YM155 Induces DNA Damage and Cell Death in Anaplastic Thyroid Cancer Cells by Inhibiting DNA Topoisomerase IIα at the ATP-Binding Site.
YM155 Induces DNA Damage and Cell Death in Anaplastic Thyroid Cancer Cells by Inhibiting DNA Topoisomerase IIα at the ATP-Binding Site.
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DOI：
10.1158/1535-7163.mct-21-0619
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发表时间：
2022-06-01
影响因子：
5.7
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中科院分区：
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间变性甲状腺癌是人类最具侵袭性的癌症之一，目前对大多数患者几乎没有有效的治疗方法。YM155最初被确定为Survivin抑制剂，在美国国家癌症研究所进行的高通量筛查中得到了强调，它在体外和体内都能杀死间变性甲状腺癌细胞。然而，在临床试验中，Survivin的表达与YM155的疗效之间没有关联，尽管YM155具有良好的药代动力学和毒性，但YM155大多已被放弃开发。目前，一些团体正在探索YM155的替代机制。在这项研究中，与良性甲状腺组织和分化性甲状腺癌相比，间变性甲状腺癌患者样本中TOP2α的过度表达。过表达TOP2α的间变性甲状腺癌细胞对YM155更敏感。我们建立了一株YM155抗性细胞系，该细胞系表现出TOP2α表达降低，并被TOP2α过表达重新致敏。分子模拟预测了YM155与TOP2ATP结合位点的结合，并确定了YM155-TOP2α相互作用的关键氨基酸。一个TOP2α突变体取消了YM155的作用，证实了TOP2α对YM155作用机制的贡献。我们的结果提示了YM155的一种新的作用机制，并可能成为治疗未分化甲状腺癌的一种新的治疗方法。
Anaplastic thyroid cancer is among the most aggressive of human cancers, and currently there are few effective treatments for most patients. YM155, first identified as a survivin inhibitor, was highlighted in a high-throughput screen performed by the National Cancer Institute, killing anaplastic thyroid cancer cells in vitro and in vivo. However, there was no association between survivin expression and response to YM155 in clinical trials, and YM155 has been mostly abandoned for development despite favorable pharmacokinetic and toxicity profiles. Currently, alternative mechanisms are being explored for YM155 by a number of groups. In this study, anaplastic thyroid cancer patient samples show overexpression of topoisomerase Top2α compared to benign thyroid samples and to differentiated thyroid cancers. Anaplastic thyroid cancer cell lines that overexpress Top2α are more sensitive to YM155. We created a YM155-resistant cell line, which showed decreased expression of Top2α and is re-sensitized with Top2α overexpression. Molecular modeling predicts binding for YM155 in the Top2α ATP binding site and identifies key amino acids for YM155-Top2α interaction. A Top2α mutant abrogates the effect of YM155, confirming the contribution of Top2α to YM155 mechanism of action. Our results suggest a novel mechanism of action for YM155 and may represent a new therapeutic approach for the treatment of anaplastic thyroid cancer.