Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks
Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks
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DOI：
10.1182/blood-2008-09-177774
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发表时间：
2009-04-16
期刊：
影响因子：
20.3
通讯作者：
Pandiella, Atanasio
中科院分区：
文献类型：
--
作者：
Ocio, Enrique M.;Maiso, Patricia;Pandiella, Atanasio
多发性骨髓瘤（MM）仍然是无法治愈的，仍然需要具有新的作用机制的新药。在本报告中，我们分析了Zalypsis（一种类似于某些天然海洋化合物的生物碱）在MM中的作用。Zalypsis被证明是迄今为止我们测试过的最有效的抗骨髓瘤剂，其IC（50）值从皮摩尔到低纳摩尔范围。对患者的浆细胞和移植到小鼠体内的MM细胞也有显著的体外效力。除了诱导细胞凋亡和细胞周期阻滞外，Zalypsis还引起DNA双链断裂（DSBs），其证据是磷酸化组蛋白h2ax和磷酸化chk2的增加，随后p53在p53野生型细胞系中显著过表达。此外，在p53发生突变的细胞系中，Zalypsis也引起dsb并诱导细胞死亡，尽管需要更高的浓度。肿瘤免疫组化研究也显示组蛋白- h2ax磷酸化和p53过表达。基因表达谱研究与这些结果一致，揭示了参与DNA损伤反应的基因的重要解除管制。Zalypsis在体外和体内的抗骨髓瘤活性揭示了肿瘤浆细胞对DSBs的高敏感性，并有力地支持了该化合物在MM患者中的应用。（血液。2009;113:3781-3791）
Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC(50) values from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumor plasma cells to DSBs and strongly supports the use of this compound in MM patients. (Blood. 2009; 113: 3781-3791)