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Enhancement of the Antileukemic Action of the Inhibitors of DNA and Histone Methylation: 5-Aza-2′-Deoxycytidine and 3-Deazaneplanocin-A by Vitamin C

1
Département de Pharmacologie-Physiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
2
Centre de Recherche, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Ernesto Guccione
Received: 14 January 2021 / Revised: 20 March 2021 / Accepted: 20 March 2021 / Published: 24 March 2021
(This article belongs to the Special Issue Epigenetic Cancer Therapy: Targeting DNA and Histone Methylation)
Epigenetic gene silencing by DNA methylation and histone methylation by EZH2 play an important role in the development of acute myeloid leukemia (AML). EZH2 catalyzes the trimethylation of histone H3-lysine 27-trimethylated (H3K27me3). These epigenetic alterations silence the expression of the genes that suppress leukemogenesis. Reversal of this gene silencing by 5-aza-2′-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methylation, and by 3-deazaneplanocin-A (DZNep), an inhibitor of EZH2, results in synergistic gene reactivation and antileukemic interaction. The objective of this study is to determine if the addition of another epigenetic agent could further enhance the antileukemic action of these inhibitors of DNA and histone methylation. Vitamin C (Vit C) is reported to enhance the antineoplastic action of 5-Aza-CdR on AML cells. The mechanism responsible for this action of Vit C is due to its function as a cofactor of alpha-ketoglutarate-dependent dioxygenases (α-KGDD). The enhancement by Vit C of the catalytic activity of α-KGDD of the ten eleven translocation (TET) pathway, as well as of the Jumonji C histone demethylases (JHDMs), is shown to result in demethylation of DNA and histones, leading to reactivation of tumor suppressor genes and an antineoplastic effect. This action of Vit C has the potential to complement the antileukemic action of 5-Aza-CdR and DZNep. We observe that Vit C remarkably increases the antineoplastic activity of 5-Aza-CdR and DZNep against myeloid leukemic cells. An important step to bring this novel epigenetic therapy to clinical trial in patients with AML is the determination of its optimal dose schedule. View Full-Text
Keywords: epigenetics; leukemia; chemotherapy; DNA methylation; histone methylation; 5-aza-2′-deoxycytine; 3-deazaneplanocin-A; vitamin C; EZH2 epigenetics; leukemia; chemotherapy; DNA methylation; histone methylation; 5-aza-2′-deoxycytine; 3-deazaneplanocin-A; vitamin C; EZH2
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MDPI and ACS Style

Momparler, R.L.; Côté, S.; Momparler, L.F. Enhancement of the Antileukemic Action of the Inhibitors of DNA and Histone Methylation: 5-Aza-2′-Deoxycytidine and 3-Deazaneplanocin-A by Vitamin C. Epigenomes 2021, 5, 7. https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes5020007

AMA Style

Momparler RL, Côté S, Momparler LF. Enhancement of the Antileukemic Action of the Inhibitors of DNA and Histone Methylation: 5-Aza-2′-Deoxycytidine and 3-Deazaneplanocin-A by Vitamin C. Epigenomes. 2021; 5(2):7. https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes5020007

Chicago/Turabian Style

Momparler, Richard L.; Côté, Sylvie; Momparler, Louise F. 2021. "Enhancement of the Antileukemic Action of the Inhibitors of DNA and Histone Methylation: 5-Aza-2′-Deoxycytidine and 3-Deazaneplanocin-A by Vitamin C" Epigenomes 5, no. 2: 7. https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes5020007

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