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
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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]
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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
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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
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
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