Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells.
Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells.
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评估在培养的人胶质母细胞瘤细胞中诱导 ApoE 和酪氨酸羟化酶的新型 RXR 激动剂。
DOI：
10.1021/acschemneuro.0c00707
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发表时间：
2021
影响因子：
5
通讯作者：
Jurutka,PeterW
中科院分区：
文献类型：
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作者：
Mallick,Sanchita;Marshall,PamelaA;Wagner,CarlE;Heck,MichaelC;Sabir,ZhelaL;Sabir,MaryaS;Dussik,ChristoperM;Grozic,Aleksandra;Kaneko,Ichiro;Jurutka,PeterW
有相当大的兴趣，确定有效和安全的药物治疗神经退行性疾病。细胞培养和动物模型研究表明，通过RXR介导的途径调节基因表达可以减轻或逆转认知能力下降。然而，由于RXR是几种转录因子的二聚体伴侣，因此激活脱靶转录是RXR配体（rexinoids）的一个问题。这种脱靶基因调节导致不必要的副作用，包括甲状腺功能低下和显著的高脂血症。需要开发对RXR异二聚体的子集具有结合特异性的类Rexinoids，以驱动所需的基因调节，但不诱导假效应。在本文中，我们描述了实验中，我们分析了一系列新的和以前报道的rexinoids的能力，以调节特定的基因通路涉及神经退行性疾病采用U87细胞培养模型。我们证明，与FDA批准的rexinoid贝沙罗汀（1）相比，这些化合物中的几种在通过LXRE或Nurr 1/NBREs刺激基因表达方面同样有效或更有效，并且在诱导ApoE和/或酪氨酸羟化酶（TH）基因和蛋白质表达方面具有上级优势，包括类似物8、9、13、14、20、23和24，提示这些化合物在阿尔茨海默病或帕金森病（PD）中可能的治疗作用。这些有效的RXR激动剂的子集可以与假定的Nurr 1配体和抗疟疾药物（阿莫地喹）协同作用，以进一步增强Nurr 1/NBREs定向转录。这一新发现对PD的治疗具有潜在的临床意义，因为它表明RXR激动剂和Nurr 1配体的组合可以显著增强RXR-Nurr 1异二聚体活性并驱动TH基因的增强的治疗表达以增加多巴胺的内源性合成。这些数据表明，开发新的rexinoids用于测试基因表达和副作用谱以用于神经退行性疾病的潜在治疗是可能的和谨慎的，因为单个rexinoids可以具有明显不同的基因表达谱但具有相似的结构。
There is considerable interest in identifying effective and safe drugs for neurodegenerative disorders. Cell culture and animal model work have demonstrated that modulating gene expression through RXR-mediated pathways may mitigate or reverse cognitive decline. However, because RXR is a dimeric partner for several transcription factors, activating off-target transcription is a concern with RXR ligands (rexinoids). This off-target gene modulation leads to unwanted side effects that can include low thyroid function and significant hyperlipidemia. There is a need to develop rexinoids that have binding specificity for subsets of RXR heterodimers, to drive desired gene modulation, but that do not induce spurious effects. Herein, we describe experiments in which we analyze a series of novel and previously reported rexinoids for their ability to modulate specific gene pathways implicated in neurodegenerative disorders employing a U87 cell culture model. We demonstrate that, compared to the FDA-approved rexinoid bexarotene (1), several of these compounds are equally or more effective at stimulating gene expression via LXREs or Nurr1/NBREs and are superior at inducing ApoE and/or tyrosine hydroxylase (TH) gene and protein expression, including analogs8,9,13,14,20,23, and24, suggesting a possible therapeutic role for these compounds in Alzheimer’s or Parkinson’s disease (PD). A subset of these potent RXR agonists can synergize with a presumed Nurr1 ligand and antimalarial drug (amodiaquine) to further enhance Nurr1/NBREs-directed transcription. This novel discovery has potential clinical implications for treatment of PD since it suggests that the combination of an RXR agonist and a Nurr1 ligand can significantly enhance RXR-Nurr1 heterodimer activity and drive enhanced therapeutic expression of the TH gene to increase endogenous synthesis of dopamine. These data indicate that is it possible and prudent to develop novel rexinoids for testing of gene expression and side effect profiles for use in potential treatment of neurodegenerative disorders, as individual rexinoids can have markedly different gene expression profiles but similar structures.