药学学报, 2016, 51(6): 907-912
引用本文:
来芳芳, 李杰, 季鸣, 周秦, 王丽嫄, 王春阳, 陈晓光. 奥拉帕尼对Taxol抗乳腺癌4T1的增敏作用[J]. 药学学报, 2016, 51(6): 907-912.
LAI Fang-fang, LI Jie, JI Ming, ZHOU Qin, WANG Li-yuan, WANG Chun-yang, CHEN Xiao-guang. Olaparib potentiates the antitumor effect of Taxol on 4T1 breast cancer[J]. Acta Pharmaceutica Sinica, 2016, 51(6): 907-912.

奥拉帕尼对Taxol抗乳腺癌4T1的增敏作用
来芳芳1, 李杰2, 季鸣1, 周秦1, 王丽嫄1, 王春阳1, 陈晓光1
1. 中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050;
2. 北京朝阳医院乳腺外科, 北京 100020
摘要:
聚ADP-核糖聚合酶1/2(PARP1/2, poly ADP-ribose polymerase1/2)能催化底物蛋白的多聚ADP-核糖化(PAR)修饰,在细胞DNA损伤修复、细胞死亡和转录调节中具有重要调控功能。其抑制剂奥拉帕尼(olaparib,AZD2281)可作为放化疗增敏剂,能够在多种肿瘤的放化疗中发挥较好的增敏作用。通过建立生物荧光标记的体内4T1异位乳腺肿瘤模型,研究奥拉帕尼对于小鼠乳腺癌4T1细胞的体内外单药抗肿瘤和对紫杉醇(Taxol)的增敏活性。实验结果表明,单独使用AZD2281对4T1肿瘤的治疗作用较差(包括体外MTT和流式实验,体内荷瘤小鼠实验),而在联合Taxol使用时,能显著增敏Taxol的抗肿瘤作用,并降低肿瘤组织的PAR水平,且没有明显增加化疗药物的毒性。此研究证实了以奥拉帕尼为代表的PARP抑制剂可以在小鼠乳腺癌4T1异位模型上增敏化疗药物Taxol的作用,为下一步研究其作用机制奠定了基础。
关键词:    奥拉帕尼      乳腺癌      活体生物荧光成像      聚ADP-核糖聚合酶      增敏     
Olaparib potentiates the antitumor effect of Taxol on 4T1 breast cancer
LAI Fang-fang1, LI Jie2, JI Ming1, ZHOU Qin1, WANG Li-yuan1, WANG Chun-yang1, CHEN Xiao-guang1
1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
2. Department of Breast Surgery, Beijing Chao-Yang Hospital, Beijing 100020, China
Abstract:
Poly (ADP-ribose) polymerase 1/2(PARP1/2) can catalyze the poly (ADP ribose) (PAR) substrate protein modification and play an important role in the regulation of DNA damage repair, cell death and transcriptional activity. The PARP inhibitor olaparib (AZD2281) can be used as a sensitizer of radiotherapy and chemotherapy in the cancer treatment. Through establishment of biological fluorescent labeled 4T1 ectopic breast tumor model, we found that olaparib exhibited a poor effect on 4T1 breast cancer alone. However, in the combination with Taxol, olaparib significantly increased the anti-tumor effect of Taxol, and reduced the PAR levels of the tumor tissues. Importantly, olaparib did not amplify the toxicity of chemotherapy drugs. This study suggests that olaparib is a representative of the PARP inhibitor that can enhance Taxol 's antitumor effect in the 4T1 ectopic breast tumor model, which sets the foundation for future study of the mechanism of olaparib action.
Key words:    olaparib    breast cancer    in vivo biological fluorescence imaging    poly ADP-ribose polymerase    sensitize   
收稿日期: 2016-01-28
DOI: 10.16438/j.0513-4870.2016-0079
基金项目: 国家自然科学基金青年基金资助项目(81301916).
通讯作者: 陈晓光,Tel/Fax:86-10-63165207,E-mail:chxg@imm.ac.cn
Email: chxg@imm.ac.cn
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