Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wild-type p53.
Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wild-type p53.
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DOI：
10.1038/sj.bjc.6605739
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发表时间：
2010-07-13
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
原发性放射治疗（RT）是喉鳞状细胞癌（LSCC）的主要治疗方法。虽然早期（T1）声带肿瘤的治愈率很高，但RT在高达三分之一的T3癌中无效。此外，RT与使人衰弱的早期和晚期治疗相关毒性相关，因此非常需要找到降低治疗水平同时保持/增强治疗有效性的方法。p53是辐射反应的关键介质;因此，我们研究了Nutlin-3，MDM 2的小分子抑制剂（小鼠双微体2; p53的重要负调节因子），是否可能使LSCC细胞放射增敏。我们进行了克隆形成试验，以测量在存在和不存在Nutlin-3的情况下，一组喉鳞状细胞癌细胞系（我们确定了p53突变状态）的放射敏感性。携带野生型p53的喉鳞状细胞癌细胞被Nutlin-3显著地放射增敏（P<0.0001;对数秩标度），并且在没有增加的凋亡的情况下显示增加的细胞周期停滞和显著增加的衰老（P<0.001）;因此，我们的数据表明衰老可能介导这种增加的放射增敏。这是第一项显示Nutlin-3在保留野生型p53的LSCC细胞中作为有效的放射增敏剂的研究。Nutlin-3的临床应用可能会改善这些患者的局部复发率或允许治疗降级。
Primary radiotherapy (RT) is a mainstay of treatment for laryngeal squamous cell carcinoma (LSCC). Although the cure rates for early (T1) vocal cord tumours are high, RT proves ineffective in up to a third of T3 carcinomas. Moreover, RT is associated with debilitating early- and late-treatment-related toxicity, thus finding means to de-escalate therapy, while retaining/augmenting therapeutic effectiveness, is highly desirable. p53 is a key mediator of radiation responses; we therefore investigated whether Nutlin-3, a small-molecule inhibitor of MDM2 (mouse double minute 2; an essential negative regulator of p53), might radiosensitise LSCC cells. We performed clonogenic assays to measure radiosensitivity in a panel of LSCC cell lines (for which we determined p53 mutational status) in the presence and absence of Nutlin-3. LSCC cells harbouring wild-type p53 were significantly radiosensitised by Nutlin-3 (P<0.0001; log-rank scale), and displayed increased cell cycle arrest and significantly increased senescence (P<0.001) in the absence of increased apoptosis; thus, our data suggest that senescence may mediate this increased radiosensitivity. This is the first study showing Nutlin-3 as an effective radiosensitiser in LSCC cells that retain wild-type p53. The clinical application of Nutlin-3 might improve local recurrence rates or allow treatment de-escalation in these patients.
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影响因子：
3.9
作者：
Olivier, M;Eeles, R;Hainaut, P
通讯作者：
Hainaut, P
影响因子：
4.3
作者：
Lehmann, Brian D.;McCubrey, James A.;Terrian, David M.
通讯作者：
Terrian, David M.
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
2.3
作者：
Masterson, Joanne C.;O'Dea, Shirley
通讯作者：
O'Dea, Shirley
影响因子：
11.2
作者：
Kan, Charlene E.;Patton, John T.;Jackson, Mark W.
通讯作者：
Jackson, Mark W.