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

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

doi:10.1186/s13148-019-0739-5

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

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

19 Citations (Scopus)

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.

Original language	English
Journal	Clinical Epigenetics
Volume	11
Issue number	1
Pages (from-to)	143-153
Number of pages	11
ISSN	1868-7075
DOIs	https://doi.org/10.1186/s13148-019-0739-5
Publication status	Published - 17 Oct 2019

Keywords

Azacitidine
Epigenetics
Hydroxymethylcytosine
Myeloid cancer
Vitamin C

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Gillberg, L., Ørskov, A. D., Nasif, A., Ohtani, H., Madaj, Z., Hansen, J. W., Rapin, N., Mogensen, J. B., Liu, M., Dufva, I. H., Lykkesfeldt, J., Hajkova, P., Jones, P. A., & Grønbæk, K. (2019). Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes. Clinical Epigenetics, 11(1), 143-153. https://doi.org/10.1186/s13148-019-0739-5

Gillberg, L , Ørskov, AD, Nasif, A, Ohtani, H, Madaj, Z, Hansen, JW, Rapin, N, Mogensen, JB, Liu, M, Dufva, IH, Lykkesfeldt, J, Hajkova, P, Jones, PA & Grønbæk, K 2019, 'Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes', Clinical Epigenetics, vol. 11, no. 1, pp. 143-153. https://doi.org/10.1186/s13148-019-0739-5

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title = "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.",

keywords = "Azacitidine, Epigenetics, Hydroxymethylcytosine, Myeloid cancer, Vitamin C",

author = "Linn Gillberg and {\O}rskov, {Andreas D.} and Ammar Nasif and Hitoshi Ohtani and Zachary Madaj and Hansen, {Jakob W.} and Nicolas Rapin and Mogensen, {Johanne B.} and Minmin Liu and Dufva, {Inge H.} and Jens Lykkesfeldt and Petra Hajkova and Jones, {Peter A.} and Kirsten Gr{\o}nb{\ae}k",

year = "2019",

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doi = "10.1186/s13148-019-0739-5",

language = "English",

volume = "11",

pages = "143--153",

journal = "Clinical Epigenetics",

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TY - JOUR

T1 - Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment

T2 - Normalization of plasma vitamin C induces epigenetic changes

AU - Gillberg, Linn

AU - Ørskov, Andreas D.

AU - Nasif, Ammar

AU - Ohtani, Hitoshi

AU - Madaj, Zachary

AU - Hansen, Jakob W.

AU - Rapin, Nicolas

AU - Mogensen, Johanne B.

AU - Liu, Minmin

AU - Dufva, Inge H.

AU - Lykkesfeldt, Jens

AU - Hajkova, Petra

AU - Jones, Peter A.

AU - Grønbæk, Kirsten

PY - 2019/10/17

Y1 - 2019/10/17

N2 - 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.

AB - 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.

KW - Azacitidine

KW - Epigenetics

KW - Hydroxymethylcytosine

KW - Myeloid cancer

KW - Vitamin C

U2 - 10.1186/s13148-019-0739-5

DO - 10.1186/s13148-019-0739-5

M3 - Journal article

C2 - 31623675

AN - SCOPUS:85073614048

SN - 1868-7075

VL - 11

SP - 143

EP - 153

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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