Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors
Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors
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DOI：
10.3390/molecules25092220
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发表时间：
2020-05-01
期刊：
影响因子：
4.6
通讯作者：
El-Azab, Adel S.
中科院分区：
文献类型：
--
作者：
Abdalla, Ashraf N.;Abdallah, Mohamed E.;El-Azab, Adel S.
急性髓性白血病（AML）是沙特国民的四大恶性肿瘤之一，也是全球最常见的白血病亚型。对现有AML药物的耐药性需要确定新的靶点和药物。Hsp 90是AML中新兴的重要靶点之一，其通过客户蛋白（包括生长因子受体和细胞周期蛋白依赖性激酶）在调节细胞凋亡和细胞增殖中起核心作用。本研究的第一部分的目的是调查推定的Hsp 90抑制活性的三个新的先前合成的喹唑啉类化合物，其显示HL 60细胞毒性和VEGFR 2和EGFR激酶抑制活性。使用表面等离子体共振，与17-AAG相比，化合物1（HAA（2020））显示出更好的Hsp 90抑制，并且对接研究显示其很好地适合ATP酶位点。第二部分的目的是最大限度地提高HAA（2020）的抗白血病活性，HAA与11种标准抑制剂中的每一种组合。在HL 60细胞中产生的最佳协同效应是使用泛细胞周期蛋白依赖性激酶（CDK）抑制剂dinaciclib，使用MTT测定。此外，HAA（2020）和dinaciclib联合用药对Hsp 90 α基因的抑制作用与caspase-7和TNF-α增加相关，导致HL 60细胞凋亡。此外，该组合上调p27的同时抑制cyclinD 3和CDK 2，导致取消HL 60增殖和存活。HAA（2020）的作用增强了dinaciclib的细胞凋亡和细胞周期控制特性，显示了共同靶向Hsp 90和CDK的重要性，这可能导致更好的白血病管理。
Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in AML, which has a central role in the regulation of apoptosis and cell proliferation through client proteins including the growth factor receptors and cyclin dependent kinases. The objective of the first part of this study is to investigate the putative Hsp90 inhibition activity of three novel previously synthesized quinazolines, which showed HL60 cytotoxicity and VEGFR2 and EGFR kinases inhibition activities. Using surface plasmon resonance, compound 1 (HAA(2020)) showed better Hsp90 inhibition compared to 17-AAG, and a docking study revealed that it fits nicely into the ATPase site. The objective of the second part is to maximize the anti-leukemic activity of HAA(2020), which was combined with each of the eleven standard inhibitors. The best resulting synergistic effect in HL60 cells was with the pan cyclin-dependent kinases (CDK) inhibitor dinaciclib, using an MTT assay. Furthermore, the inhibiting effect of the Hsp90 alpha gene by the combination of HAA(2020) and dinaciclib was associated with increased caspase-7 and TNF-alpha, leading to apoptosis in HL60 cells. In addition, the combination upregulated p27 simultaneously with the inhibition of cyclinD3 and CDK2, leading to abolished HL60 proliferation and survival. The actions of HAA(2020) propagated the apoptotic and cell cycle control properties of dinaciclib, showing the importance of co-targeting Hsp90 and CDK, which could lead to the better management of leukemia.