Dr. Weeks’ Comment: Does your oncologist keep upon the research?
1
Review
Semin Cancer Biol. 2018 Aug;51:59-67. doi: 10.1016/j.semcancer.2017.11.001. Epub 2017 Nov 2.
Vitamin C – A new player in regulation of the cancer epigenome
Linn Gillberg ET AL
Abstract
Over the past few years it has become clear that vitamin C, as a provider of reduced iron, is an essential factor for the function of epigenetic regulators that initiate the demethylation of DNA and histones. Vitamin C deficiency is rare in the general population, but is frequently observed in patients with cancer.Genes encoding epigenetic regulators are often mutated in cancer, underscoring their central roles in carcinogenesis. In hematological cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), drugs that reverse epigenetic aberrations are now the standard of care. Recent in vitro studies suggest that vitamin C at physiological concentrations, combined with hypomethylating agents may act synergistically to cause DNA demethylation through active and passive mechanisms, respectively. Additionally, several recent studies have renewed interest in the use of pharmacological doses of vitamin C injected intravenously to selectively kill tumor cells.This review will focus on the potential of vitamin C to optimize the outcome of epigenetic therapy in cancer patients and alternatively to act as a therapeutic at high doses.
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Leuk Res. 2018 Mar;66:1-7. doi: 10.1016/j.leukres.2017.12.009. Epub 2018 Jan 2.
Huihui Zhao 1 ET AL
Abstract
Background: Decitabine is widely used in the treatment of acute myeloid leukemia (AML) in elderly patients. Low-dose Vitamin C has also been indicated to induce DNA demethylation at the cellular level. However, little is known whether low-dose Vitamin C has a synergistic effect with decitabine in clinic.
Results: We found that low-dose Vitamin C and decitabine has a synergistic efficacy on proliferation, apoptosis, TET2 expression and activity, compared to drug-alone treatment in HL60 and NB4 cell lines in vitro. In clinic, feasibility and safety evaluations revealed that patients who received A-DCAG regimen have a higher complete remission (CR) rate than those who received the DCAG regimen (79.92% vs. 44.11%; P = 0.004) after one cycle of chemotherapy. The median overall survival (OS) was better in the A-DCAG group compared with the DCAG group (15.3 months vs. 9.3 months, P = 0.039). Patients with adverse cytogenetics did benefit from CR. There was no clinically significant additional toxicity observed with the addition of IVC.
Conclusion: On the basis of these results, the addition of IVC at low doses to DCAG appeared to improve CR and prolong OS, compared with DCAG, in elderly patients with AML.
3
Blood Adv. 2019 Dec 23;3(24):4187-4201. doi: 10.1182/bloodadvances.2019000531.
Supinya Iamsawat 1 ET AL
Free PMC article
Abstract
Adoptive transfer of induced regulatory T cells (iTregs) can ameliorate graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). CD4+ iTregs can effectively prevent GVHD but impair the graft-versus-leukemia (GVL) effect, whereas CD8+ iTregs preserve the GVL effect but have limited efficacy in GVHD control because of their instability under inflammatory conditions. Thus, we aimed to stabilize CD8+ iTregs via treatment with vitamin C (Vit C) to improve their efficacy in controlling GVHD. We found that addition of Vit C significantly improved the stability of forkhead box P3 (Foxp3) expression in CD8+ iTregs. Moreover, Vit C-treated CD8+ iTregs exhibited high efficacy in attenuating acute and chronic GVHD. The mechanistic study revealed that addition of Vit C to CD8+ iTreg culture markedly increased DNA demethylation in the conserved noncoding sequence 2 region and, hence, maintained higher Foxp3 expression levels compared with untreated controls. In acute GVHD, Vit C-treated CD8+ iTregs were able to inhibit pathogenic T-cell expansion and differentiation while reducing thymus damage and B-cell activation in cGVHD. Importantly, in contrast to CD4+ iTregs, Vit C-treated CD8+ iTregs retained the ability to control tumor relapse. These results provide a strong rationale to use Vit C in the clinic to stabilize CD8+ iTregs for the control of GVHD and preservation of GVL after allo-HCT.
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. 2020 Jun;28(3):833-841. doi: 10.19746/j.cnki.issn.1009-2137.2020.03.019.
[Effect of High Dose Vitamin C on Proliferation and Apoptosis of Acute Myeloid Leukemia Cells]
[Article in Chinese]
Xiao-Jing Lin et al
Affiliations expand
- PMID: 32552944 DOI: 10.19746/j.cnki.issn.1009-2137.2020.03.019
Abstract in English, Chinese
Objective: To investigate the effects of high dose vitamin C on proliferation and apoptosis of acute myeloid leukemia (AML) cell lines including HL-60, U937 and primary CD34+ leukemia cells in AML.
Conclusion: High dose vitamin C can inhibit the proliferation and promote the apoptosis of acute myeloid leukemia cells, and selectively kill primary CD34+ leukemia cells in AML.
5
Br J Cancer. 2020 May;122(10):1445-1452. doi: 10.1038/s41416-020-0788-8. Epub 2020 Mar 16.
Jun Liu et al
Affiliations expand
- PMID: 32203209 PMCID: PMC7217885 (available on 2021-03-16) DOI: 10.1038/s41416-020-0788-8
Abstract
Background: Vitamin C suppresses leukaemogenesis by modulating Tet methylcytosine dioxygenase (TET) activity. However, its beneficial effect in the treatment of patients with acute myeloid leukaemia (AML) remains controversial. In this study, we aimed to identify a potential predictive biomarker for vitamin C treatment in AML.
Results: SLC2A3 expression was significantly decreased in leukaemic blast cells. Below-median SLC2A3 expression was associated with poor overall survival. Low SLC2A3 expression was associated with less effective demethylation, and a diminished vitamin C effect in the AML and lymphoma cell lines. SLC2A3 knockdown in the KG-1 cell line decreased the response of vitamin C. In patient-derived primary AML cells, vitamin C only restored TET2 activity when SLC2A3 was expressed.
Conclusion: SLC2A3 could be used as a potential biomarker to predict the effect of vitamin C treatment in AML.
6
Comment
Cell Stem Cell. 2017 Nov 2;21(5):561-563. doi: 10.1016/j.stem.2017.09.015.
Vitamin C: C-ing a New Way to Fight Leukemia
Katharina Schönberger 1 , Nina Cabezas-Wallscheid 2
Affiliations expand
PMID: 29100007 DOI: 10.1016/j.stem.2017.09.015
Free article
Abstract
Metabolic cues and (epi-)genetic factors are emerging regulators of hematopoietic stem cell (HSC) potency. Two new studies in Nature and Cell, from Agathocleous et al. (2017) and Cimmino et al. (2017), respectively, show that vitamin C regulates HSC function and suppresses leukemogenesis by modulating Tet2 activity.
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Anticancer Res. 2018 Mar;38(3):1407-1414. doi: 10.21873/anticanres.12364.
Donika Ivanova 1 , et al
Affiliations expand
PMID: 29491065 DOI: 10.21873/anticanres.12364
Abstract
Background/aim: Recent studies provided convincing evidence for the anticancer activity of combined application of vitamin C and pro-vitamin K3 (menadione).The molecular pathways underlying this process are still not well established. The present study aimed to investigate the effect of the combination of vitamin C plus pro-vitamin K3 on the redox status of leukemia and normal lymphocytes, as well as their sensitizing effect for a variety of anticancer drugs.
Materials and methods: Cytotoxicity of the substances was analyzed by trypan blue staining and automated counting of live and dead cells. Apoptosis was analyzed by fluorescein isothiocyanate-annexin V test. Oxidative stress was evaluated by the intracellular levels of reactive oxygen and nitrogen species and protein-carbonyl products.
Results: Combined administration of 300 μM vitamin C plus 3 μM pro-vitamin K3 reduced the viability of leukemia lymphocytes by ~20%, but did not influence the viability of normal lymphocytes. All combinations of anticancer drug plus vitamins C and K3 were characterized by synergistic cytotoxicity towards Jurkat cells, compared to cells treated with drug alone for 24 h. In the case of barasertib and everolimus, this synergistic cytotoxicity increased within 72 hours. It was accompanied by strong induction of apoptosis, but a reduction of level of hydroperoxides and moderately increased protein-carbonyl products in leukemia cells.
Conclusion: Leukemia lymphocytes were more sensitive to combined administration of anticancer drug (everolimus or barasertib) plus vitamins C and K3, compared to normal lymphocytes. The combination of vitamin C plus K3 seems to be a powerful redox system that could specifically influence redox homeostasis of leukemia cells and sensitize them to conventional chemotherapy.
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Nature. 2017 Sep 28;549(7673):462-464. doi: 10.1038/nature23548. Epub 2017 Sep 6.
Leukaemia: Vitamin C regulates stem cells and cancer
Peter G Miller 1 , Benjamin L Ebert 1
Affiliations expand
PMID: 28869971 DOI: 10.1038/nature23548
No abstract available
Free PMC article.
Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Agathocleous M, Meacham CE, Burgess RJ, Piskounova E, Zhao Z, Crane GM, Cowin BL, Bruner E, Murphy MM, Chen W, Spangrude GJ, Hu Z, DeBerardinis RJ, Morrison SJ. Nature. 2017 Sep 28;549(7673):476-481. doi: 10.1038/nature23876. Epub 2017 Aug 21. PMID: 28825709 Free PMC article.
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J Exp Clin Cancer Res. 2020 Oct 28;39(1):228. doi: 10.1186/s13046-020-01738-0.
Walaa Darwiche et al PMID: 33115525 PMCID: PMC7594454 DOI:10.1186/s13046-020-01738-0
Free PMC article
Abstract
Background: Novel, less toxic, cost-effective and safe therapeutic strategies are needed to improve treatment of chronic lymphocytic leukemia (CLL). Ascorbic acid (AA, vitamin C) has shown a potential anti-cancer therapeutic activity in several cancers. However, the anti-cancer effects of ascorbic acid on CLL B-cells have not been extensively studied. We aimed in this study to evaluate the in vitro therapeutic activity using clinically relevant conditions.
Methods: Primary CLL B-cells and two CLL cell lines were exposed to a dose that is clinically achievable by AA oral administration (250 μM), and cell death and potential mechanisms were assessed. The role of the protective CLL microenvironment was studied. Synergistic interaction between AA and CLL approved drugs (Ibrutinib, Idelalisib and Venetoclax) was also evaluated.
Results: Ascorbic acid is cytotoxic for CLL B-cells at low dose (250 μM) but spares healthy B-cells.Ascorbic-acid-induced cytotoxicity involved pro-oxidant damage through the generation of reactive oxygen species in the extracellular media and in CLL cells, and induced caspase-dependent apoptosis. We also found that AA treatment overcame the supportive survival effect provided by microenvironment including bone marrow mesenchymal stem cells, T-cell cues (CD40L + IL-4), cytokines and hypoxia. Our data suggest that resistance to AA could be mediated by the expression of the enzyme catalase in some CLL samples and by the glucose metabolite pyruvate. We also demonstrated that AA synergistically potentiates the cytotoxicity of targeted therapies used in or being developed for CLL.
Conclusion: These preclinical results point to AA as an adjuvant therapy with potential to further improve CLL treatments in combination with targeted therapies.
10
Review
Nutrients. 2013 Sep 9;5(9):3496-505. doi: 10.3390/nu5093496.
The effects of high concentrations of vitamin C on cancer cells
Affiliations expand
PMID: 24022818 PMCID: PMC3798917 DOI:10.3390/nu5093496
Free PMC article
Abstract
The effect of high doses of vitamin C for the treatment of cancer has been controversial. Our previous studies, and studies by others, have reported that vitamin C at concentrations of 0.25-1.0 mM induced a dose- and time-dependent inhibition of proliferation in acute myeloid leukemia (AML) cell lines and in leukemic cells from peripheral blood specimens obtained from patients with AML. Treatment of cells with high doses of vitamin C resulted in an immediate increase in intracellular total glutathione content and glutathione-S transferase activitythat was accompanied by the uptake of cysteine. These results suggest a new role for high concentrations of vitamin C in modulation of intracellular sulfur containing compounds, such as glutathione and cysteine. This review, discussing biochemical pharmacologic studies, including pharmacogenomic and pharmacoproteomic studies, presents the different pharmacological effects of vitamin C currently under investigation.
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Anticancer Res. Sep-Oct 2001;21(5):3439-44.
Synergistic cytotoxic action of vitamin C and vitamin K3
W Zhang et al
PMID: 11848506
Abstract
We investigated the combination effect of sodium ascorbate (vitamin C) and menadione (vitamin K3) on the viability of various cultured cells. Human oral squamous cell carcinoma (HSC-2, HSC-3) and human promyelocytic leukemia (HL-60) cells were more sensitive to these vitamins as compared to normal cells (human gingival fibroblast HGF, human periodontal ligament fibroblast HPLF, human pulp cell HPC). The combination of vitamin C and vitamin K3 produced synergistic cytotoxicity against all these 6 cell lines. Treatment with vitamin C or vitamin K3, or their combination, induced internucleosomal DNA fragmentation only in HL-60 cells, but not in the oral tumor cell lines (HSC-2, HSC-3, HSG). ESR spectroscopy showed that vitamins C and K3 produce radicals under alkaline conditions and that the combination of these two vitamins synergistically enhanced their respective radical intensities.
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Cancer Res. 2008 Oct 1;68(19):8031-8. doi: 10.1158/0008-5472.CAN-08-1490.
Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs
Mark L Heaney et al
PMID: 18829561 PMCID: PMC3695824 DOI:10.1158/0008 5472.CAN-08-1490
Free PMC article
Abstract
Vitamin C is an antioxidant vitamin that has been hypothesized to antagonize the effects of reactive oxygen species-generating antineoplastic drugs. The therapeutic efficacy of the widely used antineoplastic drugs doxorubicin, cisplatin, vincristine, methotrexate, and imatinib were compared in leukemia (K562) and lymphoma (RL) cell lines with and without pretreatment with dehydroascorbic acid, the commonly transported form of vitamin C. The effect of vitamin C on viability, clonogenicity, apoptosis, P-glycoprotein, reactive oxygen species (ROS), and mitochondrial membrane potential was determined. Pretreatment with vitamin C caused a dose-dependent attenuation of cytotoxicity, as measured by trypan blue exclusion and colony formation after treatment with all antineoplastic agents tested. Vitamin C given before doxorubicin treatment led to a substantial reduction of therapeutic efficacy in mice with RL cell-derived xenogeneic tumors. Vitamin C treatment led to a dose-dependent decrease in apoptosis in cells treated with the antineoplastic agents that was not due to up-regulation of P-glycoprotein or vitamin C retention modulated by antineoplastics. Vitamin C had only modest effects on intracellular ROS and a more general cytoprotective profile than N-acetylcysteine, suggesting a mechanism of action that is not mediated by ROS. All antineoplastic agents tested caused mitochondrial membrane depolarization that was inhibited by vitamin C. These findings indicate that vitamin C given before mechanistically dissimilar antineoplastic agents antagonizes therapeutic efficacy in a model of human hematopoietic cancers by preserving mitochondrial membrane potential. These results support the hypothesis that vitamin C supplementation during cancer treatment may detrimentally affect therapeutic response. [ Dr. Weeks’ Comment: this must have been LOW DOSE vitamin C which acts as an anti-oxidant. As adjunctive care for cancer patients, only HIGH DOSE vitamin C is beneficial as at high doses, vitamin C becomes a PRO-OXIDANT.]
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Case Reports
Antioxidants (Basel). 2018 Jul 16;7(7):92. doi: 10.3390/antiox7070092.
Mike N Foster et al
PMID: 30012948 PMCID: PMC6070822 DOI:10.3390/antiox7070092
Free PMC article
Abstract
A 52-year-old female presented to Integrated Health Options Clinic in October 2014 with a history of relapsed acute myeloid leukaemia (AML, diagnosed in 2009 and relapsed in 2014). Intravenous (IV) vitamin C therapy was initiated (in 2014) following completion of chemotherapy as an alternative to haematopoietic stem cell transplantation. IV vitamin C was administered twice weekly at a dose of 70 g/infusion. Within 4 weeks of initiation of IV vitamin C therapy, there was a dramatic improvement in the patient’s blood indices with platelet cell counts increasing from 25 × 10⁸/L to 196 × 10⁸/L and white blood cell counts increasing from 0.29 × 10⁸/L to 4.0 × 10⁸/L, with further improvements observed over the next 18 months. Furthermore, there was a clear and sustained improvement in the patient’s health-related quality of life scores assessed using a validated questionnaire. She has remained healthy and in complete remission until the present day. This case study highlights the benefits of IV vitamin C as a supportive therapy for previously relapsed AML.
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Oncotarget. 2017 May 16;8(20):32550-32565. doi: 10.18632/oncotarget.15925.
Nélida I Noguera 1 et al
PMID: 28427227 PMCID: PMC5464808 DOI:10.18632/oncotarget.15925
Free PMC article
Abstract
The use of high-dose ascorbate (ASC) for the treatment of human cancer has been attempted several decades ago and has been recently revived by several in vitro and in vivo studies in solid tumors. We tested the cytotoxic effects of ASC, alone or in combination with arsenic trioxide (ATO) in acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL). Leukemic cell lines and primary blasts from AML and APL patients were treated with graded concentrations of ASC, alone or in association with standard concentration (1 μM) of ATO. The ASC/ATO combination killed myeloid blasts, including leukemic CD34+ cells, while sparing CD34+ progenitors obtained from normal cord blood and bone marrow. Actually, approximately one-third (11/36) of primary AML cases were highly sensitive to the ASC/ATO combination. The mechanism of cell killing appeared to be related to increased oxidative stress and overproduction of ROS in a non-quantitative fashion, which resulted in induction of apoptosis. These effects were reverted by the addition of the antioxidant N-Acetyl-Cysteine (NAC). In the APL NB4 model, ASC induced direct degradation of the PML and PML/RARA proteins via caspase activation, while the transcriptional repressor DAXX was recruited in re-constituted PML nuclear bodies. Our findings encourage the design of pilot studies to explore the potential clinical benefit of ASC alone or in combination with ATO in advanced AML and APL.
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Cancer Lett. 1998 Jan 9;122(1-2):93-9. doi: 10.1016/s0304-3835(97)00376-5.
M W Roomi 1 et al
PMID: 9464496 DOI: 10.1016/s0304-3835(97)00376-5