Thymoquinone exerts potent growth-suppressive activity on leukemia through DNA hypermethylation reversal in leukemia cells
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Jiuxia Pang1, Na Shen1, Fei Yan1, Na Zhao1, Liping Dou1,2, Lai-Chu Wu3, Christopher L. Seiler4, Li Yu2, Ke Yang5, Veronika Bachanova6, Eric Weaver7, Natalia Y. Tretyakova4, Shujun Liu1
1The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
2Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China
3Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43021, USA
4Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
5Chongqing Engineering Research Center of Stem Cell Therapy, The Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
6Division of Hematology, Oncology and Transplantation, Minneapolis, MN 55455, USA
7Prairie Pharms LLC, Nora Springs, IA 50458, USA
Shujun Liu, email: firstname.lastname@example.org
Keywords: DNA methylation, leukemia, thymoquinone, DNA methyltransferase, bioactive compounds
Received: February 10, 2017 Accepted: March 14, 2017 Published: March 21, 2017
Thymoquinone (TQ), a bioactive constituent of the volatile oil of Monarda fistulosa and Nigella sativa, possesses cancer-specific growth inhibitory effects, but the underlying molecular mechanisms remain largely elusive. We propose that TQ curbs cancer cell growth through dysfunction of DNA methyltransferase 1 (DNMT1). Molecular docking analysis revealed that TQ might interact with the catalytic pocket of DNMT1 and compete with co-factor SAM/SAH for DNMT1 inhibition. In vitro inhibitory assays showed that TQ decreases DNMT1 methylation activity in a dose-dependent manner with an apparent IC50 of 30 nM. Further, exposure of leukemia cell lines and patient primary cells to TQ resulted in DNMT1 downregulation, mechanistically, through dissociation of Sp1/NFkB complex from DNMT1 promoter. This led to a reduction of DNA methylation, a decrease of colony formation and an increase of cell apoptosis via the activation of caspases. In addition, we developed and validated a sensitive and specific LC-MS/MS method and successfully detected a dynamic change of TQ in mouse plasma after administration of TQ through the tail vein, and determined a tolerable dose of TQ to be 15 mg/kg in mouse. TQ administration into leukemia-bearing mice induced leukemia regression, as indicated by the reversed splenomegaly and the inhibited leukemia cell growth in lungs and livers. Our study for the first time demonstrates that DNMT1-dependent DNA methylation mediates the anticancer actions of TQ, opening a window to develop TQ as a novel DNA hypomethylating agent for leukemia therapy.
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