Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells
Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells
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DOI：
10.1021/acschemneuro.6b00251
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发表时间：
2017-01-01
影响因子：
5
通讯作者：
Rapposelli, Simona
中科院分区：
文献类型：
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作者：
Daniele, Simona;Sestito, Simona;Rapposelli, Simona
多形性胶质母细胞瘤（GBM）预后差主要归因于耐药机制和胶质瘤干细胞（GSC）亚群的存在。多靶点化合物能够影响不同的去调控途径和GSC亚群，可以逃避肿瘤耐药性，最重要的是，消除干细胞库。在这方面，同时抑制磷酸肌醇依赖性激酶-1（PDK 1）和极光激酶A（AurA），每一个都在细胞存活/迁移/分化中发挥关键作用，可能代表了克服GBM耐药性和复发的创新策略。在此，使用单靶点参比化合物MP 7（PDK 1抑制剂）和Alisertib（AurA抑制剂）研究了这些途径之间的串扰。此外，一个新的配体，SA 16，被确定为它的能力，抑制PDK 1和AurA途径的一次，从而证明是一个有用的工具，同时抑制这两种激酶。SA 16阻断GBM细胞增殖，降低肿瘤侵袭力，并引发细胞凋亡。最重要的是，AurA/PDK 1阻断剂对GSC的功效增加，诱导其分化和凋亡。据我们所知，这是第一份关于PDK 1和AurA联合靶向的报告。这种药物代表了一种有吸引力的多靶点先导支架，用于开发GBM和GSC的新的潜在治疗方法。
The poor prognosis of glioblastoma multiforme (GBM) is mainly attributed to drug resistance mechanisms and to the existence of a subpopulation of glioma stem cells (GSCs). Multitarget compounds able to both affect different deregulated pathways and the GSC subpopulation could escape tumor resistance and, most importantly, eradicate the stem cell reservoir. In this respect, the simultaneous inhibition of phosphoinositide-dependent kinase-1 (PDK1) and aurora kinase A (AurA), each one playing a pivotal role in cellular survival/migration/differentiation, could represent an innovative strategy to overcome GBM resistance and recurrence. Herein, the cross-talk between these pathways was investigated, using the single-target reference compounds MP7 (PDK1 inhibitor) and Alisertib (AurA inhibitor). Furthermore, a new ligand, SA16, was identified for its ability to inhibit the PDK1 and the AurA pathways at once, thus proving to be a useful tool for the simultaneous inhibition of the two kinases. SA16 blocked GBM cell proliferation, reduced tumor invasiveness, and triggered cellular apoptosis. Most importantly, the AurA/PDK1 blocker showed an increased efficacy against GSCs, inducing their differentiation and apoptosis. To the best of our knowledge, this is the first report on combined targeting of PDK1 and AurA. This drug represents an attractive multitarget lead scaffold for the development of new potential treatments for GBM and GSCs.