Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma
Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma
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DOI：
10.1215/15228517-2006-004
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发表时间：
2006-07-01
期刊：
影响因子：
15.9
通讯作者：
Boegler, Oliver
中科院分区：
文献类型：
--
作者：
Billecke, Christine;Finniss, Susan;Boegler, Oliver
我们在培养和动物模型中评估了多核铂类化疗药物BBR3464、BBR3571和BBR3610对胶质瘤细胞的疗效，并在细胞水平上研究了它们的作用机制。在克隆生成实验中，最有效的化合物BBR3610对LNZ308和LN443胶质瘤细胞的IC90剂量（达到90%的集落形成抑制）比顺铂低250倍。在U87MG胶质瘤细胞的皮下异种移植物中，当这些细胞植入颅内时，BBR3610使肿瘤达到预定大小所需的时间大约增加了一倍，并显着延长了存活时间。细胞凋亡和细胞周期分布分析表明，BBR化合物在没有细胞死亡的情况下诱导G2/M阻滞，而顺铂主要诱导细胞凋亡。有趣的是，BBR化合物和顺铂均诱导细胞外信号调节的激酶1/2磷酸化，在MEK水平上抑制该途径分别拮抗诱导G2/M阻滞或凋亡。对Chk1和Chk2状态的分析没有显示出药物的任何差异作用，因此不太可能是反应差异的基础。同样，这些药物对survivin水平没有差异调节，survivin的下调也不会将对BBR3610的反应转化为细胞凋亡。总之，这些发现支持了BBR3610用于临床治疗胶质瘤的持续开发，并为未来研究其作用机制提供了框架。
We have evaluated the efficacy of the multinuclear platinum chemotherapeutics BBR3464, BBR3571, and BBR3610 against glioma cells in culture and animal models and investigated their mechanism of action at the cellular level. In a clonogenic assay, BBR3610, the most potent compound, had an IC90 dose (achieving 90% colony formation inhibition) that was 250 times lower than that of cisplatin for both LNZ308 and LN443 glioma cells. In subcutaneous xenografts of U87MG glioma cells, BBR3610 approximately doubled the time it took for a tumor to reach a predetermined size and significantly extended survival when these cells were implanted intracranially. Analysis of apoptosis and cell cycle distribution showed that BBR compounds induced G2/M arrest in the absence of cell death, while cisplatin predominantly induced apoptosis. Interestingly, the BBR compounds and cisplatin both induced extracellular signal-regulated kinase 1/2 phosphorylation, and inhibition of this pathway at the level of MEK antagonized the induction of G2/M arrest or apoptosis, respectively. Analysis of Chk1 and Chk2 status did not show any differential effects of the drugs, and it is thus unlikely to underlie the difference in response. Similarly, the drugs did not differentially modulate survivin levels, and knockdown of survivin did not convert the response to BBR3610 to apoptosis. Together, these findings support continued development of BBR3610 for clinical use against glioma and provide a framework for future investigation of mechanism of action.