Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes.

Abstract

BACKGROUND:

Patients with haematological malignancies are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the first step in active DNA demethylation. Here, we investigate whether oral vitamin C supplementation can correct vitamin C deficiency and affect the 5hmC/5mC ratio in patients with myeloid cancers treated with DNA methyltransferase inhibitors (DNMTis).

RESULTS:

We conducted a randomized, double-blinded, placebo-controlled pilot trial (NCT02877277) in Danish patients with myeloid cancers performed during 3 cycles of DNMTi-treatment (5-azacytidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n = 10) or placebo (n = 10) daily during the last 2 cycles. Fourteen patients (70%) were deficient in plasma vitamin C (< 23 μM) and four of the remaining six patients were taking vitamin supplements at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (< 11.4 μM; 4.997 vs 4.656% 5mC relative to deoxyguanosine, 95% CI [0.126, 0.556], P = 0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (mean increase 34.85 ± 7.94 μM, P = 0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in mononuclear myeloid cells from patients receiving oral vitamin C compared to placebo (0.037% vs - 0.029%, 95% CI [- 0.129, - 0.003], P = 0.041).

CONCLUSIONS:

Normalization of plasma vitamin C by oral supplementation leads to an increase in the 5hmC/5mC ratio compared to placebo-treated patients and may enhance the biological effects of DNMTis. The clinical efficacy of oral vitamin C supplementation to DNMTis should be investigated in a large randomized, placebo-controlled clinical trial.

TRIAL REGISTRATION:

ClinicalTrials.gov, NCT02877277 . Registered on 9 August 2016, retrospectively registered.

• Authors: Linn Gillberg, Andreas D Ørskov, Ammar Nasif, Hitoshi Ohtani, Zachary Madaj, Jakob W Hansen, Nicolas Rapin, Johanne B Mogensen, Minmin Liu, Inge H Dufva, Jens Lykkesfeldt, Petra Hajkova, Peter A Jones, Kirsten Grønbæk
• Journal: Clinical epigenetics (Clin Epigenetics) Vol. 11 Issue 1 Pg. 143 (10 17 2019) ISSN: 1868-7083 [Electronic] Germany
• PMID: 31623675 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Azacitidine
• Ascorbic Acid

Topics

• Administration, Oral
• Aged
• Aged, 80 and over
• Ascorbic Acid (administration & dosage, blood, pharmacology)
• Azacitidine (administration & dosage, pharmacology)
• CpG Islands (drug effects)
• DNA Methylation (drug effects)
• Denmark
• Double-Blind Method
• Epigenesis, Genetic (drug effects)
• Female
• Humans
• Leukemia, Myeloid (blood, genetics, therapy)
• Male
• Middle Aged
• Myelodysplastic Syndromes (blood, genetics, therapy)
• Pilot Projects