Effect and Mechanism of Radiosensitization of Poly (ADP-Ribose) Polymerase Inhibitor on Lewis Cells and Xenografts

• Published in: Zhongguo fei ai za zhi Vol. 19; no. 1; pp. 16 - 23
• Main Authors: WANG, Wei, DUAN, Bixia, ZENG, Li
• Format: Journal Article
• Language: Chinese
• Published: Tianjin Chinese Anti-Cancer Association Chinese Antituberculosis Association 01.01.2016; Chinese Anti-Cancer Association; Chinese Antituberculosis Association
• Subjects: Apoptosis; Breast cancer; Cancer therapies; Deoxyribonucleic acid; DNA; DNA repair; Gene expression; Kinases; Poly (ADP -Ribose) polymerase inhibitors; Proteins; Radiation therapy; Radiosensitization; Repair of radiation damage; Beijing China; China
• ISSN: 1009-3419; 1999-6187
• DOI: 10.3779/j.issn.1009-3419.2016.01.02

背景与目的 受电离辐射的肿瘤细胞DNA损伤主要为单链断裂（single strand break, SSB）与双链断裂（double strand break, DSB），其中SSBs发生的频率数十倍于DSBs，而SSBs多能通过聚腺苷二磷酸核糖聚合酶［Poly(ADP-Ribose) polymerase, PARP］等因子进行修复。相关新药Olaparib（PARP1/PARP2/PARP3抑制剂）靶向作用于细胞SSBs损伤修复，其联合化疗的临床研究取得令人鼓舞结果。本实验旨在研究Olaparib对Lewis肺癌细胞及移植瘤放疗增敏作用，初步探讨其可能机制。方法 采用MTT法检测Olaparib对Lewis细胞10%抑制浓度（10% inhibitory concentration, IC）值，克隆形成实验验证Olaparib联合放疗的体外增敏作用；成瘤小鼠分为空白对照、Olaparib、放疗（radiotherapy, RT, 2 Gy×5 d）、Olaparib+RT组，动态测量各组移植瘤体积变化；流式细胞术比较各组细胞体外凋亡率，TUNEL法比较移植瘤细胞凋亡；Western blot检测各组DNA损伤相关蛋白γH2AX，凋亡相关蛋白Bax/Bcl-2、Caspase-3表达。结果 Olaparib对Lewis细胞IC值为4.4 μmol/L，克隆形成实验测得Olaparib放疗增敏比为1.211；移植瘤初体积（处理前）增长4倍所需天数，Olaparib+RT组显著高于单纯RT组（P<0.001）；流式及TUNEL法检测Lewis细胞体内外凋亡率均Olaparib+RT组高于RT组（P<0.05）；Olaparib+RT组细胞及移植瘤中γH2AX、Bax、Caspase-3显著高于RT组，Bcl-2显著低于RT组（均P<0.05）。结论 Olaparib对Lewis肺癌细胞及移植瘤起到显著放疗增敏作用，其机制可能与增加受照肿瘤细胞DNA双链断裂形成，上调Bax/Bcl-2促凋亡体系蛋白有关。 Background and objective The DNA damage of the irradiated tumor cells is mainly single strand breaks (SSBs) and double strand breaks (DSBs), in which the freq