Jayanthan Aarthi, Hofmann Bradley, Meier-Stephenson Vanessa, Perinpanayagam Maneka, Dunn Sandra E, Boklan Jessica, Trippett Tanya M, Truong Tony H, Narendran Aru
Division of Pediatric Oncology, Alberta Children's Hospital, and POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary, Calgary, AB.
Phoenix Molecular Designs, Vancouver, BC, Canada.
J Pediatr Hematol Oncol. 2019 Aug;41(6):e359-e370. doi: 10.1097/MPH.0000000000001416.
Recent studies have shown that cell cycle events are tightly controlled by complex and shared activities of a select group of kinases. Among these, polo-like kinases (Plks) are regulatory mitotic proteins that are overexpressed in several types of cancer and are associated with poor prognosis.
We have evaluated, in preclinical in vitro studies, the activity of a panel of Plk inhibitors against cell lines derived from refractory pediatric leukemia, as well as primary leukemia cells, in culture. Through in vitro growth inhibition studies, Western blot analysis for the expression and activation of key regulators of cell growth and survival and gene silencing studies, we specifically examined the ability of these agents to induce cytotoxicity through the activation of apoptosis and their capacity to interact and modulate the expression and phosphorylation of Aurora kinases.
Our findings show that the various Plk-1 inhibitors in development show potential utility for the treatment of pediatric leukemia and exhibit a wide range of phosphorylation and target modulatory capabilities. Finally, we provide evidence for a complex interregulatory relationship between Plk-1 and Aurora kinases enabling the identification of synergy and biologic correlates of drug combinations targeting the 2 distinct enzyme systems.
This information provide the rationale for the evaluation of Plk-1 as an effective target for therapeutics in refractory pediatric leukemia and indicate compensatory activities between Plk-1 and Aurora kinases, providing insight into some of the complex mechanisms involved in the process of cell division.
最近的研究表明，细胞周期事件受到一组特定激酶的复杂且共同活动的严格控制。其中，polo样激酶（Plks）是调节有丝分裂的蛋白质，在几种类型的癌症中过度表达，且与预后不良相关。
在临床前体外研究中，我们评估了一组Plk抑制剂对源自难治性小儿白血病的细胞系以及培养中的原发性白血病细胞的活性。通过体外生长抑制研究、对细胞生长和存活关键调节因子的表达及激活进行蛋白质印迹分析以及基因沉默研究，我们专门研究了这些药物通过激活凋亡诱导细胞毒性的能力，以及它们与Aurora激酶相互作用并调节其表达和磷酸化的能力。
我们的研究结果表明，正在研发的各种Plk-1抑制剂在治疗小儿白血病方面显示出潜在效用，并展现出广泛的磷酸化和靶点调节能力。最后，我们为Plk-1与Aurora激酶之间复杂的相互调节关系提供了证据，这有助于确定针对这两种不同酶系统的药物组合的协同作用和生物学相关性。
这些信息为评估Plk-1作为难治性小儿白血病治疗的有效靶点提供了理论依据，并表明Plk-1与Aurora激酶之间存在补偿性活动，从而深入了解细胞分裂过程中涉及的一些复杂机制。
