The "survivin suppressants" NSC 80467 and YM155 induce a DNA damage response
The "survivin suppressants" NSC 80467 and YM155 induce a DNA damage response
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DOI：
10.1007/s00280-012-1868-0
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发表时间：
2012-07-01
影响因子：
3
通讯作者：
Newton, Dianne L.
中科院分区：
文献类型：
--
作者：
Glaros, Trevor G.;Stockwin, Luke H.;Newton, Dianne L.
目的确定一种新型稠合萘醌咪唑鎓化合物NSC 80467是否具有与已充分表征的“存活素抑制剂”YM 155相似的活性谱，并扩展对这种结构类型的药剂的机理研究。结果两种化合物在NCI-60筛选中产生的GI（50）值产生的相关系数为0.748，表明显著一致。这两种药物也显示出抑制生存素的蛋白表达[BIRC 5]。比较分析鉴定了DNA损伤剂色霉素A3和盐酸比生群以及一种DNA定向转录抑制剂放线菌素D与NSC 80467和YM 155的活性相关。此外，这两种药物都被证明优先抑制DNA而不是RNA和蛋白质合成。因此，进一步检查了NSC 80467和YM 155诱导DNA损伤应答的能力。用任一试剂处理PC 3细胞导致γ H2 AX和pKAP 1的剂量依赖性诱导，γ H2 AX和pKAP 1是DNA损伤的两个标记。刺激γ H2 AX所需的试剂浓度大大低于抑制生存素所需的浓度，这表明DNA损伤是一个起始事件。DNA损伤反应，然后证实在一个面板中的细胞系与NSC 80467或YM 155处理，表明γ H2 AX和pKAP 1有潜力作为响应biological.Conclusions这些数据提供了第一个证据，NSC 80467和YM 155是DNA损伤剂，其中抑制生存素是一个次要事件，可能是转录抑制的后果。
Purpose To establish whether NSC80467, a novel fused naphthquinone imidazolium, has a similar spectrum of activity to the well-characterized "survivin suppressant" YM155 and to extend mechanistic studies for this structural class of agent.Methods NSC80467 and YM155 were analyzed in parallel using assays measuring viability, survivin suppression, inhibition of DNA/RNA/protein synthesis and the cellular response to DNA damage.Results GI(50) values generated for both compounds in the NCI-60 screen yielded a correlation coefficient of 0.748, suggesting significant concordance. Both agents were also shown to inhibit protein expression of survivin [BIRC5]. COMPARE analysis identified DNA damaging agents chromomycin A3 and bisantrene HCl and one DNA-directed inhibitor of transcription, actinomycin D, as correlating with the activity of NSC80467 and YM155. Furthermore, both agents were shown to preferentially inhibit DNA, over RNA and protein synthesis. Thus, the ability of NSC80467 and YM155 to induce a DNA damage response was examined further. Treatment of PC3 cells with either agent resulted in dose-dependent induction of gamma H2AX and pKAP1, two markers of DNA damage. The concentrations of agent required to stimulate gamma H2AX were considerably lower than those required to inhibit survivin, implicating DNA damage as an initiating event. The DNA damage response was then confirmed in a panel of cell lines treated with NSC80467 or YM155, suggesting that gamma H2AX and pKAP1 have potential as response biomarkers.Conclusions These data provide the first evidence that NSC80467 and YM155 are DNA damaging agents where suppression of survivin is a secondary event, likely a consequence of transcriptional repression.