Curcumin and Dimethoxycurcumin Induced Epigenetic Changes in Leukemia Cells
Curcumin and Dimethoxycurcumin Induced Epigenetic Changes in Leukemia Cells
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DOI：
10.1007/s11095-014-1502-4
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发表时间：
2015-03-01
影响因子：
3.7
通讯作者：
Fandy, Tamer E.
中科院分区：
文献类型：
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作者：
Hassan, Hazem E.;Carlson, Samuel;Fandy, Tamer E.
姜黄素是一种理想的化学预防和抗肿瘤药物，但生物利用度低，稳定性差。合成结构类似物如二甲氧基姜黄素（DMC）的开发可以克服这些缺点。本研究比较了两种药物对白血病细胞的毒性、代谢和表观遗传学的影响，并采用流式细胞仪分析了两种药物对白血病细胞凋亡和细胞周期的影响。实时荧光定量PCR用于基因表达分析。通过DNA焦磷酸测序分析DNA甲基化。使用人合并肝微粒体测定代谢稳定性。染色质免疫沉淀法检测组蛋白甲基化水平，临床相关浓度的姜黄素和DMC对白血病细胞无细胞毒性作用，并诱导白血病细胞G2/M期阻滞。DMC比姜黄素代谢更稳定。姜黄素和DMC没有DNA低甲基化活性。DMC可诱导启动子甲基化基因的表达，但不逆转DNA甲基化，并可增加高甲基化基因启动子区附近的H3 K36 me 3标记。DMC是一种更稳定的姜黄素类似物，可诱导姜黄素不能诱导的表观遗传学变化。DMC诱导启动子甲基化基因的表达。DMC与DNA甲基转移酶抑制剂的组合可以利用它们组合诱导的表观遗传变化来优化表观遗传沉默基因的再表达。
Curcumin is an ideal chemopreventive and antitumor agent characterized by poor bioavailability and low stability. The development of synthetic structural analogues like dimethoxycurcumin (DMC) could overcome these drawbacks. In this study we compared the cytotoxicity, metabolism and the epigenetic changes induced by both drugs in leukemia cells.Apoptosis and cell cycle analysis were analyzed by flow cytometry. Real-time PCR was used for gene expression analysis. DNA methylation was analyzed by DNA pyrosequencing. The metabolic stability was determined using human pooled liver microsomes. Chromatin Immunoprecipitation was used to quantify histone methylation.Clinically relevant concentration of curcumin and DMC were not cytotoxic to leukemia cells and induced G2/M cell cycle arrest. DMC was more metabolically stable than curcumin. Curcumin and DMC were devoid of DNA hypomethylating activity. DMC induced the expression of promoter methylated genes without reversing DNA methylation and increased H3K36me3 mark near the promoter region of hypermethylated genes.DMC is a more stable analogue of curcumin that can induce epigenetic changes not induced by curcumin. DMC induced the expression of promoter methylated genes. The combination of DMC with DNA methyltransferase inhibitors could harness their combined induced epigenetic changes for optimal re-expression of epigenetically silenced genes.