The DOI matches its Crossref record; 146 of the 147 references it cites were found in a registry or an index; 4 of the 155 sources its claims cite were checked for support.
Targeting cancer vulnerabilities with high-dose vitamin C
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
102 Not checked yet · 25 Own interpretation · 12 No basis given · 1 Supported · 1 Partly supported · 1 Own method · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“we propose that pharmacological ascorbate can potentially circumvent this problem by exploring two common features of cancer cells: their increased levels of labile transition metals, especially iron21, and their increased reliance on glucose uptake and glycolysis22.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Supportedcites [21] Torti, S. V. & Torti, F. M. Iron and cancer: more ore to be mined. Nat. Rev. Cancer 13, 342–355 (2013). source
Citation 21 is attached to the claim about increased labile metals, especially iron, not to the separate ascorbate proposal or the glycolysis claim cited to reference 22. In “Intracellular iron regulation is modified in cancer” (page unavailable), the review says cancer-specific changes often increase intracellular iron; its subsection on iron storage describes oncogene-induced expansion of the labile iron pool. (LLM, conf=0.87)
- Supportedcites [22] DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016). source
Citation 22 is attached to the claim about cancer cells’ glucose uptake and glycolysis, not the separate claim about iron or the authors’ proposed ascorbate treatment. The source’s “Metabolic Reprogramming and Oncometabolites in Cancer” section says glucose uptake and increased glycolytic flux occur in many cancer cells and tumors. Its “Bioenergetics” section also cautions that high glycolytic rates do not mean most cancer cells rely on glycolysis for the majority of their ATP. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“other αKGDDs such as JmjC domain-containing histone demethylase family (JHDM) and αKGDD AlkB (ALKB) are also known to be epigenetic regulators that can be potentially regulated by vitamin C73,74.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
What the sources say
- Partly supportedcites [73] Monfort, A. & Wutz, A. Breathing-in epigenetic change with vitamin C. EMBO Rep. 14, 337–346 (2013). sourceExperimental — accuracy not yet measured
The review’s discussion of histone demethylases and its Fig. 3 caption link JHDM activity to vitamin C and epigenetic regulation. Its AlkB discussion describes the family as iron- and 2-oxoglutarate-dependent, but says only that some members could potentially have epigenetic roles; it does not establish AlkB as a known vitamin-C-regulated epigenetic regulator. Page numbers are unavailable in our copy. (LLM, conf=0.85)
- Partly supportedcites [74] Fedeles, B. I. et al. The AlkB family of Fe(II)/α-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond. J. Biol. Chem. 290, 20734–20742 (2015). sourceExperimental — accuracy not yet measured
The Structural Features section (p. 2) identifies AlkB proteins as Fe(II)/α-ketoglutarate-dependent dioxygenases, and Eukaryotic and Mammalian AlkB Homologs (p. 2) describes homologs that demethylate RNA. But the passages do not address vitamin C regulation of AlkB or JHDM, or identify JHDM as an epigenetic regulator; searches for vitamin C, ascorbate, and JmjC did not establish those parts of the claim. (LLM, conf=0.83)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
In the paper
“we recently showed that high-dose ascorbate can target these vulnerabilities in KRAS or BRAF mutant colorectal cancer (CRC) cells47.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“our study indicated that DHA is the pharmacologically active agent”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The elevated ROS, in turn, inactivates a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), by oxidizing a cysteine residue in the active site.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Inside the cell, DHA is rapidly reduced back to ascorbate at the expense of GSH and NADPH47,49.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“recent results from both human and animal studies have found no clear evidence of the benefit of antioxidant treatment in preventing or suppressing cancer development.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [14] Sayin, V. I. et al. Antioxidants accelerate lung cancer progression in mice. Sci. Transl Med. 6, 221ra15 (2014). This study demonstrates that dietary supplementation of antioxidants ( N -acetylcysteine and vitamin E) markedly increases tumour progression and reduces survival in mouse models of KRAS-induced or BRAF-induced lung cancer. source
- Not checked yetcites [15] Le Gal, K. et al. Antioxidants can increase melanoma metastasis in mice. Sci. Transl Med. 7, 308re8 (2015). source
- Not checked yetcites [16] Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015). source
- Not checked yetcites [17] Klein, E. A. et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 306, 1549–1556 (2011). source
- Not checked yetcites [18] Omenn, G. S. et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150–1155 (1996). source
- Not checked yetcites [19] Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330, 1029–1035 (1994). source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we discuss three distinct vulnerabilities in cancer that can be exploited by pharmacological ascorbate.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“cancer cells often enhance pathways that help mitigate the toxic effects of ROS13”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [13] Chio, I. I. C. & Tuveson, D. A. ROS in cancer: the burning question. Trends Mol. Med. 23, 411–429 (2017). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 4
In the paper
“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”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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 yetcites [48] Nualart, F. J. et al. Recycling of vitamin C by a bystander effect. J. Biol. Chem. 278, 10128–10133 (2003). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This reduction depletes intracellular antioxidants and increases endogenous levels of ROS47,50.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“current pro-oxidant strategies often cause serious collateral damage, resulting in a narrow therapeutic window20”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [20] Wondrak, G. T. Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Antioxid. Redox Signal. 11, 3013–3069 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“they are not mutually exclusive and can occur simultaneously, synergizing the selective toxicity of ascorbate in cancer cells”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“millimolar concentrations of pharmacological vitamin C can kill cancer cells in vitro and slow tumour growth in vivo”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“certain cancer types may rely on antioxidants for survival and may thus be vulnerable to pro-oxidant therapies.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ascorbate effectively donates electrons to Fe3+ to regenerate redox-active Fe2+, thereby generating ROS continuously and contributing to cell death25”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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).
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
What the sources say
- Not checked yetcites [44] Xia, J. et al. Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid. EBioMedicine 18, 41–49 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
What the sources say
- Not checked yetcites [62] Yun, J. et al. Interactions between epigenetics and metabolism in cancers. Front. Oncol. 2, 163 (2012).
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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)”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting redox imbalance
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [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
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In the paper
“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”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
What the sources say
- Not checked yetcites [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
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In the paper
“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”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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In the paper
“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”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
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In the paper
“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).”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
What the sources say
- Not checked yetcites [68] Mingay, M. et al. Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia. Leukemia 32, 11–20 (2018). source
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy
What the sources say
- Not checked yetcites [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
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [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
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In the paper
“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”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
What the sources say
- Not checked yetcites [70] Gustafson, C. B. et al. Epigenetic reprogramming of melanoma cells by vitamin C treatment. Clin. Epigenetics 7, 51 (2015). source
- Not checked yetcites [71] Peng, D. et al. Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer. Clin. Epigenetics 10, 94 (2018).
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
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In the paper
“This implies that ascorbate treatment may enhance the activity of HIF hydroxylases, thus inhibiting HIF1α activity and suppressing tumour growth77.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
What the sources say
- Not checked yetcites [66] Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [75] Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“VHL-deficient RCC cells undergo cell death when exposed to vitamin C in normoxia, in contrast to isogenic VHL-proficient cells52.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“ascorbate deficiency was shown to dysregulate HSC function in both a TET2-dependent and TET2-independent manner, leading to leukaemogenesis.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting epigenetic regulators
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“patients with CRC who had high levels of ascorbate in their tumour had a better patient outcome and longer patient survival after surgery84.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [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).
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy > From bench to bedside
What the sources say
- Not checked yetcites [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 yetcites [103] Tian, Y. et al. Association of TET1 expression with colorectal cancer progression. Scand. J. Gastroenterol. 52, 312–320 (2017). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Given that more than forty αKGDDs exist112, it is possible that other αKGDDs could contribute to the anticancer mechanisms of ascorbate.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Concluding remarks
What the sources say
- Not checked yetcites [112] Hausinger, R. P. FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes. Crit. Rev. Biochem. Mol. Biol. 39, 21–68 (2004). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy
What the sources say
- Not checked yetcites [3] Nauman, G. et al. Systematic review of intravenous ascorbate in cancer clinical trials. Antioxidants 7, E89 (2018). source
- Not checked yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy > From bench to bedside
What the sources say
- Not checked yetcites [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 yetcites [103] Tian, Y. et al. Association of TET1 expression with colorectal cancer progression. Scand. J. Gastroenterol. 52, 312–320 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“many of these studies were not designed as large-scale RCTs; thus, the efficacy of high-dose ascorbate therapy remains to be determined.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy > From bench to bedside
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“GEMMs are powerful tools for studying the pathogenesis of cancer and examining the systemic effects of vitamin C in vivo113.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Concluding remarks
What the sources say
- Not checked yetcites [113] Kersten, K. et al. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol. Med. 9, 137–153 (2017). source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Concluding remarks
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Rests on an assumption: Ascorbate therapy has a low financial cost.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > References
What the sources say
- Not checked yetcites [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 patients with GBM and NSCLC. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy > Combination therapy
What the sources say
- Not checked yetcites [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 yetcites [111] Ang, A. et al. Vitamin C and immune cell function in inflammation and cancer. Biochem. Soc. Trans. 46, 1147–1159 (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > References
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > References
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy
“whereas large-scale randomized controlled trials (RCTs) in the 1980s failed to confirm these initial findings because ascorbate was given orally instead95,96.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > References
“95. Creagan ET 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).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Targeting cancer vulnerabilities with high-dose vitamin C > Vitamin C as anticancer therapy > From bench to bedside
“ascorbate may be more effective in patients with cancer with mutations in KRAS, BRAF, TET2, IDH1 and/or IDH2, VHL, SH or FDH.”
§ Targeting cancer vulnerabilities with high-dose vitamin C > Anticancer mechanism of vitamin C > Targeting HIF1 signalling
“Loss-of-function mutations in SDH and FH cause a build-up of succinate and fumarate, respectively87.”
Citations
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The Pecking Order of Free Radicals and Antioxidants: Lipid Peroxidation, α-Tocopherol, and Ascorbate
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Cited by
Sorted by citations
Items 401–424 of 424
Pharmacological Vitamin C Plus Oncolytic Adenoviruses Orchestrate Immunogenic Tumor Ferroptosis
Zhang, Y., Yang, H., Chen, M., Zhao, B., Zhang, H., Gao, X., Chen, P., Wang, Z., & Feng, L. (2026) · Journal of Medical Virology · doi:10.1002/jmv.70844
Vitamin C in the Treatment of Colorectal Cancer: Between Hope and Despair
Wasmer, M., Weber, M., & Faes, S. (2026) · Cancers · doi:10.3390/cancers18040654
Ma, X., Liu, J., Ma, Q., Hu, D., Wang, P., Shanli, Y. A. N. G., Wang, M., Li, Y., Wang, H., Liang, J., et al. (2026) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-01845
Júnior, J. J. D. S., Sousa, L. D. R., de Oliveira, V. A., Braga, A. L., de Meneses, A.-A. P. M., de Carvalho, R. M., Pereira, J. C., Silva, R. R. E., de Aguiar, R. P. S., dos Reis, A. C., et al. (2026) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2026.503927
Nitroreductase-Responsive Oligomeric crRNAs for Enzyme-Triggered Regulation of CRISPR Activity
Chen, W., Liu, L., & Cheng, L. (2026) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.5c02287
Al-Mosawi, R. A., Al-Azawe, E. M., & Waggiallah, H. A. (2026) · Al-Kitab Journal for Pure Sciences · doi:10.32441/kjps.2026.10.01.p6
Yin, Q., Wang, Y., Wu, H., Wang, Q., Xu, H., Long, X., Peng, J., Wu, J., Zhou, F., & Yang, L. (2026) · Translational Oncology · doi:10.1016/j.tranon.2026.102834
Boretti, A. A. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110290 · Cited by 1
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Zulfiqar, H., Tasnim, J., Khalid, N., Khan, M. U., Al‐Shaalan, N. H., Alharthi, S., Amin, M., & Hossain, K. R. (2026) · Journal of Herbal Medicine · doi:10.1016/j.hermed.2026.101128
H, A. S., Nixon, S., Ananda, H., Nune, M., & Rao, V. K. (2026) · Clinical Epigenetics · doi:10.1186/s13148-026-02211-z
Nutrition as Modulator of Oxidative Stress in Cancer Prevention and Treatment
Vallorani, L., Balashova, T., Cremon, C., Vivarelli, F., Canistro, D., Morosini, C., Paolini, M., & Rossi, A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27157047
Impact of oxidative stress on malignant tumor progression and emerging therapeutic strategies
Feng, X.-D., Liang, G.-C., Sun, J.-J., Wang, Z.-Q., Li, T., Fu, Y., Deng, W.-W., Li, X.-Y., Luo, J., Jin, P., et al. (2026) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2026.1916698
Henghui, Y., Huang, J., Wang, Y., Meng, J., Fan, W., Shao, Y., Zhang, X., & Wang, S. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105567
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IV Vitamin C with Chemotherapy for Cisplatin-Ineligible Bladder Cancer Patients: A Forgotten Group
Taylor, J. A., Parikh, R. A., Chen, Q., Woolbright, B. L., Chen, P., Dai, J., Sardiu, M., He, J., & Drisko, J. (2026) · Antioxidants · doi:10.3390/antiox15101318
Ganamurali, N., Sabarathinam, S., Dutta, G., & Manojkumar, N. (2026) · Kuwait Journal of Science · doi:10.1016/j.kjs.2026.100707
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Selected list of papers that cite the Karlowski (1975) trial on vitamin C and the common cold
Hemilä, H. (2026) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.20204507
Misleading and erroneous papers on vitamin C: A list of critiques by Harri Hemilä
Hemilä, H. (2026) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.19791426
Hemilä, H. (2026) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.20344539
Omar, S. R. (2026) · Health Innovation Reports · doi:10.64048/hir.v2n2.005
Metadata
- 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
- Venue
- Nature Reviews Cancer
- Published
- 2019-04-09
- Volume
- 19
- Issue
- 5
- Pages
- 271-282
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- 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
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- 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 (medical) › 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.
A language model drew the claims from the paper on 2026-10-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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