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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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“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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The Cure from Nature: The Extraordinary Anticancer Properties of Ascorbate (Vitamin C)
Mastrangelo, D., & Massai, L. (2016) · Journal of Integrative Oncology · doi:10.4172/2329-6771.1000157 · Cited by 5
“• It improves the quality of life of cancer patients [72] • It prolongs their survival [26,27,73] • It potentiates the cytotoxic effects and reduces the side effects of conventional chemotherapy [74] • It is remarkably safe in both physiologic, and pharmacologic concentrations [75] • It boosts the immune response, in…”
BackgroundLiu, Y., Liu, J., Guo, X., Lin, A., Wen, Y., Chen, X., Zhu, X., Liu, J., & Luo, Z. (2020) · Journal of Biomaterials Applications · doi:10.1177/0885328220940541 · Cited by 6
“The procedure of experiment was carried out using 50mM H2O2, 0.625mM terephthalic acid, and four groups nanoparticles in 0.2mM HAc-NaAc buffer (pH 4.0) at 40 C for 8 h, then used fluorospectrophotometer to track the fluorescent.38 Cytotoxicity and hemolysis of TiO2@V2O5 nanoparticles HEK-293 cells were supplied by Ame…”
MethodInfluentialRestored Ketosis Drives Anticancer Immunity in Colorectal Cancer
Montrose, D. C., & Galluzzi, L. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-0686 · Cited by 6
Firdoos, S., Dai, R., Tahir, R. A., Khan, Z. Y., Li, H., Zhang, J., Ni, J., Quan, Z., & Qing, H. (2023) · Journal of Molecular Modeling · doi:10.1007/s00894-023-05609-1 · Cited by 6
“Oxidants are mainly involved in the maintenance of the cell’s redox homeostasis [23, 60] and elevated oxidative stress prompts the progression of chronic disorders such as neurodegenerative and cardiovascular diseases [61].”
BackgroundVitamin C Inhibited Pulmonary Metastasis through Activating Nrf2/HO‐1 Pathway
Man, S., Bi, J., Liu, F., Xie, W., & Ma, L. (2024) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202300706 · Cited by 7
Vitamin C in the Management of Thyroid Cancer: A Highway to New Treatment?
Gorini, F., & Tonacci, A. (2024) · Antioxidants · doi:10.3390/antiox13101242 · Cited by 7
“Alternatively, GADPH activity can be suppressed through activation of poly(ADP-ribose) polymerase, which plays a crucial role in DNA repair and preservation of genome integrity, thereby depleting cellular stores of GADPH cofactor NAD + [168,201,202].”
gRASping the redox lever to modulate cancer cell fate signaling
Foo, C. H. J., & Pervaiz, S. (2018) · Redox Biology · doi:10.1016/j.redox.2018.101094 · Cited by 5
Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance
Río-Vilariño, A., del Puerto‐Nevado, L., García‐Foncillas, J., & Cebrián, A. (2021) · Cancers · doi:10.3390/cancers13153757 · Cited by 6
“Targeting Ras Upstream Effectors Failure of the first Ras-GTPases inhibition approaches which aimed to impede their correct location in the cell membranes along with the late development of RAS-selective inhibitors has led to the search for alternative procedures.”
BackgroundInfluentialChen, Z., Higashi, K., Shigehisa, Y., Ueda, K., Yamamoto, K., & Moribe, K. (2022) · Nanoscale · doi:10.1039/d2nr04987b · Cited by 6
Self-citationCenigaonandia‐Campillo, A., García-Bautista, A., Río-Vilariño, A., Cebrián, A., del Puerto, L., Pellicer, J. A., Gabaldón, J. A., Pérez‐Sánchez, H., Carmena‐Bargueño, M., Meroño, C., et al. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13616 · Cited by 6
“[15] published a groundbreaking scientific article concluding that vitamin C selectively kills KRAS mutant colorectal cancer (CRC) cell lines targeting aberrant glucose metabolism.”
BackgroundA fasting-mimicking diet and vitamin C: turning anti-aging strategies against cancer
Tano, M. D., & Longo, V. D. (2020) · Molecular & Cellular Oncology · doi:10.1080/23723556.2020.1791671 · Cited by 6
“Recent findings have shown that tumor cells bearing activating mutation in Kirsten Rat Sarcoma viral oncogene homologue, best known as KRAS, are more susceptible to pharmacological dose of vitamin C than KRAS-wild type ones.(6) KRAS mutations have been detected in the most lethal tumor types (in ~45% of colorectal can…”
BackgroundMiller, C. G., Kundert, J. A., Prigge, J. R., Amato, J., Perez, A., Coppo, L., Rizzo, G. N., Kavanaugh, M. P., Orlicky, D. J., Shearn, C. T., et al. (2021) · Antioxidants · doi:10.3390/antiox10030359 · Cited by 6
“This is half the daily dose that had previously been shown under chronic administration to inhibit growth of oncogene-driven tumors without adversely affecting the mice, themselves [47].”
BackgroundWang, Y., Wang, Q., Zhang, G., Li, Y., Guo, H., Zhou, J., Wang, T., Jia, H., & Zhu, L. Y. (2024) · Environmental Science & Technology · doi:10.1021/acs.est.4c03399 · Cited by 5
Tian, S. I. P., & Chen, M. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1466156 · Cited by 5
“Vitamin C can selectively kill CRC cells with KRAS and BRAF mutations (Yun et al., 2015).”
BackgroundSaitoh, Y., Takeda, K., Okawachi, K., & Tanimura, Y. (2024) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2024.130738 · Cited by 5
Zhao, M., Ye, M., & Zhao, Y. (2025) · Medicine · doi:10.1097/md.0000000000041531 · Cited by 5
Targeting Strategies for Glucose Metabolic Pathways and T Cells in Colorectal Cancer
Wang, G., Wang, J., Guan, R., Sun, Y., Shi, F., Gao, J., & Fu, X. (2018) · Current Cancer Drug Targets · doi:10.2174/1568009618666181015150138 · Cited by 5
Klener, P., Alexander, M. S., Cullen, J. J., Stejskal, V. D. M., Slíva, J., Kotlářová, L., Kostiuk, P., Procházka, Z., & Kučerová, M. (2020) · Journal of Applied Biomedicine · doi:10.32725/jab.2020.003 · Cited by 5
“New mechanisms for the effect of P-AscH- have recently been proposed (Yun et al., 2015).”
BackgroundFasting and cancer: from yeast to mammals
Tano, M. D., & Longo, V. D. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.02.005 · Cited by 6
Çi̇çek, S. (2023) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2023.109559 · Cited by 6
Temraz, S. N., Jabbour, J., Nassar, F. J., Helou, R. E., Hadla, R., Mezher, M., Lakkiss, A. E., Charafeddine, M., Nasr, R., & Shamseddine, A. I. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1110405 · Cited by 5
“A previous study has found that mutant KRAS or BRAF CRC cells exhibit high expression of GLUT1, leading to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA) (13).”
BackgroundInfluentialLeischner, C., Marongiu, L., Piotrowsky, A., Niessner, H., Venturelli, S., Burkard, M., & Renner, O. (2023) · Antioxidants · doi:10.3390/antiox12040916 · Cited by 6
“Recently, GLUT3 was found to play a role distinct from that of GLUT1 in CRC, suggesting both prognostic value and therapeutic potential for GLUT3 expression [215].”
BackgroundInfluentialChen, S., Li, D., Zeng, Z., Zhang, W., Xie, H., Tang, J., Liao, S., Cai, W., Liu, F., Tang, D., et al. (2023) · World Journal of Surgical Oncology · doi:10.1186/s12957-023-03155-x · Cited by 5
Machine learning-based meta-analysis of colorectal cancer and inflammatory bowel disease
Sardari, A., & Usefi, H. (2023) · PLoS ONE · doi:10.1371/journal.pone.0290192 · Cited by 5
“Investigations have examined GAPDH’s interaction with mutated KRAS and BRAF, suggesting that GAPDH suppression via vitamin C may disrupt tumor growth [43].”
BackgroundPeng, C., Ye, H., & Yi, Z. (2023) · PubMed Central · Cited by 5
Zhang, P., Dong, X., Du, H., Cui, S., Liu, J., He, Y., Ren, W., Wang, H., Zhang, Y., & Xu, Y. (2024) · Macromolecules · doi:10.1021/acs.macromol.4c02108 · Cited by 5
Copper in the colorectal cancer microenvironment: pioneering a new era of cuproptosis-based therapy
Feng, Q., Sun, Y., Yang, Z., Wang, Z., Chen, Z., Liu, F., & Liu, L. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2024.1522919 · Cited by 5
Self-citationAscorbate and Tumor Cell Iron Metabolism: The Evolving Story and Its Link to Pathology
Bae, D.-H., Azad, M. G., Kalinowski, D. S., Lane, D. J. R., Jansson, P. J., & Richardson, D. R. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7903 · Cited by 6
“In vitro and in vivo studies examining KRAS and BRAF mutant tumor cells have demonstrated an upregulation of GLUT1 expression (288).”
Zhu, L., Wang, J., Li, Z., Ma, H., Zhu, Y., Yang, X., & Yang, X. (2020) · British Journal Of Nutrition · doi:10.1017/s0007114520004717 · Cited by 5
Bistrović, A., Meščić, A., Jakopec, S., Prpić, H., Harej, A., Pavelić, S. K., & Raić‐Malić, S. (2022) · Future Medicinal Chemistry · doi:10.4155/fmc-2022-0047 · Cited by 5
RAS: Circuitry and therapeutic targeting
Singh, G., Thakur, N., & Kumar, U. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110505 · Cited by 6
So You Can Teach Old Fibroblasts New Tricks
Virós, A., Girotti, M. R., & Marais, R. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0503 · Cited by 5
An Electrochemiluminescent Platform for Living Cell Oxygen Metabolism Monitoring
Wang, Y., Zhang, F., Miao, P., Li, H., & Tu, Y. (2018) · Journal of Analysis and Testing · doi:10.1007/s41664-018-0058-4 · Cited by 5
A differential study on oxidized/reduced ascorbic acid induced tumor cells’ apoptosis under hypoxia
Gao, X., Zhao, C., Wei, K., Hu, B., Chen, Y., Xu, K., & Tang, B. (2020) · The Analyst · doi:10.1039/d0an01011a · Cited by 5
The dimer of human SVCT1 is key for transport function
Woubshete, M., Chan, L. I., Diallinas, G., & Byrne, B. (2024) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2024.184390 · Cited by 4
Liu, K., Liu, J., Meng, T., Wu, N., Liu, J., Qiao, M., Dong, L., & Liu, J. (2025) · Molecular Medicine Reports · doi:10.3892/mmr.2025.13439 · Cited by 4
“…resistance by decreasing cellular senescence and inducing glycolytic metabolism in ovarian cancer‑like organs and cells (35), whereas promoting mitochondrial reactive oxygen species (ROS) generation and triggering cell death in rectal cancer cells can improve chemotherapeutic effectiveness (36).”
Mazambani, S., Park, S.-H., Choe, J. H., Nguyen, A. H., Lee, B., Jeong, J. Y., Lee, S. Y., Kim, C., Park, Y., Padilla, J., et al. (2025) · Cancer Research Communications · doi:10.1158/2767-9764.crc-23-0506 · Cited by 4
“Given that vitamin C, in its oxidized form dehydroascorbate, is primarily transported into cells via GLUT1, it is possible that vitamin C may more acutely disrupt redox in HNSCC cells (42, 60).”
Sun, H., Jiang, Y., Luo, K., Xing, D. H., Zhai, Y., He, X., Wu, W., & Zhao, Z. (2025) · Human & Experimental Toxicology · doi:10.1177/09603271251345656 · Cited by 4
“35 However, our data indicate that the expression of SVCTs, particularly SLC23A1, is signi fi - cantly elevated in ALL cells compared to AML cells (Figure 3), suggesting a preferential uptake of LAA rather than DHA.”
Pan-RAS inhibitors and polo-like kinase 1: promising targets in colorectal cancer
Jayachandran, P., Elliott, A., Soni, S., Battaglin, F., Mittal, P., Algaze, S. D., Lo, J. H., Yang, Y., Ashouri, K., Torres, E. T. R., et al. (2025) · Oncogene · doi:10.1038/s41388-025-03484-z · Cited by 6
“It is true that KRAS mutant cells die when exposed to high doses of ascorbic acid (vitamin C) due to oxidative stress and oxygen radicals [91, 92].”
Anticancer Effects of Ascorbic Acid: Not All Sides Fit All
Arunsi, U. O., Olugbami, J. O., & Oyelere, A. K. (2025) · Cancers · doi:10.3390/cancers17172877 · Cited by 4
“The antiproliferative effect of AA is through the generation of ROS in the form of H 2 O 2 [15].”
InfluentialTang, M., Ge, J., Sun, K., Cui, B., Guan, Y., & Wang, J. (2021) · Seminars in Dialysis · doi:10.1111/sdi.13021 · Cited by 4
Vitamin C in Cancer Management: Clinical Evidence and Involvement of Redox Role
Bhattacharya, S. (2022) · Springer eBooks · doi:10.1007/978-981-15-9411-3_161 · Cited by 4
The Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth
Бегимбетова, Д., Kukanova, А., Fazyl, F., Manekenova, K., Омаров, Т. М., Burska, A. N., Khamijan, M., Gulyayev, A., Yermekbayeva, B., Макишев, А. К., et al. (2022) · BioMed Research International · doi:10.1155/2022/9426623 · Cited by 5
“KRAS mutant tumors tend to be more glycolytic than wild-type tumors and require glycolysis for survival and proliferation [13].”
He, M.-M., Wang, K., Lo, C., Zhang, Y., Polychronidis, G., Knudsen, M. D., Zhong, R., Ma, Y., Wu, K., Chan, A. T., et al. (2024) · Cancer · doi:10.1002/cncr.35234 · Cited by 4
“41,42 Micronutrient components in multivitamins show antineoplastic properties in CRC xenografts, 5,11 protect the integrity of gastrointestinal epithelia, 23 ‐ 26 and enhance the efficacy of chemotherapy in clinical trials.”
Background
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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