Cited by 176Metabolism, Diabetes, and CancerCancer, Hypoxia, and MetabolismPI3K/AKT/mTOR signaling in cancer

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Are Metformin Doses Used in Murine Cancer Models Clinically Relevant

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Chandel, Navdeep S., Avizonis, Dania, Reczek, Colleen R., Weinberg, Samuel E., Menz, Stephan, Neuhaus, Roland, Christian, Sven, Haegebarth, Andrea, Algire, Carolyn, Pollak, Michael·2016·Cell Metabolism

DOI 10.1016/j.cmet.2016.03.010

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Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth
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Metformin Action: Concentrations Matter
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Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth
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Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo
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Serine deprivation enhances antineoplastic activity of biguanides
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Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition
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“However, it is suggested that treatment regimens often used in vivo are more closely representative of the concentration of the drug that would accumulate in target tissues, and which activate AMPK [43].”
BackgroundMethodInfluential
Effect of metformin on biomarkers of placental- mediated disease: A systematic review and meta-analysis
Anness, A. R., Baldo, A., Webb, D. R., Khalil, A. A., Robinson, T. G., & Mousa, H. (2021) · Placenta · doi:10.1016/j.placenta.2021.02.021 · Cited by 16
Obesity-specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin
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Menéndez, J. A., Martı́n-Castillo, B., & Joven, J. (2016) · Oncotarget · doi:10.18632/oncotarget.10262 · Cited by 14
“(2016) NOD/SCID 1000 mg/kg/16 days 125 mg/kg/15 days 34 μM [2-126] 145 μM [66215]”
BackgroundInfluential
Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
Hébert, A., Parisotto, M., Rowell, M., Doré, A., Ruiz, A. F., Lefrançois, G., Kalegari, P., Ferbeyre, G., & Schmitzer, A. R. (2021) · Scientific Reports · doi:10.1038/s41598-021-87993-3 · Cited by 14
Metformin enhances the antitumor activity of oncolytic herpes simplex virus HF10 (canerpaturev) in a pancreatic cell cancer subcutaneous model
Abdelmoneim, M., Eissa, I. R., Aboalela, M. A., Naoe, Y., Matsumura, S., Sibal, P. A., Bustos‐Villalobos, I., Tanaka, M., Kodera, Y., & Kasuya, H. (2022) · Scientific Reports · doi:10.1038/s41598-022-25065-w · Cited by 14
Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinomaPreprint
Chung, K. M., Singh, J., Lawres, L., Dorans, K. J., Garcia, C. C., Burkhardt, D. B., Robbins, R., Bhutkar, A. J., CARDONE, R. L., Zhao, X., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/663583 · Cited by 14
“proglumide, leading to an average dose exposure of ~456, 436, and 26 mg/kg per day, respectively, in-line with prior studies using these agents (Chandel et al., 2016; Smith et al., 2014).”
Respiratory Complex I dysfunction in cancer: from a maze of cellular adaptive responses to potential therapeutic strategies
Sollazzo, M., Luise, M. D., Lemma, S., Bressi, L., Iorio, M. C., Miglietta, S., Milioni, S., Kurelac, I., Iommarini, L., Gasparre, G., et al. (2021) · FEBS Journal · doi:10.1111/febs.16218 · Cited by 13
Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib
Schlesser, C., Meul, T., Stathopoulos, G. T., & Meiners, S. (2022) · Biomolecules · doi:10.3390/biom12060756 · Cited by 15
“High concentrations of metformin might be obtained locally in tumor cells due to increased expression of metformin importing organic cation transporters (OCTs) by cancer cells resulting in the local accumulation of metformin even at low plasma concentrations [34,35].”
Background
Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations
Hemalatha, A., Li, Z., Tai, K., Gonzalez, D. G., Lathrop, E., Gil, D., Matte-Martone, C., Ganesan, S., Yun, S., Gonzalez, L. E., et al. (2025) · Nature Cell Biology · doi:10.1038/s41556-024-01574-w · Cited by 15
“…that its systemic effects are likely not limited to mild inhibition of mitochondrial activity; however, as the preponderance of evidence suggests a role for it to reduce mitochondrial oxidation 47 within a physiologically relevant range 48 , we selected it for further phenotype and flux assessment.”
Effect of Metformin on Sertoli Cell Fatty Acid Metabolism and Blood–Testis Barrier Formation
Rindone, G. M., Dasso, M. E., Centola, C. L., Sobarzo, C., Galardo, M. N., Meroni, S. B., & Riera, M. F. (2024) · Biology · doi:10.3390/biology13050330 · Cited by 12
Biguanides antithetically regulate tumor properties by the dose-dependent mitochondrial reprogramming-driven c-Src pathway
Park, J. H., Jung, K. H., Jia, D., Yang, S., Attri, K. S., Ahn, S., Murthy, D., Samanta, T., Dutta, D., Ghidey, M., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.101941 · Cited by 13
“18,21 Thus, it is imperative to ﬁnd suitable therapeutic combinations to counter the limited effect of biguanides due to poor bioavailability.”
Metformin and oxyphotodynamic therapy as a novel treatment approach for triple-negative breast cancer
Pei, X., Wang, X., Xian, J., Mi, J., Gao, J., Li, X., Li, Z., Yang, M., Bi, L., Yan, Y., et al. (2020) · Annals of Translational Medicine · doi:10.21037/atm-20-5704 · Cited by 12
Effect of a High-Fat Diet and Metformin on Placental mTOR Signaling in Mice
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The Anti-Tumor Effect of Lactococcus lactis Bacteria-Secreting Human Soluble TRAIL Can Be Enhanced by Metformin Both In Vitro and In Vivo in a Mouse Model of Human Colorectal Cancer
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Postnatal metformin treatment alters rat Sertoli cell proliferation and daily sperm production
Rindone, G. M., Gorga, A., Pellizzari, E. H., Camberos, M. D. C., Galardo, M. N., Ros, V. G. D., Buffone, M. G., Meroni, S. B., & Riera, M. F. (2020) · Andrology · doi:10.1111/andr.12957 · Cited by 10
Myeloid AMPK signaling restricts fibrosis but is not required for metformin improvements during CDAHFD-induced NASH in mice
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“Given that lower dosing of metformin (50 mpk) failed to activate AMPK signaling, we focused our characterization of NASH measures on the group receiving the higher, yet still physiological (250 mpk) dose of metformin (38, 39).”
Background
Metformin: A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation
Yang, T., Yuan, J., Peng, Y., Pang, J., Qiu, Z. D., Chen, S., Huang, Y., Jiang, Z., Fan, Y., Liu, J., et al. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.08.012 · Cited by 10
“It was determined that the plasma concentration of Met by administration of a dose of 250 mg/kg Met in rodents was achieved in routine diabetes treatment [39,40].”
Biguanide MC001, a Dual Inhibitor of OXPHOS and Glycolysis, Shows Enhanced Antitumor Activity Without Increasing Lactate Production
Fu, J., Liu, S., Hu, M., Liao, X., Wang, X., Xu, Z., Li, Q., & Quan, J. (2022) · ChemMedChem · doi:10.1002/cmdc.202100674 · Cited by 9
The antidiabetic drug metformin acts on the bone microenvironment to promote myeloma cell adhesion to preosteoblasts and increase myeloma tumour burden in vivo
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“ically relevant [45,46] and was well tolerated.”
Comparison of the effects of metformin on MDA-MB-231 breast cancer cells in a monolayer culture and in tumor spheroids as a function of nutrient concentrations
Bizjak, M., Malavašič, P., Pirkmajer, S., & Pavlin, M. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.05.090 · Cited by 8
Hacking Cancer Metabolism
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“The precise mechanism of action of metformin, as well as clinically relevant concentrations, remains the subject of intense investigations (see, for example, He and Wondisford, 2015; Chandel et al., 2016; Dowling et al., 2016).”
Background
Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts
Catalano, L., Aminzadeh-Gohari, S., Weber, D. D., Poupardin, R., Stefan, V. E., Smiles, W. J., Tevini, J., Feichtinger, R. G., Derdak, S. V., Bilban, M., et al. (2023) · Metabolites · doi:10.3390/metabo13080910 · Cited by 7
“It is noteworthy that in the present study as well as in previous studies [26,57], the concentration of MET required to reduce cell respiration in vitro (millimolar) is a magnitude of order higher than the plasma levels of MET detected in vivo (micromolar) [58].”
Background
CURRENTLY TRENDING AND FUTURISTIC BIOLOGICAL MODALITIES IN THE MANAGEMENT OF DIFFERENT TYPES OF DIABETES: A COMPREHENSIVE REVIEW
ALi, A., Manzoor, U., Ali, S. L., Marsool, M. D. M., Parida, P. K., Marsool, A. D. M., & Swathi, N. L. (2023) · doi:10.53555/jptcp.v30i18.3467 · Cited by 7
Low carbohydrate diet prevents Mcl-1-mediated resistance to BH3-mimetics
Rubio‐Patiño, C., Bossowski, J. P., Villa, E., Mondragón, L., Zunino, B., Proïcs, E., Chiche, J., Bost, F., Verhoeyen, E., & Ricci, J. (2016) · Oncotarget · doi:10.18632/oncotarget.12309 · Cited by 7
“However the exact mechanism on how those compounds are working at the molecular level and what are the efficient doses required in vivo to mimic the effects of CR in patients is still highly debated in the field [33].”
Background
Metformin suppresses atherosclerosis by dampening extramedullary myelopoiesis
Lee, M. K., Cooney, O. D., Zhu, Y., Zhang, Y., Lin, X., Onda, D.-A., Galić, S., Kemp, B. E., Murphy, A. J., & Loh, K. (2025) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00056.2025 · Cited by 7
Offset of apparent hyperpolarized 13C lactate flux by the use of adjuvant metformin in ionizing radiation therapy in vivo
Choi, Y., Lee, J., Lee, H., Song, J. E., Kim, D., & Song, H. (2021) · NMR in Biomedicine · doi:10.1002/nbm.4561 · Cited by 5
“Most in vitro studies reported that an anticancer effect was observed in a dose range of 1-50 mM of effective metformin concentration for cancer therapy, so it seems debatable whether the dose used in the clinical trial had a therapeutic effect.(40) In this in vivo study, 300 mg/kg/d, a dose 10 tomes higher than the h…”
Background
Disparate Effects of Metformin on Mycobacterium tuberculosis Infection in Diabetic and Nondiabetic Mice
Sathkumara, H. D., Hansen, K., Miranda‐Hernandez, S., Govan, B., Rush, C. M., Henning, L., Ketheesan, N., & Kupz, A. (2020) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01422-20 · Cited by 5
“25 mg/ml in drinking water delivers 250 mg/kg to mice (12).”
Background
Metformin
Maniar, K., Singh, V., Kumar, D., Moideen, A., Bhattacharyya, R., & Banerjee, D. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-815249-2.00042-7 · 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
Modulation of Altered Immune Parameters IL-2 and TNF-α in Diabetic Animal Models: A Therapeutic Insinuation of Metformin Beyond Diabetes
Ali, A., Shaheen, S., Imran, M., Memon, Z., Zahid, N., Ahmad, F., & Hameed, A. (2023) · Cureus · doi:10.7759/cureus.45216 · Cited by 4
“5 mL normal saline to groups 1 and 4, 50 mg/kg metformin to groups 2 and 5, and 80 mg/kg metformin to groups 3 and 6 [13].”
Method
Combination of Metformin and Laser against Head and Neck Cancer Cells In Vitro
Ebrahimi, G., Abdolahinia, E. D., Pouya, P., Bolhasani, A. J., Sharifi, S., & Dizaj, S. M. (2023) · The Open Dentistry Journal · doi:10.2174/0118742106276363231123071425 · Cited by 4
Salsalate and/or metformin therapy confer beneficial metabolic effects in olanzapine treated female mice
Shamshoum, H., Medak, K. D., McKie, G. L., Jeromson, S., Hahn, M., & Wright, D. C. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115671 · Cited by 4
Targeted Multiplex Gene Expression Profiling to Measure High-Fat Diet and Metformin Effects on Fetal Gene Expression in a Mouse Model
Vora, N. L., Grace, M. R., Smeester, L., Dotters-Katz, S. K., Fry, R. C., Bae-Jump, V. L., & Boggess, K. (2018) · Reproductive Sciences · doi:10.1177/1933719118786453 · Cited by 4
An anti-neoplastic tale of metformin through its transport
Bhati, F. K., & Bhat, M. K. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.123060 · Cited by 3
Metformin and rosiglitazone affect motility, lipid peroxidation and mitochondrial activity of thawed equine spermatozoa
Úsuga, A., Vergara, A. K., Tobón, M. C., Vargas, S., Rojano, B. A., & Betancur, G. R. (2025) · Journal of Equine Veterinary Science · doi:10.1016/j.jevs.2025.105570 · Cited by 3
A Highly Sensitive UPLC-MS/MS Method for the Quantification of the Organic Cation Transporters’ Mediated Metformin Uptake and Its Inhibition in Cells
Bajraktari‐Sylejmani, G., Bay, C., Gebauer, L., Burhenne, J., Weiß, J., & Sauter, M. (2024) · Molecules · doi:10.3390/molecules29215162 · Cited by 3
Xihuang pill triggers dual gasdermin-mediated pyroptosis in glioma-associated endothelial cells via AMPK inhibition
Xiao, Z., Feng, J., Su, Z., Chen, J., Wu, X., Gao, H., Li, H., Zou, Y., Yin, Z., & Wang, Q. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.120978 · Cited by 2
A New Combination Therapy Utilizing Mitochondria-Targeting Small-Molecule Ligands and Clinical Inhibitors against Melanoma
Chan, K., Zheng, B., Zheng, Y., Zheng, W.-D., Zeng, Y.-X., Long, W. S., Zhang, S., Hou, N., Yuan, W., & Wong, W. (2026) · ACS Chemical Biology · doi:10.1021/acschembio.5c00562 · Cited by 2
Metformin suppresses β-cell apoptosis under ER stress by inhibiting protein translation
Inoue, R., Tajima, K., Okuyama, T., Sakai, C., Kanno, T., Zou, M., Kyohara, M., Matsunaga, K., Tsuno, T., Luo, J., et al. (2026) · Metabolism · doi:10.1016/j.metabol.2026.156607 · Cited by 2
Metformin
Campbell, J. M. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823679-6.00013-8 · Cited by 2
Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease
Oto, Ö. A., Atwood, D. J., Chaudhary, A., He, Z., Li, A. S., Wempe, M. F., & Edelstein, C. L. (2023) · Physiological Reports · doi:10.14814/phy2.15776 · Cited by 2
Targeted inhibition of JMJD2C/MALAT1 axis compensates for the deficiency of metformin in reversing ovarian cancer platinum resistance
Li, L., Zhang, J., Li, H., Qin, L., Wu, H., Li, Z., Cai, L., Chen, D., Yang, J., Chen, Y., et al. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123663 · Cited by 2
Metabolic and Metabolomic Effects of Metformin in Murine Model of Pulmonary Adenoma Formation
Elton, A. C., Cedarstrom, V., Quraishi, A., Wuertz, B. R. K., Murray, K. J., Markowski, T. W., Seabloom, D. E., & Ondrey, F. G. (2023) · Nutrition and Cancer · doi:10.1080/01635581.2023.2165692 · Cited by 2
Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycemic controlPreprint
Sebo, Z. L., Chakrabarty, R. P., Grant, R. A., D’Alessandro, K. B., Koss, A. R., Blum, J. L. E., Davidson, S. M., Reczek, C. R., & Chandel, N. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.02.678294 · Cited by 2
“While the latter approach more closely resembles clinical practice, it still exposes animals to a variable, low-level of metformin rather than the characteristic “peak-and-trough” exposure of patients 7,98,99 .”
Reductive death is averted by a conserved de novo lipogenic switch
Ahsan, F. M., Rotti, J. F., Yerevanian, A. I., Emans, S. W., Stuhr, N. L., Aceves-Salvador, J. A., Wang, W., Baker, D. J., Pouli, D., Skinner, O. S., et al. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.05.011 · Cited by 4
High dose targeted delivery on cancer sites and the importance of short-chain fatty acids for metformin's action: Two crucial aspects of the wonder drug
Maniar, K., Singh, V., Chakrabarti, A., Bhattacharyya, R., & Banerjee, D. (2018) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2018.05.013 · Cited by 1
Translational and HIF11-Dependent Metabolic Reprograming Underpin Oncometabolome Plasticity and Synergy Between Oncogenic Kinase Inhibitors and BiguanidesPreprint
Hulea, L., Gravel, S., Morita, M., Cargnello, M., Uchenunu, O., Im, Y. K., McLaughlan, S., Larsson, O. S., Ohh, M., Ferreira, T., et al. (2018) · SSRN Electronic Journal · doi:10.2139/ssrn.3155732 · Cited by 1
Computational Development of mushroom-6-Glucan/Paclitaxel as a Synergistic Complementary Medicine for Breast Cancer TherapyPreprint
El‐Deeb, N. M., Ibrahim, O. M., KAMEL, A. M., Gomaa, A., & Kenawy, A. M. A. (2024) · Research Square · doi:10.21203/rs.3.rs-4784256/v1 · Cited by 1
Metformine et cancer : repositionnement ou non ? … La question se pose
Bost, F., & Tanti, J. (2021) · Médecine des Maladies Métaboliques · doi:10.1016/j.mmm.2021.04.008 · Cited by 2
Carbohydrate metabolism in prostate cancer
Koltai, T., Reshkin, S. J., Baltazar, F., & Fliegel, L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-90528-2.00015-1
Análisis molecular del tipo de muerte celular inducido por la terapia coadyudante: metformina y el oxamato de sodio como inhibidores de la vía mTOR y la glucólisis en un modelo celular triple negativo de cáncer de mama
García-Castillo, V. (2018) · doi:10.24275/uami.2v23vt52f
Metformin
Campbell, J. M. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.62141-4 · Cited by 3
The effect of metformin on viability and mitochondrial status of tumor and non-tumor cell line
Ljubičić, J., Pešić, A., & Isaković, A. (2022) · Medicinski podmladak · doi:10.5937/mp73-37593
Potential Role of Metformin in Central Nervous System with a Focus on Its Mechanism of Actions
Bora, K., & James, R. (2023) · International Journal For Multidisciplinary Research · doi:10.36948/ijfmr.2023.v05i04.4279 · Cited by 1
Metformin Reduces Tumor Growth in a Murine Flank Schwannoma Model
Manickavel, S., Hartman, Y. E., Burns, A. C., Gonzalez, M. L., Warram, J. M., Walsh, E. M., Hunter, J. B., & Killeen, D. E. (2023) · Otology & Neurotology · doi:10.1097/mao.0000000000004001
Computational development of mushroom-6-glucan/paclitaxel as a synergistic complementary medicine for breast cancer therapy
El‐Deeb, N. M., Ibrahim, O. M., Kamel, A., Gomaa, A. I., & Kenawy, A. M. A. (2025) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-025-04772-7 · Cited by 1
“…cancer cells, mitochondria plays an important role in controlling multiple signaling pathways, including the initiation of apoptosis by releasing Cytochrome C, responsible for the release of bioactive ROS, and the production of metabolites such as acetyl-CoA for regulating protein acetylation [59].”
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Authors: Chandel, N. S., Avizonis, D., Reczek, C. R., Weinberg, S. E., Menz, S., Neuhaus, R., Christian, S., Haegebarth, A., Algire, C., & Pollak, M.
Affiliations: Northwestern University (US)
Bayer (Germany) (DE)
Corresponding author: Chandel, Navdeep S.
ORCID: Chandel, Navdeep S.
Reczek, Colleen R.
Weinberg, Samuel E.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2016-04
Volume: 23
Issue: 4
Pages: 569-570
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2016.03.010
OpenAlex: W2336052913
Cited by: 176
References: 10
Citations by year: 2026: 18 · 2025: 9 · 2024: 9 · 2023: 17 · 2022: 15 · 2021: 22 · 2020: 19 · 2019: 16 · 2018: 20 · 2017: 20 · 2016: 11
FWCI: 9.54
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 376 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: Cancer Research Institute
McGill University
Terry Fox Research Institute
National Institutes of Health
National Institute on Aging (P01AG049665)
National Heart, Lung, and Blood Institute (R01HL122062, T32HL076139)
National Cancer Institute (R01CA123067, R01 CA12306708)
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, AMPK, hepatic gluconeogenesis, AMPK-independent mechanism, oxidative phosphorylation inhibition, energy stress, tumor models, drug dosing, antidiabetic drugs
MeSH terms: Animals, Antineoplastic Agents, Disease Models, Animal, Dose-Response Relationship, Drug, Humans, Hypoglycemic Agents, Metformin, Mice, Inbred C57BL, Neoplasms, Mice

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