The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH
Open accessAbstract
Getting all stressed out by vitamin C: Few experimental cancer therapies have incited as much debate as vitamin C. Yet the mechanistic effect of vitamin C on cancer cells is still poorly understood. Yun et al. studied human colorectal cancer cells with KRAS or BRAF mutations and found that they “handle” vitamin C in a different way than other cells, ultimately to their detriment (see the Perspective by Reczek and Chandel). Because a certain receptor is up-regulated in the mutant cells, they take up the oxidized form of vitamin C (dehydroascorbate). This leads to oxidative stress, inactivation of a glycolytic enzyme required by the mutant cells for growth, and finally cell death. Whether the selective toxicity of vitamin C to these mutant cells can be exploited therapeutically remains unclear. Science , this issue p. 1391 ; see also p. 1317
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
In the citing paper
“Therapeutic interventions that decrease intracellular glutathione levels, such as administration of the oxidized form of vitamin C, dehydroascorbate (DHA), can result in cancer cell death and impaired tumor progression (Yun et al., 2015)”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Yun et al., 2015
In the citing paper
“Highly glycolytic RAS-mutant cells have been found to be vulnerable to inhibition of the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) with Vitamin C, providing a mechanistic rationale for exploring the therapeutic use of this vitamin against KRAS or BRAF mutant colorectal cancer preclinical models 38.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [38]
In the citing paper
“Inside the cell, DHA is rapidly reduced back to ascorbate at the expense of GSH and NADPH47,49.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing paper
“we recently showed that high-dose ascorbate can target these vulnerabilities in KRAS or BRAF mutant colorectal cancer (CRC) cells47.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing paper
“our study indicated that DHA is the pharmacologically active agent”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing paper
“cancer cells with high GLUT1 but not sodium-dependent vitamin C transporters exclusively take up ascorbate in the form of DHA both in vitro or in vivo6,8,47,53.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing 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”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing paper
“The elevated ROS, in turn, inactivates a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), by oxidizing a cysteine residue in the active site.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing 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”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing paper
“This reduction depletes intracellular antioxidants and increases endogenous levels of ROS47,50.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing 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.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing 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.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In the citing paper
“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.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer
Karapetis, C. S., Khambata-Ford, S., Jonker, D. J., O'Callaghan, C. J., Tu, D., Tebbutt, N. C., Simes, R. J., Chalchal, H., Shapiro, J. D., Robitaille, S., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0804385 · Cited by 3,622
Crypt stem cells as the cells-of-origin of intestinal cancer
Barker, N., Ridgway, R. A., van Es, J. H., van de Wetering, M., Begthel, H., van den Born, M., Danenberg, E., Clarke, A. R., Sansom, O. J., & Clevers, H. C. (2008) · Nature · doi:10.1038/nature07602 · Cited by 2,232 · cited 2×
“Compoundmutantmice were generated by crossing availableApc floxmice (14), LSL-KrasG12Dmice (15), and Lgr5-EGFP-creERT2 (16) animals, enabling intestinal restricted alteration of Apc and Kras.”
MethodKRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G., Penna, C., Ducreux, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0191 · Cited by 2,229
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043
Self-citationAnalysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasPreprint
Jackson, E. L., Willis, N. A., Mercer, K. L., Bronson, R. T., Crowley, D. G., Montoya, R., Jacks, T., & Tuveson, D. A. (2001) · Genes & Development · doi:10.1101/gad.943001 · Cited by 1,927 · cited 1×
“Compound mutant mice were generated by crossing available Apc mice (14), LSLKras mice (15), and Lgr5-EGFP-creER (16) animals, enabling intestinal restricted alteration of Apc and Kras.”
MethodWild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer
Di Nicolantonio, F., Martini, M., Molinari, F., Sartore-Bianchi, A., Arena, S., Saletti, P., De Dosso, S., Mazzucchelli, L., Frattini, M., Siena, S., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.0786 · Cited by 1,591
Targeting mitochondria metabolism for cancer therapy
Weinberg, S. E., & Chandel, N. S. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1712 · Cited by 1,420 · cited 2×
“indicating that the lack of mitochondrial substrates caused by glycolytic inhibition also contributes to ATP depletion in mutant cells (21).”
BackgroundVitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R. W., Washko, P. W., Dhariwal, K. R., Park, J. B., Lazarev, A., Graumlich, J. F., King, J., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.8.3704 · Cited by 1,325 · cited 1×
“are only achievable via intravenous administration, not via oral administration (30, 31).”
BackgroundAnalysis of glutathione: implication in redox and detoxification
Pastore, A., Federici, G., Bertini, E., & Piemonte, F. (2003) · Clinica Chimica Acta · doi:10.1016/s0009-8981(03)00200-6 · Cited by 1,185
Yuan, M., Breitkopf, S. B., Yang, X., & Asara, J. M. (2012) · Nature Protocols · doi:10.1038/nprot.2012.024 · Cited by 1,122 · cited 1×
“To investigate the mechanism by which vitamin C is selectively toxic to KRAS and BRAF mutant cells, we used LC-MS/MS based metabolomics to profile metabolic changes following vitamin C treatment (17).”
MethodSelf-citation
Flagged first, then by citations
Cited by
Sorted by citations
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
ROS in cancer therapy: the bright side of the moon
Perillo, B., Di Donato, M., Pezone, A., Di Zazzo, E., Giovannelli, P., Galasso, G., Castoria, G., & Migliaccio, A. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0384-2 · Cited by 2,176
The role of ROS in tumour development and progression
Cheung, E. C., & Vousden, K. H. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-021-00435-0 · Cited by 1,663
Cancer metabolism: a therapeutic perspective
Martinez-Outschoorn, U. E., Peiris-Pagés, M., Pestell, R. G., Sotgia, F., & Lisanti, M. P. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.60 · Cited by 1,505
Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
Cuadrado, A., Rojo, A. I., Wells, G., Hayes, J. D., Cousin, S. P., Rumsey, W. L., Attucks, O. C., Franklin, S., Levonen, A., Kensler, T. W., et al. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0008-x · Cited by 1,510
Jomova, K., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2024) · Archives of Toxicology · doi:10.1007/s00204-024-03696-4 · Cited by 1,445
“In addition, catalase, an enzyme that converts hydrogen peroxide, is usually downregulated in cancer cells (Glorieux et al. 2018; Yun et al. 2015).”
BackgroundZong, W., Rabinowitz, J. D., & White, E. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.011 · Cited by 1,330
“Promoting mitochondrial ROS production to induce cancer cell death may enhance the activity of chemotherapy (Yun et al., 2015).”
BackgroundAntioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases
Tan, B. L., Norhaizan, M. E., Liew, W.-P.-P., & Rahman, H. S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01162 · Cited by 1,221
Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?
Hay, N. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.77 · Cited by 1,152
Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer
Dienstmann, R., Vermeulen, L., Guinney, J., Kopetz, S., Tejpar, S., & Tabernero, J. M. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.126 · Cited by 1,075
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971
“Therapeutic interventions that decrease intracellular glutathione levels, such as administration of the oxidized form of vitamin C, dehydroascorbate (DHA), can result in cancer cell death and impaired tumor progression (Yun et al., 2015)”
BackgroundReactive oxygen species and cancer paradox: To promote or to suppress?
Galadari, S., Rahman, A. U., Pallichankandy, S., & Thayyullathil, F. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.01.004 · Cited by 918
Vitamin C: The known and the unknown and Goldilocks
Padayatty, S., & Levine, M. (2016) · Oral Diseases · doi:10.1111/odi.12446 · Cited by 753
“Pharmacologic ascorbate concentrations have antitumor activity in vitro and in animal studies (Chen et al., 2008, Chen et al., 2007) (Parrow et al., 2013, Yun et al., 2015).”
Intracellular Delivery by Membrane Disruption: Mechanisms, Strategies, and Concepts
Stewart, M. P., Langer, R., & Jensen, K. F. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00678 · Cited by 767
Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
Cimmino, L., Dolgalev, I., Wang, Y., Yoshimi, A., Martin, G. H., Wang, J., Ng, V., Xia, B., Witkowski, M. T., Mitchell-Flack, M., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.032 · Cited by 707
Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity
Kornberg, M. D., Bhargava, P., Kim, P. M., Putluri, V., Snowman, A. M., Putluri, N., Calabresi, P. A., & Snyder, S. H. (2018) · Science · doi:10.1126/science.aan4665 · Cited by 687
Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions
Yan, M., Huo, Y., Yin, S., & Hu, H. (2018) · Redox Biology · doi:10.1016/j.redox.2018.04.019 · Cited by 687
The Complex Interplay between Antioxidants and ROS in Cancer
Harris, I. S., & DeNicola, G. M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.03.002 · Cited by 659
“Recent studies have shown that vitamin C is autoxidized to dehydroascorbate (DHA) and can subsequently increase oxidative stress in cells [94,95].”
BackgroundIntegrative Proteomic Characterization of Human Lung Adenocarcinoma
Xu, J., Zhang, C., Wang, X., Zhai, L., Ma, Y., Mao, Y., Qian, K., Sun, C., Liu, Z., Jiang, S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.043 · Cited by 617
The Two Faces of Reactive Oxygen Species in Cancer
Reczek, C. R., & Chandel, N. S. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-041916-065808 · Cited by 602
“Recently, a high dose of the antioxidant vitamin C has been shown to function as a pro-oxidant (ROS generator), genotype-selective anticancer agent, inducing the cell death of Kras- and Braf-mutant colon cancer cells (Yun et al. 2015).”
BackgroundDixon, S. J., & Stockwell, B. R. (2018) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055844 · Cited by 607
“Other approaches to deplete GSH indirectly by hyperactiving GSHdependent metabolic processes, such as by incubating cells in high concentrations of vitamin C, might work in some cancers, but whether this results in the induction of ferroptosis is not known (Schoenfeld et al. 2017, Yun et al. 2015).”
BackgroundRole of Reactive Oxygen Species (ROS) in Therapeutics and Drug Resistance in Cancer and Bacteria
Allimuthu, D. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01243 · Cited by 587
Ascorbate regulates haematopoietic stem cell function and leukaemogenesis
Agathocleous, M., Meacham, C. E., Burgess, R. J., Piskounova, E., Zhao, Z., Crane, G. M., Cowin, B. L., Bruner, E., Murphy, M. M., Chen, W., et al. (2017) · Nature · doi:10.1038/nature23876 · Cited by 545
“In clinical trials, oral ascorbate administration failed to benefit patients with established cancers 42 , though supraphysiological ascorbate concentrations can slow the growth of some cancers in mice by causing oxidative stress 43,44 .”
ROS in Cancer: The Burning Question
Chio, I. I. C., & Tuveson, D. A. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.004 · Cited by 532
“…function as pro-oxidant in certain tumors due to the local oxidation and conversion of ascorbate acid to dehydroascorbate, which then readily enters cells via the glucose transporter Glut1 to mediate metabolic and nuclear damage in Kras and Braf mutant colon cancer cells in mice (Yun et al., 2015).”
BackgroundSelf-citationGlucose transporters in cancer – from tumor cells to the tumor microenvironment
Ancey, P., Contat, C., & Meylan, E. (2018) · FEBS Journal · doi:10.1111/febs.14577 · Cited by 531
The multifaceted role of reactive oxygen species in tumorigenesis
Kirtonia, A., Sethi, G., & Garg, M. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03536-5 · Cited by 452
Two Faces of Vitamin C—Antioxidative and Pro-Oxidative Agent
Kaźmierczak-Barańska, J., Boguszewska, K., Adamus-Grabicka, A., & Karwowski, B. T. (2020) · Nutrients · doi:10.3390/nu12051501 · Cited by 455
“Colon carcinoma (CRC) with KRAS or BRFA mutations appears to be another example of a high dose vitamin C sensitive tumor [53].”
BackgroundResultLiu, X., & Locasale, J. W. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.01.004 · Cited by 453
Schoenfeld, J. D., Sibenaller, Z. A., Mapuskar, K. A., Wagner, B. A., Cramer-Morales, K. L., Furqan, M., Sandhu, S., Carlisle, T. L., Smith, M. C., Abu Hejleh, T., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.02.018 · Cited by 443
Kleih, M., Böpple, K., Dong, M., Gaißler, A., Heine, S., Olayioye, M. A., Aulitzky, W. E., & Eßmann, F. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2081-4 · Cited by 433
Targeting cancer vulnerabilities with high-dose vitamin C
Ngo, B., Van Riper, J. M., Cantley, L. C., & Yun, J. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0135-7 · Cited by 423
Self-citationTherapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420
Kaur, A., Webster, M. R., Marchbank, K., Behera, R., Ndoye, A., Kugel, C. H., Dang, V. M., Appleton, J., O’Connell, M. P., Cheng, P., et al. (2016) · Nature · doi:10.1038/nature17392 · Cited by 398
RetractedHigh-fructose corn syrup enhances intestinal tumor growth in mice
Goncalves, M. D., Lu, C., Tutnauer, J., Hartman, T. E., Hwang, S.-K., Murphy, C. J., Pauli, C., Morris, R., Taylor, S., Bosch, K., et al. (2019) · Science · doi:10.1126/science.aat8515 · Cited by 374
Self-citationNRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer
Chio, I. I. C., Jafarnejad, S. M., Ponz-Sarvise, M., Park, Y., Rivera, K., Palm, W., Wilson, J., Sangar, V., Hao, Y., Öhlund, D., et al. (2016) · Cell · doi:10.1016/j.cell.2016.06.056 · Cited by 378
“This includes erastin (Yang and Stockwell, 2008), dehydroascorbic acid (oxidized vitamin C) (Yun et al., 2015), and platinumbased cytotoxics (Socinski, 2004).”
Self-citationm6A-dependent glycolysis enhances colorectal cancer progression
Shen, C., Xuan, B., Yan, T., Ma, Y., Xu, P., Tian, X., Zhang, X., Cao, Y., Ma, D., Zhu, X., et al. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01190-w · Cited by 437
A guide to plasma membrane solute carrier proteins
Pizzagalli, M. D., Bensimon, A., & Superti‐Furga, G. (2020) · FEBS Journal · doi:10.1111/febs.15531 · Cited by 413
Four Key Steps Control Glycolytic Flux in Mammalian Cells
Tanner, L. B., Goglia, A. G., Wei, M. H., Sehgal, T., Parsons, L. R., Park, J. O., White, E., Toettcher, J. E., & Rabinowitz, J. D. (2018) · Cell Systems · doi:10.1016/j.cels.2018.06.003 · Cited by 383
“GAPDH, whose catalytic cysteine can be oxidized, may exert flux control in the context of oxidative stress (Liberti et al., 2017; Ralser et al., 2007, 2009; Shestov et al., 2014; Yun et al., 2015).”
Metabolic Pathways Regulating Colorectal Cancer Initiation and Progression
La Vecchia, S., & Sebastián, C. (2020) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.05.018 · Cited by 349
Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors
Andrejeva, G., & Rathmell, J. C. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.004 · Cited by 374
“ROS detoxification mechanisms such as the glutathione system and superoxide dismutases are required for cancer cell survival, and impairing these can lead to selective killing of cancer cells (Chuang et al., 2003; Kerr et al., 2016; Yun et al., 2015).”
BackgroundTargeting the untargetable KRAS in cancer therapy
Liu, P., Wang, Y., & Li, X. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.03.002 · Cited by 366
The metabolic landscape of RAS-driven cancers from biology to therapy
Mukhopadhyay, S., Vander Heiden, M. G., & McCormick, F. (2021) · Nature Cancer · doi:10.1038/s43018-021-00184-x · Cited by 315
Vitamin C Content in Fruits: Biosynthesis and Regulation
Fenech, M., Amaya, I., Valpuesta, V., & Botella, M. A. (2019) · Frontiers in Plant Science · doi:10.3389/fpls.2018.02006 · Cited by 380
Lim, J. K. M., Delaidelli, A., Minaker, S. W., Zhang, H., Čolović, M., Yang, H., Negri, G. L., von Karstedt, S., Lockwood, W. W., Schaffer, P. C., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821323116 · Cited by 321
“This dependence on ROS-clearing mechanisms thus reveals a vulnerability that represents a tractable therapeutic strategy, such as the use of high-dose vitamin C to exacerbate oxidative stress by depleting GSH, thereby selectively killing KRAS and BRAF-mutated colorectal cancer cells (56).”
BackgroundLiposome-based drug co-delivery systems in cancer cells
Vahed, S. Z., Salehi, R., Davaran, S., & Sharifi, S. (2016) · Materials Science and Engineering C · doi:10.1016/j.msec.2016.11.073 · Cited by 317
Doskey, C. M., Buranasudja, V., Wagner, B. A., Wilkes, J. G., Du, J., Cullen, J. J., & Buettner, G. R. (2016) · Redox Biology · doi:10.1016/j.redox.2016.10.010 · Cited by 301
Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy
Aboelella, N. S., Brandle, C., Kim, T., Ding, Z., & Zhou, G. (2021) · Cancers · doi:10.3390/cancers13050986 · Cited by 303
High-dose vitamin C enhances cancer immunotherapy
Magrì, A., Germano, G., Lorenzato, A., Lamba, S., Chilà, R., Montone, M., Amodio, V., Ceruti, T., Sassi, F., Arena, S., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay8707 · Cited by 285
Drosophila as a model for ageing
Piper, M. D. W., & Partridge, L. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.09.016 · Cited by 273
“The GATA family of transcriptional regulators modify amino- acid-sensitive transcription in a TOR-dependent manner in yeast and mosquitoes (Cooper, 2002; Park et al., 2006) and have also been associated with longevity in worms (Budovskaya et al., 2008; Zhang et al., 2013).”
BackgroundParkin and mitophagy in cancer
Bernardini, J. P., Lazarou, M., & Dewson, G. (2016) · Oncogene · doi:10.1038/onc.2016.302 · Cited by 291
The Influence of Metabolism on Drug Response in Cancer
Zaal, E. A., & Berkers, C. R. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00500 · Cited by 272
Cui, B., Luo, Y., Tian, P., Peng, F., Lu, J., Yang, Y., Su, Q., Liu, B., Yu, J., Luo, X., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci121685 · Cited by 308
Vitamin C: One compound, several uses. Advances for delivery, efficiency and stability
Caritá, A. C., Fonseca‐Santos, B., Shultz, J. D., Michniak‐Kohn, B. B., Chorilli, M., & Leonardi, G. R. (2019) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2019.102117 · Cited by 305
Iron and thiol redox signaling in cancer: an exquisite balance to escape ferroptosis
Toyokuni, S., Ito, F., Yamashita, K., Okazaki, Y., & Akatsuka, S. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.04.024 · Cited by 252
“Recently, a novel mechanism was suggested; L-ascorbate may target the GAPDH enzyme with oxidation, thus killing only KRASand BRAF-mutant colorectal cancer cells [247].”
BackgroundChemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T.-A., Svensson, R. U., Olucha, J., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.051 · Cited by 262
“, 2014), and it can be affected by pharmacologically induced forms of oxidative stress (Yun et al., 2015).”
The Role of Vitamin C, Vitamin D, and Selenium in Immune System against COVID-19
Bae, M., & Kim, H. (2020) · Molecules · doi:10.3390/molecules25225346 · Cited by 269
“Vitamin C has antioxidant capacity; however, high-dose vitamin C can display pro-oxidant activity by decreasing reactive oxygen species (ROS) scavenging systems, including GSH and NADPH [33].”
BackgroundSu, X., Shen, Z., Yang, Q., Sui, F., Pu, J., Ma, J., Ma, S., Yao, D., Ji, M., & Hou, P. (2019) · Theranostics · doi:10.7150/thno.35219 · Cited by 239
Hong, X., Roh, W., Sullivan, R. J., Wong, K. H. K., Wittner, B. S., Guo, H., Dubash, T. D., Sade-Feldman, M., Wesley, B., Horwitz, E. P., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1500 · Cited by 243
Self-citationRevisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells
Abekura, F., Kim, H.-D., Chang, Y., & Kim, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231710037 · Cited by 250
“From the known GAPDH inhibitors, vitamin C inhibits GAPDH enzyme activity and is lethal to KRAS/BRAF-mutated colon cancer cells [86].”
BackgroundHunyadi, A. (2019) · Medicinal Research Reviews · doi:10.1002/med.21592 · Cited by 244
Vitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine
Liu, M., Ohtani, H., Zhou, W., Ørskov, A. D., Charlet, J., Zhang, Y. W., Shen, H., Baylin, S. B., Liang, G., Grønbæk, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612262113 · Cited by 225
“Therefore, as previously reported (26), it is possible that vitamin C was oxidized to DHA before it was transported into the cells.”
BackgroundResultInfluentialThe Role of Oxidative Stress and Its Counteractive Utility in Colorectal Cancer (CRC)
Basak, D., Uddin, M. N., & Hancock, J. (2020) · Cancers · doi:10.3390/cancers12113336 · Cited by 215
“reported selective tumor cell killing by vitamin C in colorectal tumor cells having KRAS or BRAF mutations [186].”
BackgroundDual Role of Reactive Oxygen Species and their Application in Cancer Therapy
Huang, R., Chen, H., Liang, J., Li, Y., Yang, J., Luo, C., Tang, Y., Ding, Y., Liu, X., Yuan, Q., et al. (2021) · Journal of Cancer · doi:10.7150/jca.54699 · Cited by 228
“Moreover, ROS accumulation inhibits glycolysis by the inactivation of glyceraldehyde 3-phosphate dehydrogenase via both direct post-translational modifications and depletion of the nicotinamide adenine dinucleotide oxidized form, which is consumed by PARP activated by ROS-induced DNA damage, ultimately leading to the…”
BackgroundHigh-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer
Böttger, F., Vallés‐Martí, A., Cahn, L., & Jiménez, C. R. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02134-y · Cited by 223
Vitamin C in stem cell reprogramming and cancer
Cimmino, L., Neel, B. G., & Aifantis, I. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.04.001 · Cited by 197
“Given that high-dose vitamin C can promote increased redox-active iron mobilization and GSH depletion [56, 60], the ability to induce ferroptosis could be an additional mechanism by which vitamin C can exert its function as an anti-cancer therapy.”
BackgroundInfluentialAscorbic Acid in Cancer Treatment: Let the Phoenix Fly
Shenoy, N. K., Creagan, E. T., Witzig, T. E., & Levine, M. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.07.014 · Cited by 208
Immune cell - produced ROS and their impact on tumor growth and metastasis
Kennel, K. B., & Greten, F. R. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101891 · Cited by 213
Wang, J., Ye, C., Chen, C., Xiong, H., Xie, B., Zhou, J., Chen, Y., Zheng, S. S., & Wang, L. (2017) · Oncotarget · doi:10.18632/oncotarget.15171 · Cited by 217
“In light of GLUT1 as a major receptor for uptake of Vitamin C, an interesting study discovered that cultured human colorectal cancer cells with BRAF or KRAS mutations are selectively exterminated after high dose of vitamin C treatment, as a result of elevated GLUT1facilitated uptake of the oxidized form of vitamin C,…”
BackgroundEnhanced Phototherapy by Nanoparticle-Enzyme via Generation and Photolysis of Hydrogen Peroxide
Chang, K., Liu, Z., Fang, X., Chen, H., Men, X., Yuan, Y., Sun, K., Zhang, X., Yuan, Z., & Wu, C. (2017) · Nano Letters · doi:10.1021/acs.nanolett.7b01382 · Cited by 205
Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras
Peeters, K., Van Leemputte, F., Fischer, B., Bonini, B. M., Quezada, H., Tsytlonok, M., Haesen, D., Vanthienen, W., Bernardes, N., Gonzalez-Blas, C. B., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01019-z · Cited by 203
Dietary Approaches to Cancer Therapy
Tajan, M., & Vousden, K. H. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.04.005 · Cited by 213
The pleiotropic functions of reactive oxygen species in cancer
Wu, K., Zowalaty, A. E. E., Sayin, V. I., & Papagiannakopoulos, T. Y. (2024) · Nature Cancer · doi:10.1038/s43018-024-00738-9 · Cited by 216
“Both KRAS - and BRAF -mutant colorectal cancer exhibited enhanced sensitivity to high doses of ascorbate, which was transported by GLUT1 into tumor cells and led to a decrease in GSH levels and an increase in ROS 55 .”
Critical role of AMPK in redox regulation under glucose starvation
Ren, Y., & Shen, H. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101154 · Cited by 201
“However, the ubiquitous expression of GLUT1 in normal mammalian cells and the importance of GLUT1 in glucose uptake into the brain may preclude the clinical use of GLUT1 inhibitors as cancer therapeutics [74].”
BackgroundInfluentialAntioxidant Therapy in Cancer: Rationale and Progress
Luo, M., Zhou, L., Huang, Z., Li, B., Nice, E. C., Xu, J., & Huang, C. (2022) · Antioxidants · doi:10.3390/antiox11061128 · Cited by 205
Tumor Evolution as a Therapeutic Target
Amirouchene-Angelozzi, N., Swanton, C., & Bardelli, A. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0343 · Cited by 197
“As an example, the recently reported increased dependency of KRAS-mutated clones on mitochondrial metabolism (131) and on increased uptake of dehydroascorbate (132) could be exploited to decrease the odds of emergence of KRAS-mediated resistance.”
BackgroundMetabolism and Colorectal Cancer
Sedlak, J. C., Yilmaz, Ö. H., & Roper, J. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-031521-041113 · Cited by 208
Self-citationPotential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence
Vissers, M. C. M., & Das, A. B. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00809 · Cited by 188
“…activity by ascorbate. through the diet or via high dose peritoneal administration, results in a decreased growth rate with a range of different tumors (Gao et al., 2007; Chen et al., 2008; Cha et al., 2011, 2013; Espey et al., 2011; Ma et al., 2014; Campbell et al., 2015, 2016b; Yun et al., 2015).”
RAS: Striking at the Core of the Oncogenic Circuitry
Gimple, R. C., & Wang, X. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00965 · Cited by 174
“Additionally, increased levels of the GLUT1 glucose transporter facilitates selective sensitivity of RAS driven cancers to vitamin C, the oxidized version of which is preferentially imported, depleting intracellular glutathione, and generating oxidative stress (139).”
BackgroundMiyazawa, T., Itaya, M., Burdeos, G. C., Nakagawa, K., & Miyazawa, T. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s298606 · Cited by 198
“On the other hand, Yun et al reported in 2014 a new theory in which the oxidized product of ascorbic acid (dehydroascorbic acid) is taken up by cancer cells via glucose transporter (GLUT) and inhibit the production of adenosine triphosphate (ATP) and lead the cell death to cancer.(279) Since this report, there has bee…”
BackgroundBabak, M. V., & Ahn, D. (2021) · Biomedicines · doi:10.3390/biomedicines9080852 · Cited by 189
“portant role in highly resistant colorectal cancers with KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) mutation [115].”
BackgroundZhang, P., Gao, D., An, K., Shen, Q., Wang, C., Zhang, Y., Pan, X., Chen, X., Lyv, Y., Cui, C., et al. (2020) · Nature Chemistry · doi:10.1038/s41557-020-0426-3 · Cited by 183
The current understanding on the impact of KRAS on colorectal cancer
Meng, M., Zhong, K., Jiang, T., Liu, Z., Kwan, H. Y., & Su, T. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111717 · Cited by 171
Epidemiology and risk factors for ovarian cancer
Ali, A. T., Al-ani, O., & Al-Ani, F. (2023) · Menopause Review/Przegląd Menopauzalny · doi:10.5114/pm.2023.128661 · Cited by 180
“Previous studies have shown that high intake of vitamin C is associated with a significant decrease in cells harbouring KRAS or BRAF mutations [70].”
Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment
Lin, X., Xiao, Z., Chen, T., Liang, S. H., & Guo, H. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00317 · Cited by 185
Gong, X., Smith, J., Swanson, H., & Rubin, L. P. (2018) · Molecules · doi:10.3390/molecules23040905 · Cited by 171
“Vitamin C also selectively kills KRAS and BRAF mutant cells by inducing oxidative stress [36].”
BackgroundMetabolic rewiring in melanoma
Ratnikov, B. I., Scott, D. A., Osterman, A. L., Smith, J. W., & Ronai, Z. A. (2016) · Oncogene · doi:10.1038/onc.2016.198 · Cited by 176
Kamal, F. Z., Lefter, R. M., Ali, A., Ech‐Chahad, A., Truş, C., Ciobica, A. S., & Timofte, D. V. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9965916 · Cited by 181
“The increased uptake of DHA and the subsequently increased concentration of vitamin C inside the cells can thus be correlated to death of cells undergoing above mutations [284].”
BackgroundThe Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma
Goenka, A., Tiek, D., Song, X., Huang, T., Hu, B., & Cheng, S.-Y. (2021) · Cells · doi:10.3390/cells10030484 · Cited by 169
Pawłowska, E., Szczepańska, J., & Błasiak, J. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7286737 · Cited by 178
“showed that human colorectal cancer cells (CRC) harboring mutations in either theKRAS or BRAF gene were selectively killed by vitamin C at high concentrations [87].”
BackgroundVitamin C for the treatment of sepsis: The scientific rationale
Marik, P. E. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.04.007 · Cited by 171
Dual targeting of the thioredoxin and glutathione systems in cancer and HIV
Benhar, M., Shytaj, I. L., Stamler, J. S., & Savarino, A. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85339 · Cited by 170
Targeting Metabolic–Redox Circuits for Cancer Therapy
Wang, K., Jiang, J., Lei, Y., Zhou, S., Wei, Y., & Huang, C. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.01.001 · Cited by 162
Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape
Salvadori, G., Zanardi, F., Iannelli, F., Lobefaro, R., Vernieri, C., & Longo, V. D. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.10.008 · Cited by 159
Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers
Tano, M. D., Raucci, F., Vernieri, C., Caffa, I., Buono, R., Fanti, M., Brandhorst, S., Curigliano, G., Nencioni, A., de Braud, F., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16243-3 · Cited by 155
Redox control in cancer development and progression
Helfinger, V., & Schröder, K. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.02.003 · Cited by 153
Current Use of Fenton Reaction in Drugs and Food
Abe, C., Miyazawa, T., & Miyazawa, T. (2022) · Molecules · doi:10.3390/molecules27175451 · Cited by 156
Goodwin, J., Neugent, M. L., Lee, S. Y., Choe, J. H., Choi, H., Jenkins, D. M. R., Ruthenborg, R. J., Robinson, M. W., Jeong, J. Y., Wake, M., et al. (2017) · Nature Communications · doi:10.1038/ncomms15503 · Cited by 158
Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer
Ju, H., Lu, Y.-X., Wu, Q.-N., Liu, J., Zeng, Z.-L., Mo, H.-Y., Chen, Y., Tian, T., Wang, Y., Kang, T.-B., et al. (2017) · Oncogene · doi:10.1038/onc.2017.227 · Cited by 148
Polireddy, K., Dong, R., Reed, G. A., Yu, J., Chen, P., Williamson, S. K., Violet, P.-C., Pessetto, Z. Y., Godwin, A. K., Fan, F., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-17568-8 · Cited by 158
Metabolic Abnormalities in Glioblastoma and Metabolic Strategies to Overcome Treatment Resistance
Zhou, W., & Wahl, D. R. (2019) · Cancers · doi:10.3390/cancers11091231 · Cited by 152
Metadata
- Authors
- Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I. C., Giannopoulou, E. G., Rago, C., Muley, A., Asara, J. M., Paik, J., Elemento, O., Chen, Z., Pappin, D. J., Dow, L. E., Papadopoulos, N., Gross, S. S., & Cantley, L. C.
- Affiliations
- Weill Cornell Medicine (US)
- Harvard University (US)
- Cold Spring Harbor Laboratory (US)
- Tufts Medical Center (US)
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
- Howard Hughes Medical Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Cantley, Lewis C.
- ORCID
- Venue
- Science
- Published
- 2015-12-11
- Volume
- 350
- Issue
- 6266
- Pages
- 1391-1396
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4778961
- OpenAlex
- W2144542772
- Cited by
- 913
- References
- 40
- Citations by year
- 2026: 49 · 2025: 83 · 2024: 71 · 2023: 73 · 2022: 106 · 2021: 111 · 2020: 110 · 2019: 92 · 2018: 88 · 2017: 85 · 2016: 43 · 2015: 2
- FWCI
- 69.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P01 CA120964)
- U.S. Department of Defense
- National Cancer Institute (P01 CA120964-07, P01 CA117969-09)
- Damon Runyon Cancer Research Foundation
- KL2 Career Development
- 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 › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- vitamin C, dehydroascorbic acid, KRAS mutation, BRAF mutation, colorectal cancer, glyceraldehyde-3-phosphate dehydrogenase, GLUT1 glucose transporter, glutathione depletion, reactive oxygen species, oxidative stress, glycolysis, cell death, targeted therapy
- MeSH terms
- Animals, Ascorbic Acid, Dehydroascorbic Acid, Female, Glycolysis, Humans, Mice, Mutant Strains, Mice, Nude, Proto-Oncogene Proteins, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Reactive Oxygen Species, ras Proteins, Xenograft Model Antitumor Assays, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Adenomatous Polyposis Coli Protein, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Glucose Transporter Type 1, Mice
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.
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 ›
Are you an author, or do you see a problem with this page? Request a review
