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Cited by 424Vitamin C and Antioxidants ResearchCancer, Hypoxia, and MetabolismAntioxidant Activity and Oxidative Stress

Targeting cancer vulnerabilities with high-dose vitamin C

Open access
Ngo, Bryan, Van Riper, Justin M., Cantley, Lewis C., Yun, Jihye·2019·Nature Reviews Cancer
DOI 10.1038/s41568-019-0135-7PMC PMC6526932
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Abstract

Over the past century, the notion that vitamin C can be used to treat cancer has generated much controversy. However, new knowledge regarding the pharmacokinetic properties of vitamin C and recent high-profile preclinical studies have revived interest in the utilization of high-dose vitamin C for cancer treatment. Studies have shown that pharmacological vitamin C targets many of the mechanisms that cancer cells utilize for their survival and growth. In this Opinion article, we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation. Although the mechanisms and predictive biomarkers that we discuss need to be validated in well-controlled clinical trials, these new discoveries regarding the anticancer properties of vitamin C are promising to help identify patient populations that may benefit the most from high-dose vitamin C therapy, developing effective combination strategies and improving the overall design of future vitamin C clinical trials for various types of cancer. This Opinion discusses three different mechanisms by which high-dose vitamin C can be selectively toxic to cancer cells. These findings from preclinical studies will be beneficial for the design of clinical trials testing high-dose vitamin C as an anticancer therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

This Opinion article argues that high-dose intravenous vitamin C can target three shared cancer vulnerabilities—redox imbalance, epigenetic reprogramming, and oxygen-sensing regulation—and proposes predictive biomarkers and combination strategies. It synthesizes preclinical and early clinical evidence, concluding that efficacy still requires validation in well-controlled trials.

Key findings

  • Pharmacological ascorbate can selectively kill some cancer cells through pro-oxidant mechanisms: increased labile iron and/or GLUT1-mediated dehydroascorbic acid (DHA) uptake deplete antioxidants, raise ROS, inhibit GAPDH, and cause an “energy crisis.” KRAS or BRAF mutant colorectal cancer cells are selectively killed, and daily intraperitoneal ascorbate (4 g kg−1) inhibited tumour growth in Apc−/−;KrasG12D/+ mice but not Apc−/− mice.
  • Ascorbate acts as a cofactor for α-ketoglutarate-dependent dioxygenases: it activates TETs to promote DNA demethylation (for example, TET2 restoration in leukaemia models and increased 5hmC in melanoma/bladder cancer) and enhances HIF hydroxylases (PHD/FIH) to inhibit HIF1α. VHL-deficient renal cancer cells die upon vitamin C in normoxia, and high-dose ascorbate reduced HIF1α, VEGF, and microvessel density in Gulo−/− mouse tumours.
  • Route of administration is critical: millimolar cytotoxic concentrations are achievable only intravenously, not orally. Early oral randomized controlled trials failed, whereas intravenous trials achieved peak plasma concentrations of 6 mM, and a phase I study with 100 g intravenous vitamin C reached 25–30 mM with ~10 mM sustained for at least 4 hours. Proposed putative biomarkers include mutations in KRAS, BRAF, TET2, IDH1 and/or IDH2, VHL, SH or FDH (as stated).
  • Clinical studies to date indicate intravenous high-dose ascorbate is well tolerated with minimal toxicity, improves quality of life, and may act synergistically with radiation and standard chemotherapies, but efficacy remains undetermined because many studies were not large-scale randomized controlled trials.

Methods

  • Design: Opinion article/narrative review; no new primary experiments are reported.
  • Evidence base: synthesizes in vitro cell culture, genetically engineered mouse models (including Gulo−/− mice), xenografts, human observational/retrospective studies, and phase I/II clinical trials and case reports.
  • Main analysis: conceptual synthesis of vitamin C pharmacokinetics, redox biology, epigenetic regulation, and HIF1 signalling; proposes mechanisms, predictive biomarkers, and combination strategies.

Limitations

  • Stated: the mechanisms and predictive biomarkers discussed need to be validated in well-controlled clinical trials; many clinical studies were not large-scale randomized controlled trials, so efficacy remains to be determined.
  • Stated: for HIF1, all studies prove association but not causality; the exact amount of DHA generated from ascorbate is difficult to quantify because of its instability; and in vitro H2O2 generation may be an artefact because most labile Fe2+ is sequestered by transferrin in vivo.
  • Evident: as an Opinion/narrative review, it is not systematic and reports no new primary data; conclusions depend on the cited preclinical and early clinical evidence.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41568-019-0135-7

Cites

146 of 146 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 155 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    High-dose ascorbate can attack the weaknesses of colorectal cancer cells with KRAS or BRAF mutations.

    “we recently showed that high-dose ascorbate can target these vulnerabilities in KRAS or BRAF mutant colorectal cancer (CRC) cells47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

  • Findingown data

    The active pharmacological agent in ascorbate therapy is DHA.

    “our study indicated that DHA is the pharmacologically active agent”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

  • Findingcitation

    Higher ROS inactivates the glycolytic enzyme GAPDH by oxidizing an active-site cysteine.

    “The elevated ROS, in turn, inactivates a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), by oxidizing a cysteine residue in the active site.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

  • Findingcitation

    Blocking GAPDH in highly glycolytic KRAS or BRAF mutant cells causes an energy crisis and death that wild-type cells do not suffer.

    “Inhibiting GAPDH in highly glycolytic KRAS or BRAF mutant cells ultimately leads to an ‘energy crisis’ and cell death not seen in their wild-type counterparts47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

  • Findingcitation

    Within cells, DHA is quickly converted back to ascorbate while consuming GSH and NADPH.

    “Inside the cell, DHA is rapidly reduced back to ascorbate at the expense of GSH and NADPH47,49.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

    • cites [49] May, J. M. et al. Ascorbate recycling in human erythrocytes: role of GSH in reducing dehydroascorbate. Free Radic. Biol. Med. 20, 543–551 (1996). source

      Not checked in the free run.

  • May combine two claims. 51
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Findingcitation

    ROS turns on PARP, lowering NAD+ and further blocking GAPDH.

    “ROS leads to activation of poly(ADP-ribose) polymerase (PARP), which in turn leads to depletion of NAD+ (a key cofactor of GAPDH), thereby further inhibiting GAPDH47”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In Apc−/−;KrasG12D/+ mice, daily intraperitoneal ascorbate (4 g kg−1) slowed tumour growth, but it did not affect tumours in Apc−/− mice.

    “daily intraperitoneal injection of ascorbate (4 g kg−1) inhibited tumour growth in Apc−/−;KrasG12D/+ mutant mice whereas it did not affect tumour growth in Apc−/− mice47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Administered ascorbate becomes DHA, which resembles glucose and is efficiently imported through GLUT1 in KRAS or BRAF mutant cells.

    “When ascorbate is administered, it is oxidized to DHA. Owing to its structural similarity to glucose, DHA is efficiently taken up via GLUT1 in KRAS or BRAF mutant cells47,48”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

    • cites [48] Nualart, F. J. et al. Recycling of vitamin C by a bystander effect. J. Biol. Chem. 278, 10128–10133 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    That conversion lowers intracellular antioxidants and raises endogenous ROS.

    “This reduction depletes intracellular antioxidants and increases endogenous levels of ROS47,50.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells. source

      Not checked in the free run.

    • cites [50] Tu, H. et al. Chemical transport knockout for oxidized vitamin C, dehydroascorbic acid, reveals its functions in vivo. EBioMedicine 23, 125–135 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Existing pro-oxidant cancer therapies frequently damage healthy tissue and have a small therapeutic window.

    “current pro-oxidant strategies often cause serious collateral damage, resulting in a narrow therapeutic window20”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Wondrak, G. T. Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Antioxid. Redox Signal. 11, 3013–3069 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Vitamin C can target three vulnerabilities shared by many cancer cells: redox imbalance, epigenetic reprogramming, and oxygen-sensing regulation.

    “we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These two mechanisms can operate together and enhance ascorbate's selective toxicity to cancer cells.

    “they are not mutually exclusive and can occur simultaneously, synergizing the selective toxicity of ascorbate in cancer cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Pharmacological vitamin C at millimolar levels is able to destroy cancer cells in culture and reduce tumour growth in animals.

    “millimolar concentrations of pharmacological vitamin C can kill cancer cells in vitro and slow tumour growth in vivo”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Some cancers might depend on antioxidants to survive, making them susceptible to pro-oxidant treatment.

    “certain cancer types may rely on antioxidants for survival and may thus be vulnerable to pro-oxidant therapies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a xenograft model, daily intraperitoneal high-dose ascorbate (4 g kg−1) slowed neuroblastoma growth and raised tumour CHK2 and H2AX activity.

    “daily intraperitoneal injection with high-dose ascorbate (4 g kg−1) inhibited neuroblastoma growth in a xenograft model, and tumours had the increased activity of checkpoint kinase 2 (CHK2) and histone 2AX (H2AX).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Ma, E. et al. Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis. Free Radic. Biol. Med. 113, 36–47 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats given intravenous ascorbate at 0.5 g kg−1, ascorbate radical and H2O2 formed in vivo, with amounts depending on the ascorbate dose.

    “Asc•− and H2O2 were generated in vivo following intravenous ascorbate injections in rats (0.5 g kg−1), and the production was ascorbate-dose-dependent35.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Chen, Q. et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl Acad. Sci. USA 104, 8749–8754 (2007). This study shows that pharmacological ascorbate is a prodrug for preferential steady-state formation of Asc •− and H2O2 in the extracellular space but not in the blood in vivo system. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    By giving electrons to Fe3+, ascorbate regenerates active Fe2+, sustaining ROS production and helping cause cell death.

    “ascorbate effectively donates electrons to Fe3+ to regenerate redox-active Fe2+, thereby generating ROS continuously and contributing to cell death25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Du, J., Cullen, J. J. & Buettner, G. R. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim. Biophys. Acta 1826, 443–457 (2012).

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Extracellular H2O2 can raise extracellular DHA by creating an oxidative environment; DHA then enters tumours with high GLUT1 and causes oxidative stress.

    “extracellular H2O2 can contribute to the increased level of extracellular DHA by generating an oxidative microenvironment. As a result, DHA is transported into tumours that express high levels of glucose transporter 1 (GLUT1), generating oxidative stress in those cells”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Red blood cells have more antioxidant enzymes and send more glucose through the pentose phosphate pathway to make NADPH, which normally shields them from high-dose ascorbate.

    “they have an increased level of antioxidant enzymes and enhanced glucose flux into the pentose phosphate pathway (ppp)60,61 to generate more NADPH. In a normal setting, this protects erythrocytes from high-dose ascorbate.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Gaetani, G. F. et al. Predominant role of catalase in the disposal of hydrogen peroxide within human erythrocytes. Blood 87, 1595–1599 (1996). source

      Not checked in the free run.

    • cites [61] May, J. M., Qu, Z. & Morrow, J. D. Mechanisms of ascorbic acid recycling in human erythrocytes. Biochim. Biophys. Acta 1528, 159–166 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple myeloma cells have a larger labile iron pool because they express little ferroportin 1, and this made them selectively sensitive to pharmacological ascorbate.

    “multiple myeloma cells have an elevated labile iron pool owing to the low expression of the iron exporter, ferroportin 1, which led to their selective sensitivity to pharmacological doses of ascorbate44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Xia, J. et al. Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid. EBioMedicine 18, 41–49 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer epigenetic reprogramming involves hypermethylation of CpG island promoters, silencing tumour suppressors like retinoblastoma and VHL.

    “Epigenetic reprogramming in cancer includes DNA hypermethylation, which frequently occurs on CpG island promoter regions and is known to silence tumour suppressors such as the retinoblastoma and VHL tumour suppressors62.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Yun, J. et al. Interactions between epigenetics and metabolism in cancers. Front. Oncol. 2, 163 (2012).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    When a tumour microenvironment has abundant labile iron, reaction with ascorbate can produce H2O2 and hydroxyl radicals that kill cancer cells.

    “if the tumour microenvironment is enriched for labile iron, its reaction with ascorbate will generate H2O2 and •OH, which can be lethal to cancer cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Like KRAS or BRAF mutant cells, red blood cells express high GLUT1 and rely on glycolysis for energy.

    “erythrocytes (red blood cells) have a high expression of GLUT1 and are dependent on glycolysis for their energy source (similar to KRAS or BRAF mutant cells)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    If tumour cells carry more intracellular labile iron than normal cells, extracellular H2O2 from ascorbate autoxidation can enter them and react with that iron to form hydroxyl radicals inside the tumour cells.

    “if tumour cells have increased levels of intracellular labile iron compared with normal cells, extracellular H2O2 from ascorbate autoxidation can diffuse into tumour cells and react with the intracellular pools of labile iron and generate •OH within tumour cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HIF hydroxylases are Fe2+-dependent αKGDDs that need O2 and αKG; their lower O2 affinity (Km 230-250 μM) means hypoxia inactivates PHDs and FIHs, stabilizing and activating HIF1.

    “both HIF hydroxylases belong to Fe2+-containing αKGDDs that require O2 and αKG as substrates. Because of their relatively lower affinity for O2 (Michaelis constant (Km) = 230–250 μM) compared with other αKGDDs76, under hypoxic conditions, PHDs and FIHs are inactive, leading to the stabilization and activation of HIF1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Koivunen, P. et al. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J. Biol. Chem. 279, 9899–9904 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    FIH hydroxylates an HIF1α asparagine, preventing p300 binding and blocking HIF1 transcriptional activity.

    “FIHs hydroxylate an asparagine residue on HIF1α, which blocks the association of HIF1α with the p300 co-activator protein, resulting in the inhibition of the transcription activity of HIF 1”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In some lymphomas that often carry TET mutations, ascorbate in vitro boosted TET activity, causing DNA demethylation, more tumour suppressor expression, and greater chemosensitivity.

    “In certain types of lymphomas where TETs are frequently mutated, ascorbate treatment in vitro increased TET activity, leading to DNA demethylation, increased expression of tumour suppressor genes and increased chemosensitivity69.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Shenoy, N. et al. Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. Blood Cancer J. 7, e587 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Gulo−/− mice, lung carcinoma grew slower with high-dose ascorbate (3.3 g/L drinking water or 1 g/kg daily intraperitoneal) than with low-dose ascorbate (0.33 g/L), and high-dose tumours had less HIF1α, VEGF, and microvessel density.

    “lung carcinoma implanted in Gulo−/− mice grew slowly when mice were treated with high-dose ascorbate either in drinking water (3.3 g per litre) or daily intraperitoneal injection (1 gkg−1) as compared with Gulo−/− mice treated with low-dose ascorbate in drinking water (0.33 g per litre), and tumours exposed to high-dose ascorbate also had reduced expression levels of HIF1α, VEGF and reduced microv”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Campbell, E. J. et al. Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(−/−) mice. Cancer Med. 4, 303–314 (2015). source

      Not checked in the free run.

    • cites [82] Campbell, E. J., Vissers, M. C. & Dachs, G. U. Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo−/− mice. Hypoxia 4, 41–52 (2016).

      Not checked in the free run.

    • cites [83] Campbell, E. J. et al. Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice. Free Radic. Biol. Med. 99, 451–462 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    In normoxia, PHDs add hydroxyl groups to HIF1α prolines; VHL then binds the modified HIF1α and brings an E3-ubiquitin ligase that sends it to proteasomal degradation.

    “Under normoxic conditions, PHDs hydroxylate proline residues on HIF1α. Prolyl-hydroxylated HIF1α is then bound by the VHL tumour suppressor protein, which recruits an E3-ubiquitin ligase that targets HIF1α for proteasomal degradation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In murine bone marrow cells with mutant IDH1, ascorbate in vitro raised DNA demethylation at myeloid differentiation gene enhancers and promoters and increased key haematopoietic gene expression.

    “ascorbate treatment in vitro increased DNA demethylation at enhancers and promoters of genes associated with myeloid differentiation and increased the expression of several key haematopoietic genes in murine bone marrow cells expressing mutant IDH1 (REF.68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Mingay, M. et al. Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia. Leukemia 32, 11–20 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early trials using both intravenous and oral ascorbate reached a peak plasma level of 6 mM, while later trials giving the same dose orally reached under 200 μM.

    “In the initial trials, ascorbate was administered both intravenously and orally and achieved a peak plasma concentration of 6 mM. However, in later trials, where the same dose of ascorbate was administered orally, a peak plasma concentration of less than 200 μM was achieved97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Padayatty, S. J. et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann. Intern. Med. 140, 533–537 (2004). This paper emphasizes the importance of the route of administration of vitamin C and explains why two early clinical trials of vitamin C as an anticancer therapy had conflicting results. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Normoxic VHL-deficient cells had more GLUT1 than VHL-proficient cells, which increased uptake of ascorbate-derived DHA, raising ROS and causing death; knocking down GLUT1 made them resistant to vitamin C toxicity.

    “the higher levels of GLUT1, a HIF1α downstream target, in normoxic VHL-deficient cells than in VHL-proficient cells facilitated increased uptake of ascorbate-derived DHA, leading to increased generation of ROS and cell death. In line with this, GLUT1 knockdown in VHL-deficient RCC cells conferred resistance to vitamin-C-induced toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Tian, W. et al. The hypoxia-inducible factor renders cancer cells more sensitive to vitamin C-induced toxicity. J. Biol. Chem. 289, 3339–3351 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Vitamin C acts as a TET cofactor needed for full activity, donating an electron to Fe3+ to make the Fe2+ TETs require.

    “Vitamin C can activate TETs as a cofactor and is required for optimal activity. Ascorbate can donate an electron to Fe3+ to generate Fe2+, which is required for TET activity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In melanoma and bladder cancer cells, ascorbate raised 5hmC and reduced malignancy, suggesting possible benefit in solid tumours with low 5hmC.

    “ascorbate treatment in melanoma and bladder cancer cells also enhanced 5hmC levels and decreased their malignancy70,71, suggesting that ascorbate treatment may also be effective in solid cancer with low levels of 5hmC.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Gustafson, C. B. et al. Epigenetic reprogramming of melanoma cells by vitamin C treatment. Clin. Epigenetics 7, 51 (2015). source

      Not checked in the free run.

    • cites [71] Peng, D. et al. Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer. Clin. Epigenetics 10, 94 (2018).

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because HIF hydroxylases need ascorbate to regenerate Fe2+, ascorbate-poor cells may have more HIF1α activity and thus favour tumour progression.

    “HIF hydroxylases require ascorbate as a cofactor to recycle Fe2+. Therefore, cells deficient in ascorbate can have increased HIF1α function, potentially contributing to tumour progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Ascorbate may boost HIF hydroxylase activity, lowering HIF1α activity and restraining tumour growth.

    “This implies that ascorbate treatment may enhance the activity of HIF hydroxylases, thus inhibiting HIF1α activity and suppressing tumour growth77.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Vissers, M. C. M. & Das, A. B. Potential mechanisms of action for vitamin C in cancer: reviewing the evidence. Front. Physiol. 9, 809 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neomorphic IDH1/IDH2 mutations build up 2-HG, which blocks αKG-dependent enzymes like TET2, lowering 5hmC, raising DNA methylation, and changing gene expression to promote cancer.

    “a neomorphic mutation in IDH1 and/or IDH2 causes a change in enzymatic activity and the accumulation of 2-hydroxyglutarate (2-HG), which inhibits the function of αKG-dependent enzymes such as TET2, resulting in the loss of 5hmC, an increase in DNA methylation and ultimately altered gene expression programmes that drive cancer development66.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumour cells respond to hypoxia by turning on HIF1, which activates genes and programmes that help them survive.

    “tumour cells activate the evolutionarily conserved transcription factor HIF1, leading to activation of a wide range of genes and response programmes that facilitate increased survival in such conditions75.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The data suggest high-dose ascorbate may slow tumour growth by moderating HIF1α, though existing studies show association only, not causation.

    “Taken together, these data suggest that high-dose ascorbate treatment can slow tumour growth by moderating HIF1α. However, all studies thus far prove the association but not the causality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    1970s trials in terminal cancer patients found that intravenous high-dose ascorbate prolonged survival, but 1980s large RCTs did not confirm this because they used oral ascorbate.

    “Clinical trials in the 1970s involving patients with terminal cancer showed that intravenous high-dose ascorbate extended patient survival in response to ascorbate treatment93,94, whereas large-scale randomized controlled trials (RCTs) in the 1980s failed to confirm these initial findings because ascorbate was given orally instead95,96.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [93] Cameron, E. & Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc. Natl Acad. Sci. USA 73, 3685–3689 (1976). This study is the first large-scale clinical trial designed to analyse the efficacy of high-dose ascorbate for the treatment of cancer. source

      Not checked in the free run.

    • cites [94] Cameron, E. & Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc. Natl Acad. Sci. USA 75, 4538–4542 (1978). source

      Not checked in the free run.

    • cites [95] Creagan, E. T. et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N. Engl. J. Med. 301, 687–690 (1979). This large-scale clinical trial shows that daily oral intake of high-dose vitamin C had no therapeutic benefit in patients with cancer. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In normoxia, vitamin C kills VHL-deficient RCC cells but not isogenic VHL-proficient cells.

    “VHL-deficient RCC cells undergo cell death when exposed to vitamin C in normoxia, in contrast to isogenic VHL-proficient cells52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Tian, W. et al. The hypoxia-inducible factor renders cancer cells more sensitive to vitamin C-induced toxicity. J. Biol. Chem. 289, 3339–3351 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Since most AML TET2 mutations are heterozygous and TET isoforms overlap in function, ascorbate might boost remaining TET activity and correct abnormal methylation.

    “The majority of TET2 mutations in AML are heterozygous, and each TET isoform has some functional redundancy. Therefore, ascorbate treatment may enhance the activity of residual TET proteins and thus rescue the abnormal DNA methylation pattern.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Gulo−/− and Tet2−/− mouse models, lack of ascorbate disrupted HSC function through both TET2-dependent and independent routes, causing leukaemia.

    “ascorbate deficiency was shown to dysregulate HSC function in both a TET2-dependent and TET2-independent manner, leading to leukaemogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Agathocleous, M. et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476–481 (2017). Using various GEMMs, including GULO-knockout mice, this study reveals that vitamin C is necessary for normal haematopoietic stem cell development and the prevention of leukaemia in mice. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CRC patients whose tumours contained more ascorbate had better outcomes and lived longer after surgery.

    “patients with CRC who had high levels of ascorbate in their tumour had a better patient outcome and longer patient survival after surgery84.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Kuiper, C. et al. Increased tumor ascorbate is associated with extended disease-free survival and decreased hypoxia-inducible factor-1 activation in human colorectal cancer. Front. Oncol. 4, 10 (2014).

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    That study kept plasma levels near 10 mM for at least four hours, which preclinical work suggests is enough to slow cancer cell growth.

    “plasma concentrations around 10 mM were sustained for at least 4 hours, which, on the basis of preclinical studies, is sufficient to slow the growth of cancer cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Hoffer, L. J. et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann. Oncol. 19, 1969–1974 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SDH and FH loss-of-function mutations accumulate succinate and fumarate, which compete with αKG, inhibit HIF hydroxylases, and produce normoxic HIF1α activity in vitro.

    “Loss-of-function mutations in SDH and FH cause a build-up of succinate and fumarate, respectively87. Accordingly, increased levels of succinate and fumarate caused by mutations in these genes can compete with αKG and inhibit activity of HIF hydroxylases and thus induce normoxic HIF1α activity in vitro88,89.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] King, A., Selak, M. A. & Gottlieb, E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25, 4675–4682 (2006). source

      Not checked in the free run.

    • cites [88] Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77–85 (2005). source

      Not checked in the free run.

    • cites [89] Koivunen, P. et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 282, 4524–4532 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In thyroid lesions, ascorbate levels were inversely related to HIF1α expression, and ascorbate lowered HIF1α and GLUT1 in thyroid cancer cells in a dose-dependent way.

    “Ascorbate level was inversely correlated with HIF1α expression in thyroid lesions80, and in vitro study showed that ascorbate treatment induced a dose-dependent decrease in expression of HIF1α and GLUT1 (a downstream target of HIF 1) in thyroid cancer cells80.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Józwiak, P. et al. Expression of hypoxia inducible factor 1α and 2α and its association with vitamin C level in thyroid lesions. J. Biomed. Sci. 24, 83 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Ascorbate treatment might hit several targets in tumours while causing little toxicity.

    “In fact, reports show that many CRCs have low expression levels of TETs and relatively high expression levels of HIF1α, implying that pharmacological ascorbate may attack multiple nodes in tumours with minimum toxicity102,103, making it an ideal magic bullet’ for cancer therapy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [102] Cao, D. et al. Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer 9, 432 (2009).

      Not checked in the free run.

    • cites [103] Tian, Y. et al. Association of TET1 expression with colorectal cancer progression. Scand. J. Gastroenterol. 52, 312–320 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Additional αKGDDs might play a role in how ascorbate fights cancer.

    “Given that more than forty αKGDDs exist112, it is possible that other αKGDDs could contribute to the anticancer mechanisms of ascorbate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Hausinger, R. P. FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes. Crit. Rev. Biochem. Mol. Biol. 39, 21–68 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many clinical studies report that intravenous high-dose ascorbate is well tolerated, improves quality of life, and when combined with radiation or standard chemotherapy has synergistic effects and fewer side effects.

    “a significant number of clinical studies to date have indicated that intravenous high-dose ascorbate is well tolerated in patients with minimal toxicity, improves the quality of life for patients and has demonstrated synergistic therapeutic effects as well as reduced side effects when combined with radiation and standard chemotherapies.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Nauman, G. et al. Systematic review of intravenous ascorbate in cancer clinical trials. Antioxidants 7, E89 (2018). source

      Not checked in the free run.

    • cites [99] Klimant, E. et al. Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach. Curr. Oncol. 25, 139–148 (2018). source

      Not checked in the free run.

    • cites [100] Carr, A. C. & Cook, J. Intravenous vitamin C for cancer therapy — identifying the current gaps in our knowledge. Front. Physiol. 9, 1182 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many colorectal cancers have low TET expression and relatively high HIF1α expression.

    “In fact, reports show that many CRCs have low expression levels of TETs and relatively high expression levels of HIF1α, implying that pharmacological ascorbate may attack multiple nodes in tumours with minimum toxicity102,103, making it an ideal magic bullet’ for cancer therapy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [102] Cao, D. et al. Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer 9, 432 (2009).

      Not checked in the free run.

    • cites [103] Tian, Y. et al. Association of TET1 expression with colorectal cancer progression. Scand. J. Gastroenterol. 52, 312–320 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Most of those clinical studies were not large randomized trials, so high-dose ascorbate's efficacy is still unproven.

    “many of these studies were not designed as large-scale RCTs; thus, the efficacy of high-dose ascorbate therapy remains to be determined.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The review proposes that vitamin C is a natural compound that acts on several vulnerable points to suppress cancer growth.

    “In this Review, we propose that vitamin C serves as an excellent example of a natural compound that targets multiple vulnerable nodes to inhibit cancer growth.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    GEMMs are powerful tools for studying cancer pathogenesis and examining systemic effects of vitamin C in vivo.

    “GEMMs are powerful tools for studying the pathogenesis of cancer and examining the systemic effects of vitamin C in vivo113.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Kersten, K. et al. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol. Med. 9, 137–153 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Ascorbate could become an important weapon against cancer, either as a single agent with predictive biomarkers or as an adjuvant in combination.

    “Given its low toxicity and low financial cost, ascorbate could become an important weapon in our arsenal against cancer, either acting as a single agent with predictive biomarkers or used in combination as an adjuvant therapy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ascorbate therapy has a low financial cost.

  • May combine two claims.

    Premisecitation

    In non-small-cell lung cancer and glioblastoma cells, pharmacological ascorbate selectively sensitizes the cells by generating redox-active labile iron and hydrogen peroxide, as shown in in vitro cell lines and mouse models.

    “This study shows that pharmacological ascorbate selectively sensitizes non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells by generating redox-active labile iron and H2O2 using in vitro cell lines and mouse models.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Schoenfeld, J. D. et al. O2 •− and H2O2 −mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell 31, 487–500 (2017). This study shows that pharmacological ascorbate selectively sensitizes non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells by generating redox-active labile iron and H 2O2 using in vitro cell lines and mouse models. In addition, it shows the potential efficacy of ascorbate therapy combined with other chemotherapies in patie source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ascorbate influences inflammatory response and immune cell function.

    “Moreover, a wealth of knowledge is emerging that highlights the influence of ascorbate in inflammatory response and immune cell function110,111, which suggests that ascorbate may have synergistic effects when combined with current immunotherapy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [110] Sorice, A. et al. Ascorbic acid: its role in immune system and chronic inflammation diseases. Mini Rev. Med. Chem. 14, 444–452 (2014). source

      Not checked in the free run.

    • cites [111] Ang, A. et al. Vitamin C and immune cell function in inflammation and cancer. Biochem. Soc. Trans. 46, 1147–1159 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical and clinical work indicates that high-dose vitamin C may raise the effectiveness and lower the toxicity of some standard chemotherapies when given together in ovarian cancer patients.

    “This paper shows in its preclinical and clinical studies that high-dose vitamin C can potentially increase the efficacy and reduce the toxicities of certain conventional chemotherapies when used in combination to treat patients with ovarian cancer.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Ma, Y. et al. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci. Transl Med. 6, 222ra18 (2014). This paper shows in its preclinical and clinical studies that high-dose vitamin C can potentially increase the efficacy and reduce the toxicities of certain conventional chemotherapies when used in combination to treat patients with ovarian cancer. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    How vitamin C is administered matters, and this accounts for the disagreement between two early trials of vitamin C as a cancer therapy.

    “This paper emphasizes the importance of the route of administration of vitamin C and explains why two early clinical trials of vitamin C as an anticancer therapy had conflicting results.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Padayatty, S. J. et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann. Intern. Med. 140, 533–537 (2004). This paper emphasizes the importance of the route of administration of vitamin C and explains why two early clinical trials of vitamin C as an anticancer therapy had conflicting results. source

      Not checked in the free run.

54 of 54

  • The paper relies on this without support.

    Past clinical trials of ascorbate in cancer were poorly designed and hindered research into its efficacy.

    “Poorly designed clinical trials in the past have stunted critical research on therapeutic efficacy of ascorbate as a cancer treatment.”

  • The paper relies on this without support.

    Ascorbate therapy has a low financial cost.

    “Given its low toxicity and low financial cost, ascorbate could become an important weapon in our arsenal against cancer, either acting as a single agent with predictive biomarkers or used in combination as an adjuvant therapy.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Vitamin C deficiency is associated with higher C-reactive protein levels and with higher mortality.

    “Moreover, vitamin C deficiency is associated with higher C-reactive protein levels and with higher mortality [2,175,177].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [177]

    The Biology of vitamin C section says severe vitamin C deficiency can cause death, and Targeting HIF1 signalling reports longer survival among colorectal cancer patients with higher tumour ascorbate. These passages offer limited support for the mortality part, but neither establishes a general association between deficiency and higher mortality. No passage found links vitamin C deficiency to higher C-reactive protein levels. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A significant number of clinical trials have indicated that vitamin C administered intravenously in high-doses (in most trials, 50-100 g twice or thrice weekly) as a treatment for various cancers including glioblastoma, ovarian, prostate, lung, or rectum cancer is well tolerated with minimal toxicity, improves the quality of life for patients, and has a synergistic therapeutic effect when combined

    “A significant number of clinical trials have indicated that vitamin C administered intravenously in high-doses (in most trials, 50–100 g twice or thrice weekly) as a treatment for various cancers including glioblastoma, ovarian, prostate, lung, or rectum cancer is well tolerated with minimal toxicity, improves the quality of life for patients, and has a synergistic therapeutic effect when combined”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [177]

    The “Vitamin C as anticancer therapy” section reports phase I/II trials and case reports involving ovarian, brain, prostate and lung cancers, and says intravenous high-dose ascorbate was generally well tolerated, improved quality of life and showed synergy with radiation or chemotherapy. It does not substantiate the claim that most trials used 50–100 g twice or thrice weekly, or identify rectal cancer among the clinical examples. The section also cautions that efficacy remains to be determined because many studies were not large-scale randomized trials. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Most of these studies were not designed as large-scale randomized clinical trials and clear verifications of the clinical efficacy of vitamin C are currently rather limited.

    “However, most of these studies were not designed as large-scale randomized clinical trials and clear verifications of the clinical efficacy of vitamin C are currently rather limited [177,182,183,184].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [177]

    The “Vitamin C as anticancer therapy” section says many studies were not designed as large-scale randomized controlled trials and that the efficacy of high-dose ascorbate therapy remains to be determined. It does not establish that *most* studies lacked that design, as the citing sentence claims. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Patients with cancer often have lower plasma levels of vitamin C than healthy adults.

    “As mentioned, patients with cancer often have lower plasma levels of vitamin C than healthy adults.”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [177]

    The References section (page unavailable) lists studies on vitamin C deficiency in cancer patients, supporting the narrower point that deficiency occurs. The cited paper passages do not establish that patients with cancer often have lower plasma vitamin C levels than healthy adults; the plasma concentrations discussed under “Vitamin C as anticancer therapy” concern vitamin C administration, not that comparison. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • One cited oral-vitamin-C trial was published in 1979, not the 1980s

    Minor

    The paper describes the later randomized trials cited as references 95 and 96 as occurring in the 1980s, but its reference list dates reference 95 to 1979.

  • Proposed biomarkers use different gene abbreviations

    Minor

    The proposed biomarker list names SH and FDH, while the preceding discussion identifies the relevant mutated genes as SDH and FH. The abbreviations in the list do not match those earlier in the paper.

2 of 2

Cites

Flagged first, then by citations

1 of the 147 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Ngo, B., Van Riper, J. M., Cantley, L. C., & Yun, J.
Affiliations
  • Weill Cornell Medicine (US)
  • Baylor College of Medicine (US)
Corresponding author
  • Cantley, Lewis C.
  • Yun, Jihye
ORCID
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2019-04-09
Volume
19
Issue
5
Pages
271-282
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/s41568-019-0135-7
PMC
PMC6526932
OpenAlex
W2938641131
Semantic Scholar
fa86cd6b2b3c9053928c3b25877e819323cab701
Cited by
423
References
147
Citations by year
2026: 33 · 2025: 60 · 2024: 59 · 2023: 63 · 2022: 77 · 2021: 67 · 2020: 55 · 2019: 8 · 2018: 1
FWCI
7.06
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Agios Pharmaceuticals
  • National Institutes of Health (5k22ca216036-02)
  • National Cancer Institute (F99CA234950, U54CA210184, K22 CA216036, R21CA258134, R35CA197588)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Keywords
high-dose vitamin C, vitamin C, cancer therapy, redox imbalance, epigenetic reprogramming, oxygen sensing, cancer cell vulnerability, predictive biomarkers, combination therapy, clinical trial design
MeSH terms
Animals, Antineoplastic Agents, Ascorbic Acid, Humans, Neoplasms, Oxidation-Reduction, Epigenesis, Genetic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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