The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
Mechanisms by Which Low Glucose Enhances the Cytotoxicity of Metformin to Cancer Cells Both In Vitro and In Vivo
Open accessAbstract
Different cancer cells exhibit altered sensitivity to metformin treatment. Recent studies suggest these findings may be due in part to the common cell culture practice of utilizing high glucose, and when glucose is lowered, metformin becomes increasingly cytotoxic to cancer cells. In low glucose conditions ranging from 0 to 5 mM, metformin was cytotoxic to breast cancer cell lines MCF7, MDAMB231 and SKBR3, and ovarian cancer cell lines OVCAR3, and PA-1. MDAMB231 and SKBR3 were previously shown to be resistant to metformin in normal high glucose medium. When glucose was increased to 10 mM or above, all of these cell lines become less responsive to metformin treatment. Metformin treatment significantly reduced ATP levels in cells incubated in media with low glucose (2.5 mM), high fructose (25 mM) or galactose (25 mM). Reductions in ATP levels were not observed with high glucose (25 mM). This was compensated by enhanced glycolysis through activation of AMPK when oxidative phosphorylation was inhibited by metformin. However, enhanced glycolysis was either diminished or abolished by replacing 25 mM glucose with 2.5 mM glucose, 25 mM fructose or 25 mM galactose. These findings suggest that lowering glucose potentiates metformin induced cell death by reducing metformin stimulated glycolysis. Additionally, under low glucose conditions metformin significantly decreased phosphorylation of AKT and various targets of mTOR, while phospho-AMPK was not significantly altered. Thus inhibition of mTOR signaling appears to be independent of AMPK activation. Further in vivo studies using the 4T1 breast cancer mouse model confirmed that metformin inhibition of tumor growth was enhanced when serum glucose levels were reduced via low carbohydrate ketogenic diets. The data support a model in which metformin treatment of cancer cells in low glucose medium leads to cell death by decreasing ATP production and inhibition of survival signaling pathways. The enhanced cytotoxicity of metformin against cancer cells was observed both in vitro and in vivo.
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
“These results are consistent with previous studies reporting the synergism of the metformin/low glucose combination (Birsoy et al., 2014; Zhuang et al., 2014).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Zhuang et al., 2014
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
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa012512 · Cited by 19,011 · cited 1×
“Metformin’s potential anti-cancer activity was implicated by the lower incidence of cancer in type II diabetics versus other glucose controlling drugs [9].”
BackgroundMetformin and reduced risk of cancer in diabetic patients
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005) · BMJ · doi:10.1136/bmj.38415.708634.f7 · Cited by 2,388
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157
Metformin improves healthspan and lifespan in mice
Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3192 · Cited by 1,445
El-Mir, M.-Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M., & Leverve, X. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.1.223 · Cited by 1,399
Efficacy of Metformin in Patients with Non-Insulin-Dependent Diabetes Mellitus
DeFronzo, R. A., & Goodman, A. M. (1995) · New England Journal of Medicine · doi:10.1056/nejm199508313330902 · Cited by 1,368
Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells.
Reitzer, L. J., Wice, B. M., & Kennell, D. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)30124-2 · Cited by 1,240
Aslakson, C. J., & Miller, F. R. (1992) · PubMed · Cited by 1,234
Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N., & Struhl, K. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-2994 · Cited by 1,115
Buzzai, M., Jones, R. G., Amaravadi, R. K., Lum, J. J., DeBerardinis, R. J., Zhao, F., Viollet, B., & Thompson, C. B. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4447 · Cited by 949
Flagged first, then by citations
Research works printed but not linked: 1
- VC Sandulache, 2011, Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells, Cancer, 117, 2926, 10.1002/cncr.25868 · DOI
Cited by
Sorted by citations
Items 101–149 of 149
Li, Z., Li, Z., Yao, S., Jiang, H., Zhang, X., Zheng, Y. L., & Zhu, W. (2024) · Acta Mechanica Sinica · doi:10.1007/s10409-024-24243-x · Cited by 6
Differences in glucose concentration shows new perspectives in gastric cancer metabolism
da Silva, E. L., Mesquita, F. P., Portilho, A. J. D. S., Bezerra, E. C. A., Daniel, J. P., Aranha, E. S. P., Farran, S. H., de Vasconcellos, M. C., de Moraes, M. E. A., Moreira-Nunes, C. A., et al. (2022) · Toxicology in Vitro · doi:10.1016/j.tiv.2022.105357 · Cited by 7
A hypothetical method for controlling highly glycolytic cancers and metastases
Mathews, E. H., Mathews, G. E., & Meyer, A. A. (2018) · Medical Hypotheses · doi:10.1016/j.mehy.2018.06.014 · Cited by 6
Li, Z., Stachon, T., Häcker, S., Fries, F. N., Chai, N., Seitz, B., Shi, L., Hsu, S., Li, S., Liu, S., et al. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.110163 · Cited by 5
High-dose metformin induces a low-glucose dependent genotoxic stress
Lyu, T., Zhou, H., Wang, Y., Jiang, M., Tao, Q., Chen, J., Guo, Y., Zhang, Q., Wang, X., & Guo, X. (2022) · Food and Chemical Toxicology · doi:10.1016/j.fct.2022.113129 · Cited by 5
Disruption of Hif-1α enhances cytotoxic effects of metformin in murine squamous cell carcinoma
Sanada, Y., Sasanuma, H., Takeda, S., Tano, K., & Masunaga, S. (2017) · International Journal of Radiation Biology · doi:10.1080/09553002.2018.1409443 · Cited by 5
Metformin Impairs Linsitinib Anti-Tumor Effect on Ovarian Cancer Cell Lines
Almeida-Nunes, D. L., Silva, J. P. N., Nunes, M., Silva, P. M. A., Silvestre, R., Dinis‐Oliveira, R. J., Bousbaa, H., & Ricardo, S. A. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252211935 · Cited by 4
Gao, X., Kang, J., Li, X., Chen, C., & Luo, D. (2023) · The FASEB Journal · doi:10.1096/fj.202202078rr · Cited by 4
Zhuang, Y., Haugrud, A. B., Schaefer, M. A., Messerli, S. M., & Miskimins, W. K. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1225220 · Cited by 4
Self-citationPark, J., Shin, Y. K., Kim, U., & Seol, G. H. (2023) · Pharmaceuticals · doi:10.3390/ph16091238 · Cited by 4
Pomuceno, J. P., Silva, E., Martin, R. R., Durán, I., Bizzarri, M., Cocho, G., Mansilla, R., & Nieto-Villar, J. M. (2019) · Integrative Cancer Science and Therapeutics · doi:10.15761/icst.1000301 · Cited by 4
Hu, D., Peng, F., Lin, X., Zhang, H., Xia, Y., Lin, J., Zheng, X., & Niu, W. (2019) · Journal of Cancer · doi:10.7150/jca.31184 · Cited by 4
Ketogenic diets: Dietary therapeutic potential on breast cancer
Annunziata, G., Caprio, M., Frías-Toral, E., Colao, A., & Barrea, L. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.09.001 · Cited by 3
Metformin as a Potential In Vitro Anticancer Modulator of Adenosine Monophosphate Kinase: A Review
Jinadasa, A. G. R. G., Akalanka, H. M. K., Wageesha, N. D. A., & Ekanayake, S. (2024) · International Journal of Breast Cancer · doi:10.1155/2024/1094274 · Cited by 3
Sekar, A. P., Nurmala, S., Matsuura, E., Tan, X. W., Rahmasari, R., & Sauriasari, R. (2024) · Breast Cancer Basic and Clinical Research · doi:10.1177/11782234241240173 · Cited by 3
Nutrient Availability Dictates Cancer Metabolism–Based Therapeutic Responses to Nononcology Drugs
Pyun, W. Y., Park, J. H., Roh, J. W., Jeon, D., Kim, J., Paik, J. E., Cho, S. C., Park, S. Y., Lim, H., Kim, H., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-25-1123 · Cited by 4
Villa-Fernández, E., García, A. V., Fernández-Fernández, A., García‐Villarino, M., Ares, J., Pujante, P., González‐Vidal, T., Fraga, M. F., Torre, E. L. M., Delgado, E., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052637 · Cited by 2
Al-Jada, D. N., Takruri, H. R., & Talib, W. H. (2023) · PharmaNutrition · doi:10.1016/j.phanu.2023.100340 · Cited by 2
Do MCF7 cells cope with metformin treatment under energetic stress in low glucose conditions?
Doğan, İ., Umudum, H., Pampal, A., Çandar, T., Kavasoğlu, L., & Yaren, S. A. R. I. (2018) · Molecular Biology Reports · doi:10.1007/s11033-018-4152-5 · Cited by 2
Galant, L. S., Doblado, L., Radí, R., Bem, A. F. D., & Monsalve, M. (2024) · Antioxidants · doi:10.3390/antiox13070873 · Cited by 3
Wang, L., Asheghabadi, P. S., Mashhadikhan, S., Nasirzade, S., Ettehad, Y., Gholamrezaie, S., Jafari, F., Rahmani, M., Mehdizadeh, S., Zali, N., et al. (2025) · Nutrition & Metabolism · doi:10.1186/s12986-025-01055-3 · Cited by 1
Sielski, E., Noumani, S. A., Bower, E., Cunningham, K., Beidel, G., Luchianova, A., Courreges, M. C., & Benencia, F. (2026) · Biomolecules · doi:10.3390/biom16030413 · Cited by 1
Al-Mashhadani, Z., Hummadi, Y. M. K. A. M., Al-khfajy, W. S., & Numan, N. A. M. (2026) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2026.178857 · Cited by 1
The Influence of Diet on Cancer Progression and Treatment
Barbeau, A. M., Kincaid, J. W. R., Hillis, A. L., Rashan, E. H., Zhang, Y., Oaks, G. E., & Heiden, M. G. V. (2026) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-062122-021518 · Cited by 3
Low Sugar Diet: A New Tool in War Against Tumorigenesis
Agarwal, N. R., & Maurya, N. (2018) · Proceedings of the Nature Research Society · doi:10.11605/j.pnrs.201802009 · Cited by 1
An update on the effectiveness of metformin alone and with chemotherapy drugs on tumor cells
Al-Zahrani, N. S., Ali, E. M. M., Kalantan, A. A., & Zamzami, M. A. (2020) · European Journal of Cell Science · doi:10.34154/2020-ejcs-0201-10-19/euraass · Cited by 1
Metabolism-Based Treatments to Counter Cancer
Seyfried, T. N., & Shelton, L. M. (2016) · Oxford University Press eBooks · doi:10.1093/med/9780190497996.003.0012 · Cited by 1
Noakes, T. D., Kalamian, M., Seyfried, T. N., Mukherjee, P., D’Agostino, D. P., Arismendi-Morillo, G., Chinopoulos, C., Tettenborn, M., & Winters, N. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821617-0.00012-7 · Cited by 1
Metformin in ovarian cancer therapy: A discussion
Guo, J., Ouyang, Y., Chen, X., Zhang, C., & Bunyamanop, V. (2016) · Cancer translational medicine · doi:10.4103/2395-3977.189306 · Cited by 1
Yang, W., Qin, Z., Bai, Y., Shi, W., Li, K., Song, L., Zhuang, A., & Ding, C. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4855548 · Cited by 1
Risk-Reducing (Chemopreventive) Agents in Breast Cancer Prevention
Gronich, N., & Rennert, G. (2016) · Springer eBooks · doi:10.1007/978-3-319-27135-4_8
Metformin as a potential therapy for malignant astrocytoma
Eagles, L. (2018) · Wolverhampton Intellectual Repository and E-Theses (University of Wolverhampton)
Examining the markers of vitamin C cytotoxicity in pancreatic ductal adenocarcinoma
Warren, C. (2019) · cIRcle (University of British Columbia) · doi:10.14288/1.0377751
Chen, J., Zhou, Y., Zhou, X., Li, J., Liu, F., & Zhou, Q. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10459
Cui, S., Chen, G., Yu, K. N., Cheng, C., & Han, W. (2020) · Journal of Physics D Applied Physics · doi:10.1088/1361-6463/ab938a
The metabolic determinants of the response to ketone bodies in SH-SY5Y neuroblastoma cells
Alherz, M. (2020) · Arrow@dit (Dublin Institute of Technology)
Complex Interplay of Genes Underlies Invasiveness in Fibrosarcoma Progression Model
Kripnerová, M., Parmar, H. S., Šáňa, J., Kopková, A., Radová, L., Sopper, S., Biernacki, K., Jedlička, J., Kohoutová, M., Kuncová, J., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10112297
Wen, K., Sung, P., Wu, A. T. H., Chou, P.-C., Lin, J.-H., Wang, P., Huang, C. F., Yeung, S. J., & Lee, M. (2020) · Research Square · doi:10.21203/rs.2.14622/v2
Metabolism-Based Treatments for Managing Cancer
Seyfried, T. N., Mukherjee, P., & Chinopoulos, C. (2022) · Oxford University Press eBooks · doi:10.1093/med/9780197501207.003.0014
Wen, K., Sung, P., Wu, A. T. H., Chou, P.-C., Lin, J.-H., Wang, P., Huang, C. F., Yeung, S. J., & Lee, M. (2019) · Research Square · doi:10.21203/rs.2.14622/v1
TSE, C. (2022) · Cronfa (Swansea University) · doi:10.23889/suthesis.60060
Anti-cancer Efficacy of Metformin: Recent Updates on Breast and Other Cancers
Kabir, M. I., Kumar, R., Bugata, L. S. P., & Raina, K. (2023) · Current Pharmacology Reports · doi:10.1007/s40495-023-00336-w
Research on the mechanism of ketogenic diet in radiotherapy of tumors
Wei, Y., Ning, X. I. A. O., RuiLan, M. O., HongMing, X. U., & Zhao, W. G. (2025) · Scientia Sinica Vitae · doi:10.1360/ssv-2024-0297
Nischarin agonist rilmenidine shows antimetastatic potential in pancreatic ductal adenocarcinomaPreprint
Živić, K., Pavlović, M., Ostojić, M., Galun, D. A., Pavić, A., Srdić‐Rajić, T., & Grahovac, J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.27.684770
Schmidt, K., Thatcher, A., Grobe, A. C., Broussard, P., Hicks, L. D., Gu, H., Ellies, L. G., Sears, D. D., Kalachev, L., & Kroll, E. (2024) · Figshare · doi:10.6084/m9.figshare.26085082
Liu, S., Li, S., Hsu, S.-L., Fries, F. N., Li, Z., Kundu, S., Seitz, B., Amini, M., Suiwal, S., Stachon, T., et al. (2026) · PLoS ONE · doi:10.1371/journal.pone.0340117
Precision nutrition in breast cancer: Towards patient- and tumour-informed dietary strategies
Crespo-Garcia, C., Taaffe, D. R., Peddle‐McIntyre, C. J., Jeffery, E., Campbell, J. P., Thomas, R., Galvao, D. A., & Newton, R. U. (2026) · Clinical Nutrition · doi:10.1016/j.clnu.2026.106670
Alomari, R. K., Alasmari, M. M., Alshaeri, H. K., Makai, A., Talib, W. H., & Hock, M. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1843223
Metformin Attenuates the High-Glucose Effect on MORG1 Expression in HEK293 Cells
Bondeva, T., Reuter, S., Westphal, A., Mrowka, R., & Wolf, G. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48090934
Metadata
- Authors
- Zhuang, Y., Chan, D. K., Haugrud, A. B., & Miskimins, W. K.
- Affiliations
- Sanford Research (US)
- University of South Dakota (US)
- Corresponding author
- Zhuang, Yongxian
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-09-25
- Volume
- 9
- Issue
- 9
- Pages
- e108444
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4177919
- OpenAlex
- W2011662441
- Cited by
- 149
- References
- 42
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 17 · 2023: 14 · 2022: 8 · 2021: 15 · 2020: 16 · 2019: 17 · 2018: 13 · 2017: 13 · 2016: 14 · 2015: 7
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA180033)
- National Institute of General Medical Sciences (5P20GM10358, P20GM103548)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- metformin, low glucose, tumor cell killing, breast cancer, ovarian cancer, glycolysis, AMPK, mTOR signaling, Akt phosphorylation, ATP depletion, fructose, galactose, ketogenic diet, tumor growth inhibition, metformin resistance
- MeSH terms
- Adenosine Triphosphate, Animals, Antineoplastic Agents, Blood Glucose, Cell Survival, Glucose, Glycolysis, Hypoglycemic Agents, Metformin, Neoplasms, Oxidative Phosphorylation, Phosphorylation, Drug Resistance, Neoplasm, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, Mice, AMP-Activated Protein Kinases, Diet, Ketogenic, TOR Serine-Threonine Kinases
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
