lung cancer：Nutlin-3a增加肺癌细胞对放疗的敏感性

放疗是治疗肺癌的常用方法。然而，电离辐射（IR）诱导肺癌细胞衰老的潜在机制和在肺癌治疗中的作用却知之甚少。针对这种情况，来自中国南华大学组织胚胎学系的罗红梅教授联合美国南卡罗来纳大学病理学系的Gavin Y. Wang博士等人进行了一项研究，研究结果在线发表于2013年5月15日的《肺癌》(Lung cancer)杂志上。作者发现Nutlin-3a可以活化p53基因，促进IR诱导的早衰，使肺癌细胞对放射治疗敏感。

该研究通过细胞计数和流式细胞计数检测IR放射剂量与A549和H460肺癌细胞株的增殖相关性；β-glactosidase（SA-β-半乳糖苷酶）染色和BrdU核素掺入法检测IR放射剂量与细胞早衰的相关性；western-blot检测H460细胞株中P53 -p21途径与放疗的相关性，已及Nutlin-3a与p53和放疗疗效的相关性。

研究结果表明，IR通过凋亡机制抑制人类非小细胞肺癌（NSCLC）细胞增殖。进一步研究发现，在放疗的非小细胞肺癌细胞中衰老相关的β-glactosidase（SA-β-半乳糖苷酶）染色增强，BrdU结合减少和p16INK4a（P16）表达升高，这些证据表明放疗的抗癌疗效与IR诱导的细胞早衰显著相关。机制研究表明，诱导衰老与P53 -p21途径的激活相关，PFT-α抑制p53的转录活性，减少IR诱导的肿瘤细胞杀伤和衰老。功能实验表明，p53基因表达的恢复使H1299 细胞对照射敏感，而通过siRNA沉默p53基因抑制IR诱导的H460 细胞衰老。此外， 通过一种小分子MDM2抑制剂Nutlin-3a的治疗，持续活化P53 -P21信号通路，增强了IR诱导的肿瘤细胞杀伤和衰老。

该研究表明Nutlin-3a可以活化p53基因，通过促进IR诱导的肺癌细胞早衰，使肺癌细胞对放射治疗敏感。作者认为肿瘤细胞的早衰（而非凋亡）与IR疗效相关。

Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence.
Abstract
Radiotherapy is routinely used for the treatment of lung cancer. However, the mechanisms underlying ionizing radiation (IR)-induced senescence and its role in lung cancer treatment are poorly understood. Here, we show that IR suppresses the proliferation of human non-small cell lung cancer (NSCLC) cells via an apoptosis-independent mechanism. Further investigations reveal that the anticancer effect of irradiation correlates well with IR-induced premature senescence, as evidenced by increased senescence-associated β-glactosidase (SA-β-gal) staining, decreased BrdU incorporation and elevated expression of p16INK4a (p16) in irradiated NSCLC cells. Mechanistic studies indicate that the induction of senescence is associated with activation of the p53-p21 pathway, and that inhibition of p53 transcriptional activity by PFT-α attenuates IR-induced tumor cell killing and senescence. Gain-of-function assays demonstrate that restoration of p53 expression sensitizes H1299 cells to irradiation, whereas knockdown of p53 expression by siRNA inhibits IR-induced senescence in H460 cells. Furthermore, treatment with Nutlin-3a, a small molecule inhibitor of MDM2, enhances IR-induced tumor cell killing and senescence by stabilizing the activation of the p53-p21 signaling pathway. Taken together, these findings demonstrate for the first time that pharmacological activation of p53 by Nutlin-3a can sensitize lung cancer cells to radiation therapy via promoting IR-induced premature senescence.