Radiosensitization of lung cancer by nutlin, an inhibitor of murine double minute 2
Radiosensitization of lung cancer by nutlin, an inhibitor of murine double minute 2
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DOI：
10.1158/1535-7163.mct-05-0356
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发表时间：
2006-02-01
影响因子：
5.7
通讯作者：
Lu, B
中科院分区：
文献类型：
--
作者：
Cao, C;Shinohara, ET;Lu, B
p53 在细胞周期停滞和细胞凋亡诱导中发挥着关键作用。某些恶性肿瘤携带野生型 p53，这种野生型 p53 经常因小鼠双微体 2 (MDM2) 过度表达而下调。针对 MDM2 的小分子抑制剂 nutlin 的出现，使得评估基于抗 MDM2 的治疗策略成为可能。当前研究的基本原理是功能性 p53 与放射治疗反应的改善有关。因此，本研究评估了 nutlin（一种阻止 p53 和 MDM2 相互作用的小分子抑制剂）在使癌细胞对辐射敏感方面的用途。检查了 p53 野生型和 p53 缺陷型肺癌细胞系中 MDM2、p53 和 p21 的表达。克隆形成和 7-氨基放线菌素 D 研究用于确定细胞死亡的可能机制。还研究了 MDM2 抑制和辐射对细胞周期的联合影响。我们发现 nutlin 的放射增敏作用发生在具有野生型 p53 的肺癌细胞中。给予nutlin和放射治疗后，细胞凋亡和细胞周期停滞增加。此外，如基质胶测定所示，nutlin 和辐射的组合降低了内皮细胞形成脉管系统的能力。我们的数据表明 nutlin 是 p53 野生型细胞的有效放射增敏剂。放射增敏作用似乎至少部分归因于细胞凋亡和细胞周期停滞的诱导。此外，nutlin 可能是肿瘤血管系统的有效放射增敏剂。
p53 plays a critical role in cell cycle arrest and induction of apoptosis. Certain malignancies carry wild-type p53, which is frequently down-regulated by murine double minute 2 (MDM2) overexpression. Availability of a small-molecule inhibitor against MDM2, nutlin, has made it feasible to evaluate the anti-MDM2-based therapeutic strategies. The rationale for the current study is that functional p53 has been linked with improved responses to radiation treatment. Hence, this study evaluates the use of nutlin, a small-molecule inhibitor that blocks the interaction of p53 and MDM2, in sensitizing cancer cells to radiation. Expression of MDM2, p53, and p21 in both p53 wild-type and p53-defective lung cancer cell lines was examined. Clonogenic and 7-amino-actinomycin D studies were used to determine possible mechanisms of cell death. The combined effect of MDM2 inhibition and radiation on cell cycle was also studied. We found that radiosensitization by nutlin occurs in lung cancer cells with wild-type p53. There were increased apoptosis and cell cycle arrest following administration of nutlin and radiation. Furthermore, the combination of nutlin and radiation decreased the ability of endothelial cells to form vasculature, as shown by Matrigel assays. Our data suggest that nutlin is an effective radiosensitizer of p53 wild-type cells. The radiosensitizing effect seems to be at least partially due to induction of apoptosis and cell cycle arrest. In addition, nutlin may be an effective radiosensitizer of tumor vasculature.