Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Department of Cellular & Molecular Medicine, UCSD School of Medicine, La Jolla, CA, USA.
FASEB J. 2021 May;35(5):e21476. doi: 10.1096/fj.202002454RR.
Polo-like kinase 1 (Plk1) is an important regulator of the cell cycle and it is frequently overexpressed in cancer cells. Several small molecule inhibitors have been developed to target Plk1 and some of them have reached clinical trials in adults with acute myeloid leukemia (AML). Pediatric AML patients have a poor prognosis and survivors suffer from long-term side effects. As adult AML cells have an elevated expression of Plk1, AML is a disease candidate for Plk1 inhibition. However, the relative success of clinical trials have been hampered by adverse reactions. Herein, PLK1-targeting RNA interference (RNAi) prodrugs that enter cells without a transfection reagent are used to target PLK1 selectively in primary cells from pediatric AML patients. We show that PLK1 and PLK4 mRNA expression are significantly higher in pediatric AML patients when compared to healthy donors and that PLK1 is downregulated by on average 50% using RNAi prodrugs without a significant effect on other PLK family members. In addition, the RNAi prodrug-induced decrease in PLK1 can be used to potentiate the effect of cytarabine. In summary, PLK1-targeting RNAi prodrugs can decrease the elevated levels of PLK1 in primary cells from pediatric AML patients and sensitize pediatric AML cells to chemotherapeutics.
丝氨酸/苏氨酸激酶 1（Plk1）是细胞周期的重要调节因子，在癌细胞中经常过表达。已经开发了几种小分子抑制剂来靶向 Plk1，其中一些已经在急性髓细胞白血病（AML）的成人中进行了临床试验。儿科 AML 患者的预后较差，幸存者长期遭受副作用的困扰。由于成人 AML 细胞中 Plk1 的表达水平升高，AML 是 Plk1 抑制的候选疾病。然而，临床试验的相对成功受到不良反应的阻碍。在此，使用无需转染试剂即可进入细胞的 PLK1 靶向 RNA 干扰（RNAi）前药来选择性地靶向儿科 AML 患者原代细胞中的 PLK1。我们表明，与健康供体相比，儿科 AML 患者的 PLK1 和 PLK4 mRNA 表达明显更高，并且使用 RNAi 前药平均下调 50%，而对其他 PLK 家族成员没有明显影响。此外，RNAi 前药诱导的 PLK1 减少可增强阿糖胞苷的作用。总之，PLK1 靶向 RNAi 前药可以降低儿科 AML 患者原代细胞中升高的 PLK1 水平，并使儿科 AML 细胞对化疗药物敏感。
