期刊
CLINICAL EPIGENETICS
卷 11, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13148-019-0739-5
关键词
Vitamin C; Hydroxymethylcytosine; Myeloid cancer; Azacitidine; Epigenetics
资金
- Van Andel Research Institute through the Van Andel Research Institute - Stand Up To Cancer Epigenetics Dream Team
- Rigshospitalet's Research Foundation
- Lundbeck Foundation
- LifePharm Centre for In Vivo Pharmacology
- National Research Councils
- National Cancer Institute [R35CA209859]
- Novo Nordisk Foundation [NNF13OC0003435]
- Danish Cancer Society [R124-A7695]
- Danish Cancer Society (Danish Research Center for Precision Medicine in Blood Cancer) [223-A13071-18-S68]
- Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem) [NNF17CC0027852]
- Greater Copenhagen Health Science Partners (Clinical Academic Group in Translational Hematology)
- MRC [MC_U120092689] Funding Source: UKRI
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/m(2)/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 mu M) 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 mu M; 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 mu M, 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.
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