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蔡思源, 唐子执, 曾鸣等. DNA损伤应答靶向抑制剂对卵巢癌细胞的化疗增敏作用[J]. koko体育app 学报（医学版）, 2016, 47(3): 316-320.
引用本文: 蔡思源, 唐子执, 曾鸣等. DNA拉伤回复靶向疗法克药物对卵泡癌肿瘤细胞的手术增敏影响[J]. 湖北本科大学学报（医学研究版）, 2016, 47(3): 316-320.
CAI Si-yuan, TANG Zi-zhi, ZENG Ming. et al. Employing DNA Damage Response Inhibitors to Enhance Chemosensitivity of Ovarian Carcinoma Cells[J]. Journal of Sichuan University (Medical Sciences), 2016, 47(3): 316-320.
Citation: CAI Si-yuan, TANG Zi-zhi, ZENG Ming. et al. Employing DNA Damage Response Inhibitors to Enhance Chemosensitivity of Ovarian Carcinoma Cells[J]. Journal of Sichuan University (Medical Sciences), 2016, 47(3): 316-320.

DNA损伤应答靶向抑制剂对卵巢癌细胞的化疗增敏作用

Employing DNA Damage Response Inhibitors to Enhance Chemosensitivity of Ovarian Carcinoma Cells

  • 摘要: 目的 观察DNA损伤应答抑制剂及其联合常规化疗药物（顺铂等）在卵巢癌耐药细胞株OVCAR-8中的作用，研究其化疗致敏效应。方法 利用针对DNA损伤应答关键信号蛋白质的抑制剂，与顺铂等连用处理卵巢癌细胞，分析这些药物处理方式对卵巢癌细胞的杀伤能力。MTT法检测不同药物作用后OVCAR-8的增殖抑制情况；免疫荧光法检测OVCAR-8中磷酸化组蛋白2A变体（γH2AX）和p53结合蛋白1（53BP1）的表达，观察二者在DNA损伤位点的募集和形成灶点的能力。结果 毛细血管扩张共济失调突变蛋白（ATM）/ATM和Rad 3相关蛋白（ATR）抑制剂与顺铂联用能抑制损伤修复机制的活化，明显减弱OVCAR-8细胞的增殖活力（P<0.01），促进其凋亡；在羟基脲和Wortmannin联合处理时，OVCAR-8细胞的ATR转导信号（如γH2AX）减弱，细胞生存率明显降低（P<0.05）；多聚ADP-核糖聚合酶（PARP）抑制剂与顺铂联合处理OVCAR-8细胞未发现明显的增敏作用（P>0.05）。结论 适当的DNA损伤应答抑制剂有潜力提高常规化疗药物的抗肿瘤效果，以达到快速清除肿瘤细胞和防止产生耐药性的效果。  
    Abstract: Objective To assess the sensitisation effects of DDR inhibitors combined with conventional chemotherapeutics agents (cisplatin et al) in a drug-resistant ovarian cancer cell line(OVCAR-8). Methods Inhibitors of DDR regulators with cisplatin were applied to challenge OVCAR-8, and evaluated the DNA damage response (DDR) and cytotoxic effects of different combination of chemicals. Inhibition of proliferation to OVCAR-8 of different drugs was evaluated by MTT assay. The activation of phosphorylation of histone family 2A variant(γH2AX) and p53 binding protein 1 (53BP1) in OVCAR-8 were evaluated by immunofluorescence to observe their ability of recruitment and forming foci at DNA damage site. Results We observed that combined treatment of ataxia-telangiectasia mutated(ATM)/ATM and Rad 3-related(ATR) inhibitor and cisplatin can suppress the activation of damage repair mechanisms and weakened the proliferative activity of OVCAR-8 cells (P<0.01); ATR pathway was suppressed and the signal of γH2AX weakened and cell survival rate significantly reduced when combination therapy of HU and Wortmannin (P<0.05); poly ADP-ribose polymerase (PARP) inhibitor could not enhance chemosensitivity in OVCAR-8 cells when combined with cisplatin (P>0.05). Conclusion We substantiated that appropriate inhibitors of DNA damage response may have a potential to improve the anti-tumor effect of conventional chemotherapy drugs and prevent drug resistances.  
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