Curcumin and Dimethoxycurcumin Induced Epigenetic Changes in Leukemia Cells

被引：32

作者：

Hassan, Hazem E. ^{[1
]}

Carlson, Samuel ^{[2
]}

Abdallah, Inas ^{[1
]}

Buttolph, Thomm ^{[3
]}

Glass, Karen C. ^{[2
]}

Fandy, Tamer E. ^{[2
]}

机构：

[1] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA

[2] Albany Coll Pharm, Dept Pharmaceut Sci, Colchester, VT 05446 USA

[3] Univ Vermont, Dept Neurol Sci, Burlington, VT USA

来源：

PHARMACEUTICAL RESEARCH | 2015年 / 32卷 / 03期

关键词：

curcumin; dimethoxycurcumin; DNA methylation; DNA pyrosequencing; histone methylation; DNA METHYLTRANSFERASE INHIBITORS; BREAST-CANCER CELLS; HYPOMETHYLATION AGENT; HISTONE DEACETYLASE; PANCREATIC-CANCER; GENE-EXPRESSION; CYCLE ARREST; KAPPA-B; ANALOGS; METHYLATION;

D O I：

10.1007/s11095-014-1502-4

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：863 / 875

页数：13

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