Pixantrone induces cell death through mitotic perturbations and subsequent aberrant cell divisions.
Pixantrone induces cell death through mitotic perturbations and subsequent aberrant cell divisions.
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DOI：
10.1080/15384047.2015.1070979
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发表时间：
2015
影响因子：
3.6
通讯作者：
Yen TJ
中科院分区：
文献类型：
--
作者：
Beeharry N;Di Rora AG;Smith MR;Yen TJ
吡蒽醌是一种新的氮杂蒽二酮活性对侵袭性淋巴瘤，并正在评估用于对各种血液和实体肿瘤。该药物是米托蒽醌的类似物，但显示出比米托蒽醌或更常用的多柔比星更少的心脏毒性。虽然pixantrone据称抑制拓扑异构酶II的活性和嵌入DNA，它如何诱导细胞死亡的确切机制仍然不清楚。在这里，我们评估了匹蒽醌对一组实体瘤细胞系的作用，以了解其细胞杀伤机制。与pixantrone的初始实验表明，MTS测定（短期）与克隆形成测定（长期）相比，其抗增殖作用之间存在明显差异。使用活细胞视频显微镜来跟踪细胞的命运，我们发现用pixantrone处理的细胞经历了多轮异常细胞分裂，然后在处理后约5天后最终死亡。细胞发生异常有丝分裂，其中染色体分离受损，在细胞之间或含微核的细胞内产生染色质桥。虽然经匹蒽醌处理的细胞在主核中未显示γH2AX病灶（DNA损伤的标志物），但通常在微核中检测到此类病灶。使用DNA含量分析，我们发现在克隆形成测定中诱导细胞死亡的匹蒽醌浓度并不阻碍细胞周期进展，进一步支持缺乏典型的DNA损伤信号传导。这些发现表明，匹蒽醌诱导一种潜在类型的DNA损伤，损害有丝分裂的保真度，而不触发DNA损伤反应或有丝分裂检查点激活，但在连续几轮异常分裂后是致命的。
Pixantrone is a novel aza-anthracenedione active against aggressive lymphoma and is being evaluated for use against various hematologic and solid tumors. The drug is an analog of mitoxantrone, but displays less cardiotoxicity than mitoxantrone or the more commonly used doxorubicin. Although pixantrone is purported to inhibit topoisomerase II activity and intercalate with DNA, exact mechanisms of how it induces cell death remain obscure. Here we evaluated the effect of pixantrone on a panel of solid tumor cell lines to understand its mechanism of cell killing. Initial experiments with pixantrone showed an apparent discrepancy between its anti-proliferative effects in MTS assays (short-term) compared with clonogenic assays (long-term). Using live cell videomicroscopy to track the fates of cells, we found that cells treated with pixantrone underwent multiple rounds of aberrant cell division before eventually dying after approximately 5 d post-treatment. Cells underwent abnormal mitosis in which chromosome segregation was impaired, generating chromatin bridges between cells or within cells containing micronuclei. While pixantrone-treated cells did not display γH2AX foci, a marker of DNA damage, in the main nuclei, such foci were often detected in the micronuclei. Using DNA content analysis, we found that pixantrone concentrations that induced cell death in a clonogenic assay did not impede cell cycle progression, further supporting the lack of canonical DNA damage signaling. These findings suggest pixantrone induces a latent type of DNA damage that impairs the fidelity of mitosis, without triggering DNA damage response or mitotic checkpoint activation, but is lethal after successive rounds of aberrant division.