Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential
Journal
Journal of Agricultural and Food Chemistry
Journal Volume
62
Journal Issue
24
Pages
5625-5635
Date Issued
2014
Author(s)
Wang, S.-C.
Chang, Y.-J.
Chang, M.-S.
Wang, Y.-C.
Ho, Y.-S.
Wen, W.-C.
Lin, R.-K.
Abstract
DNA methyltransferase 1 (DNMT1) catalyzes DNA methylation and is overexpressed in various human diseases, including cancer. A rational approach to preventing tumorigenesis involves the use of pharmacologic inhibitors of DNA methylation; these inhibitors should reactivate tumor suppressor genes (TSGs) in tumor cells and restore tumor suppressor pathways. Antroquinonol D (3-demethoxyl antroquinonol), a new DNMT1 inhibitor, was isolated from Antrodia camphorata and identified using nuclear magnetic resonance. Antroquinonol D inhibited the growth of MCF7, T47D, and MDA-MB-231 breast cancer cells without harming normal MCF10A and IMR-90 cells. The SRB assay showed that the 50% growth inhibition (GI50) in MCF7, T47D, and MDA-MB-231 breast cancer cells following treatment with antroquinonol D was 8.01, 3.57, and 25.08 μM, respectively. d-Antroquinonol also inhibited the migratory ability of MDA-MB-231 breast cancer cells in wound healing and Transwell assays. In addition, antroquinonol D inhibited DNMT1 activity, as assessed by the DNMT1 methyltransferase activity assay. As the cofactor SAM level increased, the inhibitory effects of d-antroquinonol on DNMT1 gradually decreased. An enzyme activity assay and molecular modeling revealed that antroquinonol D is bound to the catalytic domain of DNMT1 and competes for the same binding pocket in the DNMT1 enzyme as the cofactor SAM, but does not compete for the binding pocket in the DNMT3B enzyme. An Illumina Methylation 450 K array-based assay and real-time PCR assay revealed that antroquinonol D decreased the methylation status and reactivated the expression of multiple TSGs in MDA-MB-231 breast cancer cells. In conclusion, we showed that antroquinonol D induces DNA demethylation and the recovery of multiple tumor suppressor genes, while inhibiting breast cancer growth and migration potential. ? 2014 American Chemical Society.
Subjects
Antrodia camphorata; breast cancer; cell migration; DNA methylation; DNA methyltransferase; tumor suppressor genes
SDGs
Other Subjects
Alkylation; Bioassay; Cells; Diseases; DNA; Enzymes; Genes; Methylation; Tumors; Alkylation; Assays; Bioassay; Cells; Chemical reactions; Cytology; Diseases; DNA; Enzyme activity; Enzymes; Genes; Methylation; Tumors; Antrodia camphorata; Breast Cancer; Cell migration; DNA Methylation; DNA methyltransferases; Tumor suppressor genes; Polymerase chain reaction; Polymerase chain reaction; antineoplastic agent; antroquinonol; DNA (cytosine 5) methyltransferase; DNA (cytosine-5-)-methyltransferase 1; DNA methyltransferase 3B; ubiquinone; analogs and derivatives; Antrodia; cell motion; chemistry; DNA methylation; drug effects; genetics; human; MCF 7 cell line; metabolism; molecular docking; real time polymerase chain reaction; tumor cell line; wound healing; Antineoplastic Agents; Antrodia; Cell Line, Tumor; Cell Movement; DNA (Cytosine-5-)-Methyltransferase; DNA Methylation; Humans; MCF-7 Cells; Molecular Docking Simulation; Real-Time Polymerase Chain Reaction; Ubiquinone; Wound Healing; Taiwanofungus camphoratus
Type
journal article