Synthesis of kojic acid-derived copper-chelating apoptosis inducing agents
Synthesis of kojic acid-derived copper-chelating apoptosis inducing agents
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DOI：
10.1007/s00044-012-0094-y
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发表时间：
2013-02-01
影响因子：
2.6
通讯作者：
Shaw, Arthur Y.
中科院分区：
文献类型：
--
作者：
Chen, Yu-Hua;Lu, Pei-Jung;Shaw, Arthur Y.
合成了三类曲酸衍生物，并检测了它们对HeLa细胞的抗增殖活性。与铜离子共处理的8b和11对HeLa细胞生长抑制表现出协同效应，GI（50）值分别为11.9和7.1 μ M。流式细胞仪分析显示，11-Cu共处理诱导的sub-G1期阻滞的剂量依赖性的方式，表明生长抑制作用归因于DNA片段化。此外，HeLa细胞胞质提取物的蛋白质印迹显示116-kDa的蛋白质聚（ADP-核糖）聚合酶的裂解和caspase-3的激活的32-kDa的酶原的水平降低，表明caspase依赖性凋亡途径参与。我们进一步证明了MAPK通路调节因子如ERK和p38在11-Cu共处理中被激活，表明细胞内氧化应激被铜离子显著刺激。综上所述，我们成功地合成了曲酸衍生的铜诱导凋亡剂。
Three classes of kojic acid derivatives were synthesized and examined for their antiproliferative activity against HeLa cells. Both 8b and 11 co-treated with copper ion exhibited synergistic effect on the HeLa cell growth inhibition with GI(50) values of 11.9 and 7.1 mu M, respectively. Flow cytometric analysis of HeLa cells revealed that 11-Cu co-treatment induced the sub-G1 arrest in a dose-dependent manner, suggesting that the growth-inhibitory effect is attributed to DNA fragmentation. Moreover, western blot of HeLa cells cytosolic extracts displayed the cleavage of the 116-kDa protein poly(ADP-ribose) polymerase and activation of caspase-3 by the reduced level of the 32-kDa proenzyme, indicating that the caspase-dependent apoptotic pathway was involved. We further demonstrated that MAPK pathway regulators such as ERK and p38 were activated in response to 11-Cu co-treatment, suggesting that the intracellular oxidative stress was dramatically stimulated by the copper ion. Taken together, we have successfully synthesized kojic acid-derived copper-induced apoptotic agents.