Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA.
Stephenson Cancer Center, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA.
Aging Cell. 2020 Mar;19(3):e13109. doi: 10.1111/acel.13109. Epub 2020 Jan 25.
The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad-spectrum anticancer drugs. Cyclin-dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA-approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid-beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD-omics and preclinical animal models provided data supporting the long-standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re-entry, leading to the "amyloid-beta accumulation cycle," may be a prerequisite for amyloid-beta accumulation and AD pathology development; (b) AD-associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the "amyloid-beta accumulation cycle is an AD drug target" concept is proven, repurposing of cancer drugs may emerge as a new, fast-track approach for AD management in the clinic setting.
细胞周期及其调控因子是癌症药物的有效靶点。针对特定细胞周期阶段的细胞的试剂（例如抗有丝分裂剂或 DNA 合成抑制剂/复制应激诱导剂）已被证明是广谱抗癌药物的成功应用。细胞周期蛋白依赖性激酶（CDKs）是细胞周期转变的驱动因素。CDK 抑制剂 flavopiridol/alvocidib 已被 FDA 批准用于治疗急性髓性白血病。阿尔茨海默病（AD）是当代医学的另一个严重问题。尽管潜在的淀粉样蛋白-β 积累的作用已变得至关重要，但 AD 的病因仍然难以捉摸。现有的 AD 药物研发靶点包括淀粉样蛋白、淀粉样蛋白代谢/分解、tau、炎症、胆固醇、胆碱能系统和其他神经递质。但是，这些靶点都没有被验证为具有治疗效果。最近来自 AD-omics 和临床前动物模型的报告提供了数据支持长期以来的观点，即细胞周期进展和/或有丝分裂可能是 AD 预防和/或治疗的有效靶点。本综述将总结 AD 研究的最新进展：（a）有丝分裂再进入导致“淀粉样蛋白-β 积累循环”，可能是淀粉样蛋白-β 积累和 AD 病理发展的先决条件；（b）AD 相关病原体可导致细胞周期错误；（c）37 个人类 AD 遗传风险基因中的 13 个可能与细胞周期和/或有丝分裂功能相关；（d）用 CDK 抑制剂治疗的临床前 AD 小鼠模型在认知/行为症状方面得到改善。如果“淀粉样蛋白-β 积累循环是 AD 药物靶点”的概念得到证实，那么重新利用癌症药物可能会成为在临床环境中管理 AD 的一种新的快速方法。
