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New Cell Cycle Inhibitors Target Aneuploidy in Cancer Therapy.
Annual Review of Pharmacology and Toxicology ( IF 11.2 ) Pub Date : 2018-08-15 , DOI: 10.1146/annurev-pharmtox-010818-021649
Masanori Kawakami 1 , Xi Liu 1 , Ethan Dmitrovsky 1, 2, 3
Affiliation  

Aneuploidy is a hallmark of cancer. Defects in chromosome segregation result in aneuploidy. Multiple pathways are engaged in this process, including errors in kinetochore-microtubule attachments, supernumerary centrosomes, spindle assembly checkpoint (SAC) defects, and chromosome cohesion defects. Although aneuploidy provides an adaptation and proliferative advantage in affected cells, excessive aneuploidy beyond a critical level can be lethal to cancer cells. Given this, enhanced chromosome missegregation is hypothesized to limit survival of aneuploid cancer cells, especially when compared to diploid cells. Based on this concept, proteins and pathways engaged in chromosome segregation are being exploited as candidate therapeutic targets for aneuploid cancers. Agents that induce chromosome missegregation and aneuploidy now exist, including SAC inhibitors, those that alter centrosome fidelity and others that are under active study in preclinical and clinical contexts. This review explores the therapeutic potentials of such new agents, including the benefits of combining them with other antineoplastic agents.

中文翻译:

新的细胞周期抑制剂在肿瘤治疗中靶向非整倍性。

非整倍性是癌症的标志。染色体分离缺陷导致非整倍性。此过程涉及多种途径,包括动粒-微管附件,多余的中心体,纺锤体装配检查点(SAC)缺陷和染色体内聚缺陷的错误。尽管非整倍性在受影响的细胞中具有适应性和增殖优势,但超过临界水平的过量非整倍性可能对癌细胞具有致命性。鉴于此,假设增强的染色体错聚会限制非整倍体癌细胞的存活,特别是与二倍体细胞相比时。基于此概念,参与染色体分离的蛋白质和途径已被用作非整倍体癌症的候选治疗靶标。现在存在诱导染色体错聚和非整倍性的物质,包括SAC抑制剂,改变中心体保真度的抑制剂以及在临床前和临床环境中正在积极研究的其他抑制剂。这篇综述探讨了这种新药的治疗潜力,包括将它们与其他抗肿瘤药联合使用的好处。
更新日期:2019-01-09
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