Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential

Sheng Chao Wang, Zong-Huei Li, Chun Hua Hsu, Yu Jia Chang, Man Shan Chang, Yi Ching Wang, Yuan Soon Ho, Wu Che Wen, Ruo Kai Lin

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5625-5635
Number of pages11
JournalJournal of Agricultural and Food Chemistry
Volume62
Issue number24
DOIs
Publication statusPublished - Jun 18 2014

Fingerprint

Antrodia
Taiwanofungus camphoratus
methyltransferases
Methyltransferases
breast neoplasms
DNA
Assays
tumor suppressor genes
Tumors
assays
Cells
Breast Neoplasms
Tumor Suppressor Genes
DNA methylation
Methylation
methylation
Genes
DNA Methylation
Growth
neoplasms

Keywords

  • Antrodia camphorata
  • breast cancer
  • cell migration
  • DNA methylation
  • DNA methyltransferase
  • tumor suppressor genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Chemistry(all)
  • Medicine(all)

Cite this

Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential. / Wang, Sheng Chao; Li, Zong-Huei; Hsu, Chun Hua; Chang, Yu Jia; Chang, Man Shan; Wang, Yi Ching; Ho, Yuan Soon; Wen, Wu Che; Lin, Ruo Kai.

In: Journal of Agricultural and Food Chemistry, Vol. 62, No. 24, 18.06.2014, p. 5625-5635.

Research output: Contribution to journalArticle

Wang, Sheng Chao ; Li, Zong-Huei ; Hsu, Chun Hua ; Chang, Yu Jia ; Chang, Man Shan ; Wang, Yi Ching ; Ho, Yuan Soon ; Wen, Wu Che ; Lin, Ruo Kai. / Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential. In: Journal of Agricultural and Food Chemistry. 2014 ; Vol. 62, No. 24. pp. 5625-5635.
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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.",
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AU - Chang, Yu Jia

AU - Chang, Man Shan

AU - Wang, Yi Ching

AU - Ho, Yuan Soon

AU - Wen, Wu Che

AU - Lin, Ruo Kai

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AB - 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.

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KW - cell migration

KW - DNA methylation

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