文章摘要
汤思洁,江佳佳,程慧颖,郭佳倩,黄 灿,李晓华,顾 洛.联合应用MS⁃275和MDV3100对前列腺肿瘤干细胞样微球的作用[J].南京医科大学学报,2019,(4):465~471
联合应用MS⁃275和MDV3100对前列腺肿瘤干细胞样微球的作用
Experimental study on the combination of MDV3100 and MS⁃275 for the treatment of prostate tumorosphere cells
投稿时间:2018-10-22  
DOI:10.7655/NYDXBNS20190401
中文关键词: 前列腺肿瘤干细胞样微球  MDV3100  MS⁃275
英文关键词: prostate tumorosphere  MDV3100  MS⁃275
基金项目:国家自然科学基金(81572741,81372319);吴阶平医学基金会临床科研专项资助基金(320.6750.14120);苏州市科技发展计划(SYSD2014009)
作者单位
汤思洁 南京医科大学生理学系江苏 南京  211166 
江佳佳 江苏大学附属澳洋医院病理和检验医学中心江苏 苏州 215600 
程慧颖 江苏大学附属澳洋医院病理和检验医学中心江苏 苏州 215600 
郭佳倩 江苏大学附属澳洋医院病理和检验医学中心江苏 苏州 215600 
黄 灿 江苏大学附属澳洋医院病理和检验医学中心江苏 苏州 215600 
李晓华 江苏大学附属澳洋医院病理和检验医学中心江苏 苏州 215600
国家基因检测技术应用示范中心合肥金域医学检验所有限公司安徽 合肥 230088 
顾 洛 南京医科大学生理学系江苏 南京  211166 
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中文摘要:
      目的:探讨雄激素受体(androgen receptor,AR)拮抗剂和组蛋白去乙酰化酶(histone deacetylase,HDAC)抑制剂对前列腺肿瘤干细胞样微球的作用,并探讨其可能的分子机制。方法:采用无血清悬浮培养前列腺LNCaP和22RV1肿瘤细胞以获取干细胞样肿瘤微球细胞,然后单独和联合使用AR拮抗剂MDV3100和HDACⅠ类抑制剂MS?275分别处理2种微球细胞,镜下观察细胞形态,评估其克隆形成能力。应用实时荧光定量聚合酶链反应检测微球细胞中CD133的转录水平,Western blot检测DNA损伤标志物磷酸化H2A.X(p?H2A.X)的表达和细胞凋亡标志蛋白聚ADP?核糖聚合酶(PARP)特异性裂解片段的水平,同时检测Wnt信号通路关键分子β?catenin以及原癌基因c?Myc、cyclin D1蛋白表达情况。结果:MDV3100单独处理能明显降低肿瘤干细胞标志物CD133的表达;而MS?275单独或联合MDV3100处理均能明显抑制肿瘤干细胞样肿瘤微球的形成、降低肿瘤微球细胞CD133的表达,并促进肿瘤微球细胞产生PARP的特异性裂解,使p?H2A.X表达水平升高,同时可以明显降低β?catenin、c?Myc及cyclin D1的表达。结论:联合应用MS?275和MDV3100可以显著增强MDV3100的抗肿瘤活性,具体表现在抑制肿瘤干细胞样微球细胞生成及克隆形成、损伤细胞的DNA、诱导细胞凋亡等。该结果为临床联合应用HDACⅠ类抑制剂MS?275和AR拮抗剂MDV3100治疗前列腺肿瘤提供了一定的实验依据。
英文摘要:
      Objective:To study the treatment effects of androgen receptor(AR)antagonist combined with class I histone deacetylase(HDAC)inhibitors on prostate tumorosphere,and to investigate the possible molecular mechanisms involved in the process. Methods:Prostate cancer LNCaP and 22RV1 cells were cultured in serum?free suspension condition,and the obtained two tumorosphere stem?like cells were treated with AR antagonist MDV3100 with or without the presence of HDAC class I inhibitor MS?275 to study the morphology change and the ability of cell clone formation in monolayer culture condition. Then,quantitative real?time fluorescence polymerase chain reaction(qRT?PCR)was utilized to analyze cancer stem cell marker CD133 expression,and Western blot was used to detect the levels of DNA damage marker H2A.X(p?H2A.X),the cleavage of poly ADP?ribose polymerase(PARP),β?catenin,proto?oncogene c?Myc and cyclin D1. Results:Treatment with MDV3100 alone inhibited CD133 expression in tumorosphere cells. Combination treatment of MDV3100 with MS?275 reduced the number of tumorosphere,inhibited CD133 transcription,enhanced the level of both PARP cleavage and p?H2A.X,decreased expression of β?catenin,c?Myc and cyclin D1. Conclusion:Compared with the treatment of MDV3100 alone,combination treatment of MDV3100 with MS?275 significantly inhibited cancer stem?like tumorosphere cell formation and promoted apoptotic cell death. The drugs?reduced over activation of Wnt/β?catenin/c?Myc/cyclin D1 pathway was possibly involved in the antitumor process. These results provide guidance for clinical application of MDV3100 and MS?275 in prostate cancer management of personal medicine.
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