Journal Article

Curcumin Down-Regulates DNA Methyltransferase 1 and Plays an Anti-Leukemic Role in Acute Myeloid Leukemia

Yu, Jianhua, Wang, Qi-En, Peng, Yong, Chan, Kenneth K., Wu, Lai-Chu, Mo, XiaoKui, Chiu, Ming, He, Xiaoming, Deng, Youcai, Liu, Zhongfa, He, Shun, Liu, Shujun, Xie, Zhiliang, Hughes, Tiffany, Grever, Michael R.

2013

Overview

Bioactive components from dietary supplements such as curcumin may represent attractive agents for cancer prevention or treatment. DNA methylation plays a critical role in acute myeloid leukemia (AML) development, and presents an excellent target for treatment of this disease. However, it remains largely unknown how curcumin, a component of the popular Indian spice turmeric, plays a role in DNA hypomethylation to reactivate silenced tumor suppressor genes and to present a potential treatment option for AML. Here we show that curcumin down-regulates DNMT1 expression in AML cell lines, both in vitro and in vivo, and in primary AML cells ex vivo. Mechanistically, curcumin reduced the expression of positive regulators of DNMT1, p65 and Sp1, which correlated with a reduction in binding of these transcription factors to the DNMT1 promoter in AML cell lines. This curcumin-mediated down-regulation of DNMT1 expression was concomitant with p15(INK4B) tumor suppressor gene reactivation, hypomethylation of the p15(INK4B) promoter, G1 cell cycle arrest, and induction of tumor cell apoptosis in vitro. In mice implanted with the human AML MV4-11 cell line, administration of curcumin resulted in remarkable suppression of AML tumor growth. Collectively, our data indicate that curcumin shows promise as a potential treatment for AML, and our findings provide a basis for future studies to test the clinical efficacy of curcumin - whether used as a single agent or as an adjuvant - for AML treatment.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Acute myelocytic leukemia / Acute myeloid leukemia / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Apoptosis / Biology / Biotechnology / Cancer / Cancer genetics / Cancer prevention / Cancer therapies / Cancer treatment / Caspases - metabolism / Cell cycle / Cell Line, Tumor / Cell Proliferation - drug effects / Curcumin / Curcumin - pharmacology / Curcumin - therapeutic use / Deoxyribonucleic acid / Diet / Dietary supplements / DNA / DNA (Cytosine-5-)-Methyltransferase 1 / DNA (Cytosine-5-)-Methyltransferases - genetics / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA binding proteins / DNA methylation / DNA methyltransferase / DNMT1 protein / Down-Regulation - drug effects / Drug delivery systems / Drugs / Epigenetics / Female / G1 Phase Cell Cycle Checkpoints - drug effects / Gene expression / Gene silencing / Genes / Hematology / Humans / In vivo methods and tests / Internal medicine / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - pathology / Medical prognosis / Medical treatment / Medicine / Methylation / Methyltransferases / Mice / Mice, Nude / Myeloid leukemia / Pharmaceutical sciences / Pharmacy / Phosphatase / Promoter Regions, Genetic - drug effects / Regulators / Sp1 protein / Sp1 Transcription Factor - genetics / Surgical implants / Therapeutic applications / Transcription Factor RelA - genetics / Transcription factors / Tumor Cells, Cultured / Tumor suppressor genes / Tumors