新型PARP1/2抑制剂YHP-836与替莫唑胺联用的抗脑胶质瘤研究  

Anti-glioblastoma study of YHP-836,a novel PARP1/2 inhibitor,in combination with temozolomide

作　　者：邓佳玲 杜婷婷 周洁 徐柏玲 陈晓光 季鸣 DENG Jia-ling;DU Ting-ting;ZHOU Jie;XU Bai-ling;CHEN Xiao-guang;JI Ming(State Key Laboratory of Bioactive Substances and Functions of Natural Medicines/Beijing Key Laboratory of Non-clinical Drug Metabolism and PK/PD Study,Institute of Materia Medica,Chinese Academy of Medical Sciences,Beijing 100050,China)

机构地区：[1]中国医学科学院药物研究所,天然药物活性物质与功能国家重点实验室/创新药物非临床药物代谢及PK/PD研究北京市重点实验室,北京100050

出　　处：《药学学报》2024年第6期1656-1663,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82073891).

摘　　要：本文研究和评价一种新型多聚(ADP-核糖)聚合酶[poly(ADP-ribose)polymerase,PARP]-1和PARP2抑制剂YHP-836与替莫唑胺(temozolomide,TMZ)联用的抗脑胶质瘤(glioblastoma,GBM)作用。体外采用MTT、蛋白免疫印迹法、流式细胞术,测定化合物单用和与TMZ联用对多株脑胶质瘤细胞的细胞杀伤活性和DNA损伤修复标志物磷酸化组蛋白H2AX(histone H2AX phosphorylation,γH2AX)水平以及细胞周期的影响。通过脑胶质瘤异体移植模型和原位移植瘤模型,评价YHP-836与TMZ联用的体内药效。动物实验按照中国医学科学院、北京协和医学院药物研究所实验动物伦理委员会操作规范严格执行(00009138)。结果显示,YHP-836与TMZ联用增加了对人脑胶质瘤细胞的细胞杀伤活性和γH2AX的表达水平,使细胞周期阻滞在S期。体内动物模型结果表明,单独使用YHP-836对U251/TMZ肿瘤的治疗作用较差,而在与TMZ联用时,发现其能显著增加TMZ的抗肿瘤作用,且未显著增加化疗药物毒性。综上所述,新型PARP1/2抑制剂YHP-836可以增敏化疗药物TMZ的作用,并为下一步研究其作用机制奠定了基础。提示PARP1/2抑制剂YHP-836可能成为TMZ耐药患者联合TMZ治疗的候选药物之一。The aim of this study was to investigate and evaluate the antitumor effects of a novel poly(ADPribose)polymerase(PARP)1/2 inhibitor,YHP-836,in combination with temozolomide(TMZ)for the treatment of glioblastoma(GBM).The cytotoxicity of YHP-836 was tested alone or in combination with TMZ using MTT assay.Immunoblotting and flow cytometry were also employed to assess the combination activity of YHP-836 and TMZ in multiply GBM cell lines.Further,the antitumor activity of YHP-836 and TMZ was evaluated using subcutaneous and orthotopic mice xenograft tumor models.All procedures were approved by the Ethics Committee for Animal Experiments of the Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College and conducted under the Guidelines for Animal Experiments of Peking Union Medical College.The approval number is 00009138.It was demonstrated that the combination of YHP-836 and TMZ increased the cytotoxicity against GBM cells and upregulated histone H2AX phosphorylation(γH2AX)expression levels compared to TMZ treatment alone.The combination also led to the S-phase cell cycle arrest.Moreover,YHP-836 significantly enhanced TMZ antitumor effects without significantly increasing chemotherapy drug toxicity in vivo,whereas YHP-836 alone showed limited therapeutic efficacy against GBM.In conclusion,the novel PARP1/2 inhibitor,YHP-836,sensitizes TMZ and provides a basis for further investigation into its mechanism of action.These findings suggest that YHP-836 may be a potential candidate for combination therapy with TMZ in patients with TMZ resistance.

关 键 词：替莫唑胺 PARP抑制剂 脑胶质瘤 多聚(ADP-核糖)聚合酶 药物联用 

分 类 号：R966[医药卫生—药理学]