The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning
The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning
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DOI：
10.1073/pnas.1921649117
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发表时间：
2020-02-25
影响因子：
11.1
通讯作者：
Pritchard, Justin R.
中科院分区：
文献类型：
--
作者：
Bruno, Peter M.;Lu, Mengrou;Pritchard, Justin R.
小分子可以影响许多细胞过程。消除这些影响的歧义，以确定细胞死亡的致病机制是极具挑战性的。这一挑战影响了临床开发和化学遗传实验的解释。CX-5461被开发为选择性RNA聚合酶I抑制剂，但最近的证据表明，它可能会导致DNA损伤并诱导G-四链体形成。在这里，我们使用三种互补的数据挖掘模式以及生物化学和细胞生物学测定，以表明CX-5461通过拓扑异构酶II中毒发挥其主要的细胞毒性活性。然后，我们表明，获得性耐药性CX-5461在以前敏感的淋巴瘤细胞赋予侧阻力拓扑异构酶II毒药阿霉素。阿霉素已经是多种造血系统恶性肿瘤的一线化疗药物，CX-5461正在复发/难治性造血系统肿瘤中进行测试。我们的数据表明，CX-5461诱导的细胞死亡机制对于这些患者的合理临床开发至关重要。此外，CX-5461作为RNA聚合酶I功能的特异性化学遗传探针的使用具有挑战性。我们的多模态数据驱动方法是一种有用的方法，可以在不同的基本细胞过程中理清药物作用的预期和非预期机制。
Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that the mechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes.