ascorbic-acid and Hematologic-Neoplasms

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe

Topics: Ascorbic Acid; Basic Helix-Loop-Helix Transcription Factors; Brain Neoplasms; Breast Neoplasms; Carcinogenesis; Dehydroascorbic Acid; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Female; Glioma; Glucose Transport Proteins, Facilitative; Hematologic Neoplasms; Homeostasis; Humans; Hypoxia-Inducible Factor 1; Ketoglutaric Acids; Male; Melanoma; Mixed Function Oxygenases; Neoplasms; Oxidation-Reduction; Polymorphism, Genetic; Prostatic Neoplasms; Proto-Oncogene Proteins; Sodium-Coupled Vitamin C Transporters; Vitamins

5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) play a critical role in development and normal physiology. Alterations in 5-mC and 5-hmC patterns are common events in hematopoietic neoplasms. In this review, we begin by emphasizing the importance of 5-mC, 5-hmC, and their enzymatic modifiers in hematological malignancies. Then, we discuss the functions of 5-mC and 5-hmC at distinct genic contexts, including promoter regions, gene bodies, intron-exon boundaries, alternative promoters, and intragenic microRNAs. Recent advances in technology have allowed for the study of 5-mC and 5-hmC independently and specifically permitting distinction between the bases that show them to have transcriptional effects that vary by their location relative to gene structure. We extend these observations to their functions at enhancers and transcription factor binding sites. We discuss dietary influences on 5-mC and 5-hmC levels and summarize the literature on the effects of folate and vitamin C on 5-mC and 5-hmC, respectively. Finally, we discuss how these new themes in the functions of 5-mC and 5-hmC will likely influence the broader research field of epigenetics.

Topics: 5-Methylcytosine; Animals; Ascorbic Acid; Cytosine; Diet; DNA Methylation; Folic Acid; Hematologic Neoplasms; Humans; MicroRNAs; Promoter Regions, Genetic; Structure-Activity Relationship; Transcription Factors

Myelodysplastic syndrome (MDS) is a heterogeneous bone marrow disorder primarily affecting older adults, for whom the only curative therapy, bone marrow transplantation, is rarely an option. New therapies, or novel applications of historical therapies, are desperately needed. Arsenic trioxide (ATO), which acts through pro-apoptotic, antiproliferative, and anti-angiogenesis mechanisms, has been used successfully to treat a variety of hematologic malignancies, including MDS. As monotherapy or in combination with other agents, it can effect hematologic improvement in 22% to 26% of patients, with tolerable side effects. MDS patients whose cells express the EVI1 mutation in particular may derive benefit from this therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Cell Division; Clinical Trials as Topic; Dexamethasone; DNA-Binding Proteins; Drug Therapy, Combination; Glutathione; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; MDS1 and EVI1 Complex Locus Protein; Multicenter Studies as Topic; Myelodysplastic Syndromes; Neovascularization, Pathologic; Oxides; Proto-Oncogenes; Transcription Factors

Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation.. In a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members.. We show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals.. These results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations.. This trial was registered at EudraCT with reference number of 2018-000155-41 (01.04.2019).

Topics: Ascorbic Acid; Dioxygenases; DNA Demethylation; DNA Methylation; DNA-Binding Proteins; Germ-Line Mutation; Hematologic Neoplasms; Humans; Mutation; Vitamins

This study examined whether and how chloroquine inhibits blast progenitor self-renewal (SR) synergistically with phytochemicals or nonsteroidal anti-inflammatory drugs in seven hematological malignant cell lines.. Vitamin C, resveratrol, cyclo-oxygenase inhibitor NS-398 and indomethacin heptyl ester (Ind) were added to cell culture with or without 3 μM chloroquine.. Chloroquine synergistically inhibited blast colony formation in methylcellulose with vitamin C, resveratrol, NS-398 and Ind in one, two, none and one cell lines, respectively, in a total of four out of 28 conditions. Chloroquine synergistically inhibited blast progenitor SR in suspension with vitamin C, resveratrol, NS-398 and Ind in four, six, one and five cell lines, respectively, in a total of 16 out of 28 conditions. In contrast, chloroquine abolished SR inhibition by another agent in four out of 28 conditions.. Chloroquine exerted a marked synergistic inhibition of blast progenitor SR, but not blast colony formation.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Blast Crisis; Cell Line, Tumor; Cell Self Renewal; Chloroquine; Hematologic Neoplasms; Humans; Indomethacin; Neoplastic Stem Cells; Nitrobenzenes; Phytochemicals; Resveratrol; Stem Cells; Sulfonamides; Tumor Stem Cell Assay

Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological levels to low doses of the DNMTi 5-aza-2'-deoxycytidine (5-aza-CdR), there is a synergistic inhibition of cancer-cell proliferation and increased apoptosis. These effects are associated with enhanced immune signals including increased expression of bidirectionally transcribed endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN-inducing cellular response. This synergistic effect is likely the result of both passive DNA demethylation by DNMTi and active conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) enzymes at LTR regions of ERVs, because vitamin C acts as a cofactor for TET proteins. In addition, TET2 knockout reduces the synergy between the two compounds. Furthermore, we show that many patients with hematological neoplasia are markedly vitamin C deficient. Thus, our data suggest that correction of vitamin C deficiency in patients with hematological and other cancers may improve responses to epigenetic therapy with DNMTis.

Topics: Apoptosis; Ascorbic Acid; Ascorbic Acid Deficiency; Azacitidine; Cell Proliferation; Decitabine; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Drug Synergism; Endogenous Retroviruses; Enzyme Inhibitors; Female; Hematologic Neoplasms; Humans; Interferons; Male; Methyltransferases; Proto-Oncogene Proteins; RNA, Double-Stranded

Currently, we utilize vitamins and trace elements formulations that are not prepared specifically for patients receiving hematopoietic stem cell transplantation (HSCT), and adequacy of this strategy has not been evaluated. We prospectively measured blood level of vitamins and trace elements in 15 patients once per week at 6 time points around the acute phase of allogeneic HSCT. We provided standard nutrition support, including administration of parenteral nutrition with vitamin and trace elements formulation in case of impairment of oral intake. Most patients had vitamin B1 deficiency from the start of preparative regimens. Vitamin C deficiency was prominent throughout the acute phase of HSCT and this was significantly associated with high inflammatory markers, C-reactive protein and ferritin. Remarkable vitamin K overload associated with administration of parenteral supplementation and ferritin overload caused by repeated transfusions was observed. Moderate deficiency of zinc was at least partially linked to gastrointestinal loss by diarrhea. We revealed several features of vitamin and trace element status in the acute phase of HSCT and provided a basis for attempts to improve the nutritional condition in HSCT recipients.

Topics: Adult; Aged; Ascorbic Acid; C-Reactive Protein; Female; Ferritins; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Myeloablative Agonists; Thiamine; Trace Elements; Transplantation Conditioning; Transplantation, Homologous; Vitamin K

Patients with haematologic malignancies have a reportedly high incidence of sulfamethoxazole (SMX) hypersensitivity. The objective of this study was to determine whether deficiencies in sulfonamide detoxification pathways, to include glutathione (GSH) and ascorbate (AA), and cytochrome b(5) (b5) and cytochrome b(5) reductase (b5R), were prevalent in these patients. A secondary pilot objective was to determine whether the incidence of drug hypersensitivity following intermittent trimethoprim-SMX (TMP-SMX) prophylaxis approached that reported for high dose daily regimens.. Forty adult patients with haematologic malignancies (HM) and 35 healthy adults were studied; an additional 13 HM patients taking ascorbate supplements (HM-AA) were also evaluated. Twenty-two of 40 HM patients were prescribed and were compliant with TMP-SMX 960 mg three to four times weekly.. There were no significant differences between HM and healthy groups in plasma AA (median 37.2 µm vs. 33.9 µm) or red blood cell GSH (1.9 mmvs. 1.8 mm). However, plasma AA was correlated significantly with leucocyte b5/b5R reduction (r= 0.39, P= 0.002). Deficient b5/b5R activities were not found in HM patients. In fact, patients with chronic lymphocytic leukaemia or myeloma had significantly higher median activities (80.7 µmol mg(-1) min(-1)) than controls (18.9 µmol mg(-1) min(-1), P= 0.008). After 3-4 weeks of treatment, no patients developed SMX-specific T cells and only one patient developed rash.. Deficiencies of blood antioxidants and b5/b5R reduction were not found in this population with haematologic malignancies, and the development of skin rash and drug-specific T cells appeared to be uncommon with intermittent TMP-SMX prophylaxis.

Topics: Adult; Aged; Anti-Infective Agents; Ascorbic Acid; Case-Control Studies; Cell Proliferation; Cytochrome-B(5) Reductase; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Glutathione; Hematologic Neoplasms; Humans; Inactivation, Metabolic; Male; Middle Aged; Statistics as Topic; Sulfamethoxazole; Sulfonamides; T-Lymphocytes; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult