PARP1
PARP抑制剂
DNA损伤
聚ADP核糖聚合酶
合成致死
乳腺癌
癌细胞
DNA修复
癌症
背景(考古学)
生物
转移
化学
聚合酶
奥拉帕尼
药理学
癌症研究
DNA
生物化学
遗传学
古生物学
作者
Wenjun Liu,Ming Ji,Jie Zhou,Jing Jin,Nina Xue,Ju Chen,Bailing Xu,Xiaoguang Chen
标识
DOI:10.1016/j.bcp.2016.02.015
摘要
Poly (ADP-ribose) polymerases (PARPs) facilitate repairing of cancer cell DNA damage as a mean to promote cancer proliferation and metastasis. Inhibitors of PARPs which interfering DNA repair, in context of defects in other DNA repair mechanisms, can thus be potentially exploited to inhibit or even kill cancer cells. However, nondiscriminatory inhibition of PARPs, such as PARP2, may lead to undesired consequences. Here, we demonstrated the design and development of the Zj6413 as a potent and selective PARP1 catalytic inhibitor. It trapped PARP1/2 at damaged sites of DNA. As expected, the Zj6413 showed notable anti-tumor activity against breast cancer gene (BRCA) deficient triple negative breast cancers (TNBCs). Zj6413 treated breast cancers (BCs) showed an elevated level of DNA damage evidenced by the accumulation of γ-H2AX foci and DNA damaged related proteins. Zj6413 also induced G2/M arrest and cell death in the MX-1, MDA-MB-453 BC cells, exerted chemo-sensitizing effect on BRCA proficient cancer cells and potentiated Temozolomide (TMZ)'s cytotoxicity in MX-1 xenograft tumors mice. In conclusion, our study provided evidence that a new PARP inhibitor strongly inhibited the catalytic activity of PARPs, trapped them on nicked DNA and damaged the cancer cells, eventually inhibiting the growth of breast tumor cells in vitro and in vivo.
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