and G2/M cells, associated with an accumulation in G1. With a higher caffeine concentration, we detected a lower clonogenic survival with IC50 at 2 mM. In both cell lines incubation with caffeine completely prevents the irradiation-induced G2/M arrest. This was connected to radiosensitization, but without direct correlation to an induction of apoptosis. The effect of radiosensitization rose with higher irradiation doses. However, in comparison with LMS6-93, it was stronger in cell line US8-93. A higher radiosensitization in US8-93 correlated with the prevention of strong irradiation-induced G2/M response and higher initial DNA damage. Results of Western hybridization reveal a p53-independent mechanism of radiosensitization caused by caffeine. Our findings suggest that modulation in G2/M regulation may affect a common checkpoint for tumor cells with defective p53 function. Furthermore, our results show that the enhancer effect of caffeine is dependent on a strong reduction in the number of G2/M arrested cells and on an inhibition of DNA damage repair after irradiation. (C) 2001 Wiley-Liss, Inc.