Lab of Medicinal Chemistry, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China.
Cell Death Dis. 2018 Oct 18;9(11):1066. doi: 10.1038/s41419-018-1071-2.
Polo-like kinase 4 (PLK4) is indispensable for precise control of centriole duplication. Abnormal expression of PLK4 has been reported in many human cancers, and inhibition of PLK4 activity results in their mitotic arrest and apoptosis. Therefore, PLK4 may be a valid therapeutic target for antitumor therapy. However, clinically available small-molecule inhibitors targeting PLK4 are deficient and their underlying mechanisms still remain not fully clear. Herein, the effects of YLT-11 on breast cancer cells and the associated mechanism were investigated. In vitro, YLT-11 exhibited significant antiproliferation activities against breast cancer cells. Meanwhile, cells treated with YLT-11 exhibited effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication and mitotic defects, sequentially making tumor cells more vulnerable to chemotherapy. Furthermore, YLT-11 could strongly regulate downstream factors of PLK4, which was involved in cell cycle regulation, ultimately inducing apoptosis of breast cancer cell. In vivo, oral administration of YLT-11 significantly suppressed the tumor growth in human breast cancer xenograft models at doses that are well tolerated. In summary, the preclinical data show that YLT-11 could be a promising candidate drug for breast tumor therapy.
丝氨酸/苏氨酸蛋白激酶 4（PLK4）对于中心体复制的精确控制是必不可少的。已经在许多人类癌症中报道了 PLK4 的异常表达，并且抑制 PLK4 的活性会导致它们的有丝分裂停滞和细胞凋亡。因此，PLK4 可能是抗肿瘤治疗的有效治疗靶点。然而，临床上可用的针对 PLK4 的小分子抑制剂是缺乏的，其潜在的机制仍不完全清楚。本文研究了 YLT-11 对乳腺癌细胞的作用及其相关机制。在体外，YLT-11 对乳腺癌细胞表现出显著的增殖抑制活性。同时，用 YLT-11 处理的细胞表现出与 PLK4 激酶抑制一致的作用，包括中心体复制失调和有丝分裂缺陷，从而使肿瘤细胞更容易受到化疗的影响。此外，YLT-11 可以强烈调节 PLK4 的下游因子，这些因子参与细胞周期调控，最终诱导乳腺癌细胞凋亡。在体内，YLT-11 在可耐受的剂量下，通过口服给药显著抑制人乳腺癌异种移植模型中的肿瘤生长。总之，临床前数据表明，YLT-11 可能是一种有前途的用于治疗乳腺癌的候选药物。
