Targeting Polo-like Kinase 1 by a Novel Pyrrole-Imidazole Polyamide-Hoechst Conjugate Suppresses Tumor Growth In Vivo
Targeting Polo-like Kinase 1 by a Novel Pyrrole-Imidazole Polyamide-Hoechst Conjugate Suppresses Tumor Growth In Vivo
复制标题
新型吡咯-咪唑聚酰胺-Hoechst 缀合物靶向 Polo 样激酶 1 抑制体内肿瘤生长
DOI：
10.1158/1535-7163.mct-17-0747
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发表时间：
2018-05-01
影响因子：
5.7
通讯作者：
Li, Hongchang
中科院分区：
文献类型：
--
作者：
Liu, Ke;Fang, Lijing;Li, Hongchang
丝氨酸/苏氨酸激酶Polo样激酶1（Plk 1）在细胞增殖中起着关键作用，并已被验证为有前途的抗癌药物靶点。然而，由于缺乏对Plk 1的足够特异性，使用现有的Plk 1抑制剂在临床应用中取得了非常有限的成功。为了开发一种新型的具有高选择性和有效性的Plk 1抑制剂，我们设计并合成了一种吡咯-咪唑聚酰胺-Hoechst缀合物，PIP 3，靶向PLK 1启动子中的特定DNA序列。PIP 3可特异性抑制细胞周期调控因子Plk 1的表达，从而抑制肿瘤细胞的生长。用PIP 3处理的癌细胞表现出严重的有丝分裂缺陷和增加的凋亡，而正常细胞不受PIP 3处理的影响。此外，将PIP 3皮下注射到携带人癌症异种移植物的小鼠中诱导了显著的肿瘤生长抑制，具有低宿主毒性。因此，PIP 3显示出作为靶向癌症治疗的有效药剂的潜力。(C)2018年AACR。
The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the PLK1 promoter. PIP3 could specifically inhibit the cell cycle-regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, whereas normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy. (C) 2018 AACR.