ascorbic-acid and Myelodysplastic-Syndromes

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

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

Topics: Administration, Oral; Aged; Aged, 80 and over; Ascorbic Acid; Azacitidine; CpG Islands; Denmark; DNA Methylation; Double-Blind Method; Epigenesis, Genetic; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Azacitidine; Bone Marrow; Bone Marrow Cells; Cohort Studies; Decitabine; Dose-Response Relationship, Drug; Female; Gene Expression Profiling; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Neovascularization, Pathologic; Oxides; Young Adult

L-ascorbic acid (LAA) modifies the in vitro growth of leukemic cells from approximately 50% of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). To test the hypothesis that depletion of LAA, alternating with supplementation to prevent scurvy, would provide therapeutic benefit, a single-arm pilot trial was conducted (ClinicalTrials.gov identifier: NCT00329498). Experimental results: During depletion phase, patients with refractory AML or MDS were placed on a diet deficient in LAA; during supplementation phase, patients received daily intravenous administration of LAA. An in vitro assay was performed pretherapy for LAA sensitivity of leukemic cells from individual patients.. Of 18 patients enrolled, eight of 16 evaluable patients demonstrated a clinical response. Responses were obtained during depletion (four patients) as well as during supplementation (five patients) but at a pharmacologic plasma level achievable only with intravenous administration. Of nine patients for whom the in vitro assay indicated their leukemic cells were sensitive to LAA, seven exhibited a clinical response; compared with none of six patients who were insensitive to LAA.. The clinical benefit, along with a conspicuous absence of significant adverse events, suggests that further testing of LAA depletion alternating with pharmacologic dose intravenous supplementation in patients with these and other malignancies is warranted.

Topics: Adult; Aged; Ascorbic Acid; Female; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Risk Assessment

The oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1, deferiprone, CAS 30652-11-0) has been given daily for 3-11 months to 6 transfusion dependent iron loaded patients (myelodysplasia (MDS) 2, Diamond-Blackfan anaemia 1, thalassaemia intermedia 1, thalassaemia major 2). Daily doses of 3 g, 2 x 2 g and 3 x 2 g were administered for the first 2-7 months. Daily doses of 2 x 3 g were also used for periods up to 4 months. Urine iron excretion following 3 g of L1 was found to be related to the number of previous transfusions but not to serum ferritin or the amount of L1 excreted. In each case 24 h urinary iron excretion in response to 3 g L1 ranged from 5-21 mg in MDS, 13-25 mg in a thalassaemia intermedia and a Diamond-Blackfan patient and 16-110 mg in thalassaemia major patients. Further increases of urinary iron were observed in all the patients when the daily dose was increased. Serum ferritin levels have fluctuated but overall have remained unchanged. Biochemical assessment did not show any major abnormalities ascribed to L1 except from subnormal serum zinc levels in two patients and white blood cell absorbate in another. In a separate study we have compared urinary L1 and iron excretions in 7 transfusional iron loaded patients. In all the cases the concentration of L1 was in excess of iron and higher than the level required for 100% iron binding. There was no other apparent correlation between the concentrations of L1 and iron in the urines studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Ascorbic Acid; beta-Thalassemia; Deferiprone; Feces; Female; Ferritins; Humans; Iron; Iron Chelating Agents; Male; Middle Aged; Myelodysplastic Syndromes; Pyridones

To investigate the inhibitory effect of ascorbic acid single or combination of decitabine on tumor cells of myelodysplastic syndrome (MDS) and explore its related mechanism.. The human MDS cell lines SKM-1 and MUTZ-1 were treated with different concentrations of ascorbic acid, and the cell proliferation activity was detected by the CCK-8 assay. The reactive oxygen species (ROS) level, labile iron pool (LIP), cell cycle, and apoptosis of SKM-1 and MUTZ-1 cells were detected by flow cytometry. The control group, ascorbic acid monotherapy group, decitabine monotherapy group, and combination group of ascorbic acid and decitabine were set up, the cell proliferation activity and apoptosis were detected in each group.. High-dose ascorbic acid could reduce the cell proliferation activity of SKM-1 (R=0.886, p=0.000) and MUTZ-1 (R=0.880, p=0.000). With the increase of ascorbic acid concentration, the ROS level in SKM-1 and MUTZ-1 cells increased (r=0.816, r=0.942), the proportion of cells stagnation in G. High-dose ascorbic acid shows a cytotoxic effect on MDS tumor cells, inhibiting cell proliferation and increasing apoptosis. Ascorbic acid combined decitabine have a synergistic effect of anti-MDS tumor cells.. 抗坏血酸对骨髓增生异常综合征细胞的抑制作用及相关机制.. 观察抗坏血酸单药或与地西他滨联合用药对抑制骨髓增生异常综合征（MDS）肿瘤细胞的抑制作用，并探讨其相关机制。.. 用不同浓度抗坏血酸干预人MDS细胞系SKM-1和MUTZ-1，CCK-8法检测细胞增殖活性，流式细胞术检测细胞内活性氧和不稳定铁池水平、细胞周期及凋亡程度。分别设立对照组、抗坏血酸组、地西他滨单药组及二者联合用药组，检测细胞增殖活性和凋亡程度。.. 高剂量抗坏血酸对MDS肿瘤细胞存在细胞毒作用，抑制细胞增殖并增加其凋亡；抗坏血酸与地西他滨有协同抗MDS肿瘤细胞的作用。.

Topics: Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Decitabine; Humans; Myelodysplastic Syndromes

Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2

Topics: Animals; Ascorbic Acid; Cell Death; Cell Line, Tumor; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Gene Knockdown Techniques; Humans; Leukemia, Myeloid, Acute; Mice; Myelodysplastic Syndromes; Neoplasm Transplantation; Poly (ADP-Ribose) Polymerase-1; Proto-Oncogene Proteins; Transcription, Genetic; Transplantation, Heterologous; Vitamins

Vitamin C deficiency in developed countries is typically observed in patients with unique clinical conditions such as cystic fibrosis or anorexia nervosa, or in patients on long-term tube feeds. We report here a clinical observation in six pediatric and adolescent patients (median age 17.5 yr, range 9.8-23.5 yr) with chronic GVHD with mucous membrane involvement found to be vitamin C deficient. These patients' baseline serum vitamin C levels ranged from <0.12 to 0.94 mg/dL (normal value 0.20-1.90 mg/dL), with a mean level 0.56 ± 0.36 mg/dL and a median level 0.6 mg/dL. Among these patients, signs and symptoms of mucositis failed to respond to standard chronic GVHD therapy. After receiving treatment with 2000 mg of ascorbic acid by mouth, daily patients displayed increased serum vitamin C levels. Clinically, this correlated with a remarkable improvement in patients' mucositis and ability to eat.

Topics: Administration, Oral; Adolescent; Adult; Ascorbic Acid; Ascorbic Acid Deficiency; Child; Chronic Disease; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Mucositis; Mucous Membrane; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Scurvy; Stem Cell Transplantation; Young Adult

The Myelodysplastic Syndromes are stem cell heterogeneous disorders characterized by peripheral cytopenias and hypercellular bone marrow, which can evolute to acute leukaemia. Vitamin C can act as an antioxidant, ascorbic acid (AA) donates two electrons and becomes oxidized to dehydroascorbic acid (DHA). Under physiological conditions, vitamin C predominantly exists in its reduced (AA) form but also exists in trace quantities in the oxidized form (DHA). This study evaluates the therapeutic potential of vitamin C in Myelodysplastic Syndromes (MDSs). F36P cells (MDS cell line) were treated with ascorbate and dehydroascorbate alone and in combination with cytarabine. Cell proliferation and viability were assessed by trypan blue assay and cell death was evaluated by optical microscopy and flow cytometry. The role of reactive oxygen species, mitochondrial membrane potential, BAX, BCL-2 and cytochrome C were also assessed. Vitamin C decreases cell proliferation and viability in a concentration, time and administration dependent-manner inducing cell death by apoptosis, which was shown to be associated to an increased in superoxide production, mitochondrial membrane depolarization. These compounds modulate BCL-2, BAX and cytochrome C release. These results suggest that vitamin C induces cell death trough apoptosis in F36P cells and may be a new therapeutic approach in Myelodysplasia.

Topics: Apoptosis; Ascorbic Acid; bcl-2-Associated X Protein; Catalase; Cell Line; Cell Proliferation; Cell Survival; Cytochromes c; Dehydroascorbic Acid; Humans; Membrane Potential, Mitochondrial; Myelodysplastic Syndromes; Reactive Oxygen Species; Superoxide Dismutase

Arsenic Trioxide (ATO) is effective in about 20% of patients with myelodysplasia (MDS); its mechanisms of action have already been evaluated in vitro, but the in vivo activity is still not fully understood. Since ATO induces apoptosis in in vitro models, we compared the expression of 93 apoptotic genes in patients' bone marrow before and after ATO treatment. For this analysis, we selected 12 patients affected by MDS who received ATO in combination with Ascorbic Acid in the context of the Italian clinical trial NCT00803530, EudracT Number 2005-001321-28.. Real-time PCR quantitative assays for genes involved in apoptosis were performed using TaqMan® Assays in 384-Well Microfluidic Cards "TaqMan® Human Apoptosis Array".Quantitative RT-PCR for expression of EVI1 and WT1 genes was also performed. Gene expression values (Ct) were normalized to the median expression of 3 housekeeping genes present in the card (18S, ACTB and GAPDH).. ATO treatment induced up-regulation of some pro-apoptotic genes, such as HRK, BAK1, CASPASE-5, BAD, TNFRSF1A, and BCL2L14 and down-regulation of ICEBERG. In the majority of cases with stable disease, apoptotic gene expression profile did not change, whereas in cases with advanced MDS more frequently pro-apoptotic genes were up-regulated. Two patients achieved a major response: in the patient with refractory anemia the treatment down-regulated 69% of the pro-apoptotic genes, whereas 91% of the pro-apoptotic genes were up-regulated in the patient affected by refractory anemia with excess of blasts-1. Responsive patients showed a higher induction of BAD than those with stable disease. Finally, WT1 gene expression was down-regulated by the treatment in responsive cases.. These results represent the basis for a possible association of ATO with other biological compounds able to modify the apoptotic pathways, such as inhibitors of the BCL2 family.

Topics: Aged; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Female; Gene Expression; Genes, bcl-2; Humans; Male; Myelodysplastic Syndromes; Oxides; Real-Time Polymerase Chain Reaction

The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs.. Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective.. CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS.

Topics: Animals; Apoptosis; Ascorbic Acid; Ascorbic Acid Deficiency; Bone Marrow; Flow Cytometry; Guinea Pigs; Humans; In Situ Nick-End Labeling; Male; Myelodysplastic Syndromes; NAD(P)H Dehydrogenase (Quinone); Reactive Oxygen Species; Tobacco Smoke Pollution

Topics: Aged; Alkaloids; Ascorbic Acid; Biopsy, Needle; Bone Marrow; Humans; Macrophages; Male; Megakaryocytes; Myelodysplastic Syndromes; Pancytopenia; Plants, Medicinal; Prednisolone

In vitro colony growth was studied on bone marrow cells from 51 patients with myelodysplastic syndromes (MDS), using a cell culture method with the unique feature of daily feeding, in an effort to gain insight into the pathophysiology of MDS and to assess the clinical utility of this cell culture assay. The colony growth pattern of MDS marrow cells is remarkably similar to that of acute myeloid leukemia but quite dissimilar from that of normal marrow, in support of a common pathophysiological mechanism for these two disorders. In particular, L-ascorbic acid (LAA) enhanced colony growth in 30% and suppressed growth in 16% of cases, a finding also similar to that in acute myeloid leukemia, indicating a unique growth requirement which may be explored for therapeutic purposes. Further, these LAA effects have prognostic value, with LAA-sensitive (both LAA-enhanced and LAA-suppressed) cases displaying shorter survivals than LAA-insensitive cases (median survival of 5 months versus 18 months; P = 0.011). This prognostic value is independent of, and more powerful than, bone marrow blasts; the median survival was 18 months for less than 5% bone marrow blasts and 8 months for greater than 5% bone marrow blasts (P = 0.044). These two risk factors can be used together to identify patients with an extremely good or an extremely poor prognosis. This study establishes the clinical usefulness of the LAA effect in MDS as a prognostic factor and provides a new lead to explore in understanding differential biochemical/molecular events and, possibly, a new therapeutic approach to the management of MDS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Refractory; Ascorbic Acid; Blast Crisis; Bone Marrow; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Middle Aged; Myelodysplastic Syndromes; Predictive Value of Tests; Prognosis

L-Ascorbic acid (LAA) was shown to modulate the in vitro growth of colonies of human and mouse myeloma progenitor-stem cells through use of a unique cell-culture assay. LAA was also shown to modulate the in vitro growth of leukemic colony-forming cells (L-CFC) from bone marrow of patients with acute myelocytic leukemia. LAA enhanced the growth of L-CFC in 35% of patients and suppressed the growth of L-CFC in 15% of patients. The minimum effective concentration was 0.03 mmol/L. The modulating effect is specific to LAA because other redox compounds are without effect. From the cell kinetic standpoint, the LAA effect is cytostatic rather than cytocidal. Similar LAA effects have prognostic value in patients with myelodysplastic syndromes (MDS), with LAA-sensitive patients displaying shorter survival than LAA-insensitive patients. MDS appears to be the ideal disease for clinical trials involving in vivo LAA manipulation to control the disease process.

Topics: Adult; Ascorbic Acid; Bone Marrow; Cell Division; Humans; Leukemia; Multiple Myeloma; Myelodysplastic Syndromes; Osmolar Concentration; Preleukemia; Prognosis; Stem Cells

Vitamin C was shown to be an essential requirement for the growth of mouse myeloma cells in an in vitro colony assay. Human leukemia (acute nonlymphocytic leukemia) cell colonies grow well in a similar in vitro culture system, and vitamin C has been shown to enhance the growth of leukemic cell colonies in 77 (35%) of 219 leukemic patients while none of 34 normal bone marrows tested simultaneously shows growth enhancement by this vitamin. This vitamin C effect is reproducible in repeated experiments in same patients, specific to this vitamin, selective for leukemic cells, and is proven to be biological in nature. Further, leukemic cells are mobilized back and forth between cycling and resting states with vitamin C supplementation/depletion. Our more recent study indicates that the preleukemia (myelodysplastic syndrome), generally known to be related to acute nonlymphocytic leukemia, has similar pattern in terms of vitamin C sensitivity, with 8 of 25 patients (32%) showing the growth enhancement with this vitamin.

Topics: Ascorbic Acid; Bone Marrow; Cell Division; Humans; Leukemia; Myelodysplastic Syndromes; Tumor Cells, Cultured