Riccardin D, a Macrocyclic Bisbibenzy, Inhibits Human Breast Cancer Growth through the Suppression of Telomerase Activity
Riccardin D, a Macrocyclic Bisbibenzy, Inhibits Human Breast Cancer Growth through the Suppression of Telomerase Activity
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Riccardin D 是一种大环双联苯，通过抑制端粒酶活性来抑制人类乳腺癌的生长
DOI：
10.1111/bcpt.12267
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发表时间：
2014-12-01
影响因子：
3.1
通讯作者：
Qu, Xian-Jun
中科院分区：
文献类型：
--
作者：
Sun, Cui-Cui;Xu, Hui-Min;Qu, Xian-Jun
Riccardin D是一种地钱衍生的天然大环联苄，已被发现在多种癌细胞类型中发挥抗癌作用。本研究探讨了里卡多丁D对人乳腺癌的作用及其机制。在人乳腺癌MCF-7和MDA-MB-231细胞上进行实验。采用MTT法和人乳腺癌小鼠移植瘤模型观察Riccardin D的抗肿瘤作用。TRAPeze（（R））XL端粒酶检测试剂盒检测端粒酶活性。-H（2）AX焦点的形成用于检测DNA损伤反应的诱导。流式细胞术分析细胞周期分布，Annexin V-FITC/PI染色、TUNEL法和Western blotting检测细胞凋亡。Riccardin D在体外可有效抑制MCF-7和MDA-MB-231细胞的生长。Riccardin D还有效地延迟MCF-7和MDA-MB-231-luc-D3 H2 LN异种移植物的生长，而没有显著的体重损失。进一步的分析表明，Riccardin D的作用可能是由于其抑制端粒酶活性，导致端粒功能障碍。端粒酶抑制和端粒功能障碍可激活经典共济失调毛细血管扩张突变（ATM）激酶介导的DNA损伤反应，如-H（2）AX、p-ATM和p-Chk 2表达升高所示。最后，诱导细胞周期停滞和凋亡，如TUNEL染色细胞的增加、半胱天冬酶活化、PARP裂解和bax/bcl-2比率的增加所示。Riccardin D可使p53基因表达阳性的MCF-7细胞阻滞于G1期，使p53基因缺失的MDA-MB-231细胞阻滞于G2/M期。总之，这些结果表明，Riccardin D可能通过抑制端粒酶活性来抑制人类乳腺癌的生长。
Riccardin D, a liverwort-derived naturally occurring macrocyclic bisbibenzyl, has been found to exert anticancer effects in multiple cancer cell types. In this study, we investigated the effect and mechanism of Riccardin D on human breast cancer. Experiments were performed on human breast cancer MCF-7 and MDA-MB-231 cells. The antitumour effects of Riccardin D were assessed by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and human breast cancer xenografts mice model. TRAPeze((R)) XL Telomerase Detection assay was used for the detection of telomerase activity. -H(2)AX foci formation was tested for the induction of DNA damage response. Cell cycle distribution was analysed by flow cytometry, and cell apoptosis was determined by annexin V-FITC/PI staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay and Western blotting. Riccardin D effectively inhibited the growth of MCF-7 and MDA-MB-231 cells in vitro. And Riccardin D also effectively delayed the growth of MCF-7 and MDA-MB-231-luc-D3H2LN xenografts without significant loss of body-weight. Further analysis suggested that Riccardin D's effects may arise from its suppression of telomerase activity, which led to telomere dysfunction. Telomerase inhibition and telomere dysfunction could activate the canonical ataxia telangiectasia-mutated (ATM) kinase-mediated DNA damage response, as shown by elevated expression of -H(2)AX, p-ATM and p-Chk2. This is finally followed by the induction of cell cycle arrest and apoptosis, as shown by the increase of TUNEL-stained cells, caspase activation, PARP cleavage and the increase of bax/bcl-2 ratio. Moreover, Riccardin D induced p53-proficient MCF-7 cells to arrest in G1 phase and p53-deficient MDA-MB-231 cells to arrest in G2/M phase. Overall, these results demonstrate that Riccardin D may inhibit human breast cancer growth through suppression of telomerase activity.