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Nanoformulation of EPZ011989 Attenuates EZH2-c-Myb Epigenetic Interaction by Proteasomal Degradation in Acute Myeloid Leukemia.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-06 , DOI: 10.1021/acs.molpharmaceut.9b01071 Babita Kaundal 1 , Anup K Srivastava 1 , Atul Dev 1 , Soni Jignesh Mohanbhai 1 , Surajit Karmakar 1 , Subhasree Roy Choudhury 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-06 , DOI: 10.1021/acs.molpharmaceut.9b01071 Babita Kaundal 1 , Anup K Srivastava 1 , Atul Dev 1 , Soni Jignesh Mohanbhai 1 , Surajit Karmakar 1 , Subhasree Roy Choudhury 1
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Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic progenitor cells with a poor prognosis of 26% of patients surviving 5 years after diagnosis. Poor bioavailability and solubility are significant factors limiting the efficacy of chemopreventive agents. In AML, the epigenetic regulator polycomb group of protein member EZH2 is highly expressed and is essential for the survival of leukemic cells. An EZH2-specific inhibitor, EPZ011989, encapsulated in human serum albumin nanoparticles (HSANPs) was synthesized for the first time via the desolvation method. The noncovalent interactions between EPZ011989 and HSANPs in nanocomposites facilitating the efficient loading and sustainable release of the drug showed enhanced cellular uptake and nuclear localization of EPZ011989-loaded HSANPs in human AML cell lines. The reduction of cell viability, colony formation inhibition, cell cycle arrest at the G2/M phase, and cell proliferation assay promoting apoptosis through the loss of mitochondrial homeostasis exerting antileukemic activity were evident. The real-time polymerase chain reaction (PCR) and western blot-based studies showed that the present nanoformulation reduces the level of PcG proteins, including EZH2, BMI-1, etc. This downregulation is associated with reduced H3K27me3 and H2AK119ub modifications conferring chromatin compaction. The immunoprecipitation study showed the physical interaction of EZH2 and c-Myb can be linked to the regulation of leukemogenesis. Further investigation revealed the mechanism of EZH2 and c-Myb downregulation via ubiquitination and proteasomal degradation pathway, confirmed by using proteasome inhibitor, suggesting the key role of proteasomal degradation machinery. Moreover, c-Myb interacted with the EZH2 promoter, which is evident by the chromatin immunoprecipitation assay and siRNA silencing. Furthermore, the formulation of EPZ011989 in HSANPs improved its biodistribution in vivo and showed excellent aqueous dispersibility and biocompatibility. In vivo studies further showed that EPZ011989-loaded HSANPs reduce the expression of CD11b+ and CD45+ markers in immunophenotyping from peripheral blood and bone marrow in engrafted nude mice. Targeted depletion of EZH2 alleviated the disease progression in nude mice and prolonged their survival. The findings provide valuable experimental evidence for the targeted epigenetic therapy of AML. The present results demonstrate an epigenetic regulation-based superior antileukemic therapy.
中文翻译：
EPZ011989的纳米配方通过蛋白酶体降解在急性髓样白血病中减弱了EZH2-c-Myb表观遗传相互作用。
急性髓细胞性白血病（AML）是造血祖细胞的恶性疾病，在诊断后存活5年的患者中，有26％的患者预后不良。生物利用度和溶解度差是限制化学预防剂功效的重要因素。在AML中，蛋白质成员EZH2的表观遗传调节剂多梳基团高度表达，对于白血病细胞的生存至关重要。通过去溶剂化方法首次合成了包埋在人血清白蛋白纳米颗粒（HSANP）中的EZH2特异性抑制剂EPZ011989。纳米复合物中EPZ011989和HSANP之间的非共价相互作用促进了药物的有效负载和可持续释放，表明人AML细胞系中EPZ011989负载的HSANP的细胞摄取和核定位增强。明显的细胞活力降低，集落形成抑制，细胞周期停滞在G2 / M期以及通过丧失线粒体稳态发挥抗白血病活性促进细胞凋亡的细胞增殖试验。实时聚合酶链反应（PCR）和基于蛋白质印迹的研究表明，目前的纳米制剂降低了PcG蛋白的水平，包括EZH2，BMI-1等。这种下调与减少的H3K27me3和H2AK119ub修饰有关，从而赋予染色质紧密性。免疫沉淀研究表明EZH2和c-Myb的物理相互作用可以与白血病发生的调节有关。进一步的研究揭示了EZH2和c-Myb通过泛素化和蛋白酶体降解途径下调的机制，这一点已被蛋白酶体抑制剂证实，提示蛋白酶体降解机制的关键作用。此外，c-Myb与EZH2启动子相互作用，这通过染色质免疫沉淀测定法和siRNA沉默很明显。此外，HSANP中的EPZ011989制剂改善了其在体内的生物分布，并显示出极好的水分散性和生物相容性。体内研究进一步表明，在移植裸鼠的外周血和骨髓免疫表型分析中，加载EPZ011989的HSANP降低了CD11b +和CD45 +标记的表达。EZH2的目标耗竭减轻了裸鼠的疾病进展并延长了它们的生存期。这些发现为AML的靶向表观遗传治疗提供了有价值的实验证据。本结果证明了基于表观遗传学的优良抗白血病治疗。
更新日期：2020-01-07
中文翻译：
EPZ011989的纳米配方通过蛋白酶体降解在急性髓样白血病中减弱了EZH2-c-Myb表观遗传相互作用。
急性髓细胞性白血病（AML）是造血祖细胞的恶性疾病，在诊断后存活5年的患者中，有26％的患者预后不良。生物利用度和溶解度差是限制化学预防剂功效的重要因素。在AML中，蛋白质成员EZH2的表观遗传调节剂多梳基团高度表达，对于白血病细胞的生存至关重要。通过去溶剂化方法首次合成了包埋在人血清白蛋白纳米颗粒（HSANP）中的EZH2特异性抑制剂EPZ011989。纳米复合物中EPZ011989和HSANP之间的非共价相互作用促进了药物的有效负载和可持续释放，表明人AML细胞系中EPZ011989负载的HSANP的细胞摄取和核定位增强。明显的细胞活力降低，集落形成抑制，细胞周期停滞在G2 / M期以及通过丧失线粒体稳态发挥抗白血病活性促进细胞凋亡的细胞增殖试验。实时聚合酶链反应（PCR）和基于蛋白质印迹的研究表明，目前的纳米制剂降低了PcG蛋白的水平，包括EZH2，BMI-1等。这种下调与减少的H3K27me3和H2AK119ub修饰有关，从而赋予染色质紧密性。免疫沉淀研究表明EZH2和c-Myb的物理相互作用可以与白血病发生的调节有关。进一步的研究揭示了EZH2和c-Myb通过泛素化和蛋白酶体降解途径下调的机制，这一点已被蛋白酶体抑制剂证实，提示蛋白酶体降解机制的关键作用。此外，c-Myb与EZH2启动子相互作用，这通过染色质免疫沉淀测定法和siRNA沉默很明显。此外，HSANP中的EPZ011989制剂改善了其在体内的生物分布，并显示出极好的水分散性和生物相容性。体内研究进一步表明，在移植裸鼠的外周血和骨髓免疫表型分析中，加载EPZ011989的HSANP降低了CD11b +和CD45 +标记的表达。EZH2的目标耗竭减轻了裸鼠的疾病进展并延长了它们的生存期。这些发现为AML的靶向表观遗传治疗提供了有价值的实验证据。本结果证明了基于表观遗传学的优良抗白血病治疗。
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