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Are Metformin Doses Used in Murine Cancer Models Clinically Relevant
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“Collectively, these data suggest that expression levels of the uptake and extrusion transporters are not necessarily the limiting factors determining the anti-proliferative effects of metformin and that genetically determined variations in signaling pathways are variably important as are nutrient levels in the tumor microenvironment (249, 254).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [249]
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“Chandel et al. argue that higher concentrations of metformin are necessary in in vitro cell culture protocols because the abundance of growth factors and nutrients, such as glucose, reduces the sensitivity to the inhibitory effects of metformin thus reflecting the importance of glucose and the Warburg effect for cancer cell growth as well as the importance of glycemic control in diabetes (249).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [249]
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Metformin Action: Concentrations Matter
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Cellular and Molecular Mechanisms of Metformin Action
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“…metformin in rodents with ad libitum access to metformin-treated drinking water results in inconsistent plasma metformin concentrations, possibly due to variability in drinking and/or absorption from the gut, with studies reporting plasma concentrations ranging from 5 µ M to 180 µ M (48, 52, 53).”
BackgroundMitochondrial Metabolism as a Target for Cancer Therapy
Vasan, K., Werner, M., & Chandel, N. S. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.019 · Cited by 762
Metformin: update on mechanisms of action and repurposing potential
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Modulating the therapeutic response of tumours to dietary serine and glycine starvation
Maddocks, O. D. K., Athineos, D., Cheung, E. C., Lee, P., Zhang, T., van den Broek, N. J. F., Mackay, G. M., Labuschagne, C. F., Gay, D., Kruiswijk, F., et al. (2017) · Nature · doi:10.1038/nature22056 · Cited by 603
Hallmarks of cancer stem cell metabolism
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“…Journal of Cancer (2016) 114, 1305–1312 | doi: 10.1038/bjc.2016.152 www.bjcancer.com | DOI:10.1038/bjc.2016.152 1305 Second, cancer heterogeneity also exists within each of these subclones, despite their identical genetic background, via the acquisition of stemness features in a subset of cells.”
BackgroundInfluentialBenjamin, D., Robay, D., Hindupur, S. K., Pohlmann, J., Colombi, M., El‐Shemerly, M., Maira, S.-M., Moroni, C., Lane, H. A., & Hall, M. N. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.043 · Cited by 414
“The potential of metformin as an anti-cancer therapy may be hampered by inadequate dosing in clinical settings (Chandel et al., 2016; Dowling et al., 2016; Kordes et al., 2015).”
BackgroundHowell, J. J., Hellberg, K., Turner, M., Talbott, G., Kolar, M. J., Ross, D. S., Hoxhaj, G., Saghatelian, A., Shaw, R. J., & Manning, B. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.12.009 · Cited by 408
“…it has been established that cells grown in culture, under supraphysiological levels of nutrients and oxygen, requiremuch higher concentrations ofmetformin to elicit responses similar to those seen in vivo (He and Wondisford, 2015; Dowling et al., 2016; Memmott et al., 2010; Chandel et al., 2016).”
Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism
Lee, J., Yesilkanal, A. E., Wynne, J. P., Frankenberger, C. A., Liu, J., Yan, J., Elbaz, M., Rabe, D. C., Rustandy, F. D., Tiwari, P., et al. (2019) · Nature · doi:10.1038/s41586-019-1005-x · Cited by 381
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Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.718942 · Cited by 278
Metformin: Is it a drug for all reasons and diseases?
Triggle, C. R., Mohammed, I., Bshesh, K., Marei, I., Ye, K., Ding, H., MacDonald, R. S., Hollenberg, M. D., & Hill, M. A. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155223 · Cited by 300
The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
Ashton, T. M., Fokas, E., Kunz‐Schughart, L. A., Folkes, L. K., Anbalagan, S., Hüther, M., Kelly, M., Pirovano, G., Buffa, F. M., Hammond, E. M., et al. (2016) · Nature Communications · doi:10.1038/ncomms12308 · Cited by 249
Andrzejewski, S., Klimčáková, E., Johnson, R. M., Tabariès, S., Annis, M. G., McGuirk, S., Northey, J. J., Chénard, V., Sriram, U., Papadopoli, D. J., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.006 · Cited by 254
Gallagher, E. J., & LeRoith, D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-020-0295-5 · Cited by 241
Metformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers
Liu, X., Romero, I. L., Litchfield, L. M., Lengyel, E. R., & Locasale, J. W. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.005 · Cited by 229
“The mechanism of its anti-cancer properties has also been controversial, and it remains poorly understood whether metformin acts by altering host metabolism or by direct action on tumor cells (Chandel et al., 2016; Dowling et al., 2016).”
BackgroundEffects of Metformin on the Gut Microbiota in Obesity and Type 2 Diabetes Mellitus
Zhang, Q., & Hu, N. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s286430 · Cited by 188
“After oral administration, the half-life of metformin is approximately 3–4 hours, which is inconsistent with the duration of its hypoglycemic effect.(5,6) In addition, intravenous administration of metformin could not improve blood glucose.”
BackgroundEndocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma
Chung, K. M., Singh, J., Lawres, L., Dorans, K. J., Garcia, C., Burkhardt, D. B., Robbins, R., Bhutkar, A., Cardone, R., Zhao, X., et al. (2020) · Cell · doi:10.1016/j.cell.2020.03.062 · Cited by 150
Koh, A., Mannerås-Holm, L., Yunn, N.-O., Nilsson, P. M., Ryu, S. H., Molinaro, A., Perkins, R., Smith, J. G., & Bäckhed, F. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.07.012 · Cited by 165
Metformin targets mitochondrial electron transport to reduce air-pollution-induced thrombosis
Soberanes, S., Misharin, A. V., Jairaman, A., Morales-Nebreda, L., McQuattie-Pimentel, A. C., Cho, T., Hamanaka, R. B., Meliton, A. Y., Reyfman, P. A., Walter, J. M., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.019 · Cited by 131
“Limitations of Study First, the dose of metformin we used in mice achieves plasma/ tissue concentrations similar to those measured in humans on standard treatment doses for type 2 diabetes (Chandel et al., 2016), but it is not known if metformin is effectively taken up by human alveolar macrophages in vivo.”
Sirtuin-1 Activation Controls Tumor Growth by Impeding Th17 Differentiation via STAT3 Deacetylation
Limagne, E., Thibaudin, M., Euvrard, R., Berger, H., Châlons, P., Végan, F., Humblin, É., Boidot, R., Rébé, C., Dérangère, V., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.004 · Cited by 143
“A lower dosage of metformin of 10 mM equivalent to the dosage classically found in mouse serum (Chandel et al., 2016) also impedes the in vitro Th17 differentiation (Figure S1B).”
BackgroundLord, S., Cheng, W., Liu, D., Gaude, E., Haider, S. A., Metcalf, T., Patel, N., Teoh, E., Gleeson, F. V., Bradley, K. M., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.08.021 · Cited by 133
“Previously published pre-clinical data suggested that expression of the organic cation transporter, OCT1 (encoded by gene SLC22A1), is required for tumor uptake of metformin and metabolic response (Chandel et al., 2016; Dowling et al., 2016).”
BackgroundMetformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice
Landry, D. A., Yakubovich, E., Cook, D. P., Fasih, S., Upham, J., & Vanderhyden, B. C. (2022) · Science Advances · doi:10.1126/sciadv.abq1475 · Cited by 138
“We selected this drug concentration in the drinking water as it achieves plasma concentrations similar to the doses taken by patients with T2D (i.e., 5 to 10 M metformin) ( 78 ).”
MethodMetformin and berberine, two versatile drugs in treatment of common metabolic diseases
Wang, H., Zhu, C., Ying, Y., Luo, L., Huang, D., & Luo, Z. (2017) · Oncotarget · doi:10.18632/oncotarget.20807 · Cited by 124
Van Nostrand, J. L., Hellberg, K., Luo, E.-C., Van Nostrand, E. L., Dayn, A., Yu, J., Shokhirev, M. N., Dayn, Y., Yeo, G. W., & Shaw, R. J. (2020) · Genes & Development · doi:10.1101/gad.339895.120 · Cited by 111
“…dosage used; volumetric rodent:human comparisons and the potential for cell culture artifacts from an absence of physiological clearance from hepatocytes in the intact organism have led to a range of discrepancies and debates among researchers (He and Wondisford 2015; Chandel et al. 2016).”
BackgroundThe effects of metformin on gut microbiota and the immune system as research frontiers
Pollak, M. (2017) · Diabetologia · doi:10.1007/s00125-017-4352-x · Cited by 98
“gut lumen can be over 100-fold that present in serum, implying that mechanisms of action requiring high millimolar concentrations that are not achieved systemically [28] may be relevant to”
BackgroundSelf-citationMarrone, K. A., Zhou, X. C., Forde, P. M., Purtell, M., Brahmer, J. R., Hann, C. L., Kelly, R. J., Coleman, B., Gabrielson, E. W., Rosner, G. L., et al. (2018) · The Oncologist · doi:10.1634/theoncologist.2017-0465 · Cited by 99
Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells
Naguib, A., Mathew, G., Reczek, C. R., Watrud, K. E., Ambrico, A. J., Herzka, T. M., Casanova‐Salas, I., Lee, M. F., El-Amine, N., Zheng, W., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.032 · Cited by 94
Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux
Tai, S., Sun, J., Zhou, Y., Zhu, Z., He, Y., Chen, M., Yang, H., Xiao, Y., Tu, T., Tang, L., et al. (2021) · Journal of Advanced Research · doi:10.1016/j.jare.2021.12.009 · Cited by 99
“Male C57BL/6 mice were divided into three groups: 10 months (control) group, 20 months (old) group, and old + metformin group to receive water or 3 g/l metformin in water (a dose proved to elicit clinically relevant serum metformin concentration) [23] for 10 months.”
MethodHulea, L., Gravel, S., Morita, M., Cargnello, M., Uchenunu, O., Im, Y. K., Lehuédé, C., Ma, E. H., Leibovitch, M., McLaughlan, S., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.001 · Cited by 91
“This is explained by serine being a centralnodefor the biosynthesisofmanymetabolites (e.g.,nucleotides, folate metabolism), amino acid transport, and redox homeostasis (DeBerardinis and Chandel, 2016).”
BackgroundInfluentialHu, L., Zeng, Z., Xia, Q., Liu, Z., Feng, X., Chen, J., Huang, M., Chen, L., Fang, Z., Liu, Q., et al. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116966 · Cited by 87
Leonhard, W. N., Song, X., Kanhai, A. A., Iliuta, I.-A., Božović, A., Steinberg, G. R., Peters, D. J. M., & Pei, Y. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.08.041 · Cited by 86
“Given the concerns that therapeutic AMPK activation in the kidney might require a higher dose of oral metformin than can be achieved clinically [26,27,29,30], we tested metformin-based combination therapies for their additive (i.”
Syrosingopine sensitizes cancer cells to killing by metformin
Benjamin, D., Colombi, M., Hindupur, S. K., Betz, C., Lane, H. A., El‐Shemerly, M., Lu, M., Quagliata, L., Terracciano, L., Moes, S., et al. (2016) · Science Advances · doi:10.1126/sciadv.1601756 · Cited by 89
“The in vivo efficacy of these low doses for cancer treatment has thus been a matter of debate (19, 44, 45).”
BackgroundLac-Phe mediates the effects of metformin on food intake and body weight
Xiao, S., Li, V. L., Lyu, X., Chen, X., Wei, W., Abbasi, F., Knowles, J. W., Tung, A. S.-H., Deng, S., Tiwari, G., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-00999-9 · Cited by 85
Metformin directly targets the H3K27me3 demethylase KDM6A/UTX
Cuyàs, E., Verdura, S., Llorach-Parés, L., Fernández‐Arroyo, S., Luciano‐Mateo, F., Cabré, N., Štursa, J., Werner, L., Martı́n-Castillo, B., Viollet, B., et al. (2018) · Aging Cell · doi:10.1111/acel.12772 · Cited by 80
“, a route of administration that is equivalent to 1,200 mg/day metformin for a 60 kg individual (Reagan-Shaw, Nihal & Ahmad, 2008) and yields plasma concentrations in the low micromolar range (Chandel et al., 2016; Dowling et al., 2016; Memmott et al., 2010; Menendez, Martin-Castillo & Joven, 2016), metformin treatmen…”
BackgroundMetformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities
Pulito, C., Mori, F., Sacconi, A., Goeman, F., Ferraiuolo, M. A., Pasanisi, P., Campagnoli, C., Berrino, F., Fanciulli, M., Ford, R. J., et al. (2017) · Cell Discovery · doi:10.1038/celldisc.2017.22 · Cited by 75
Haikala, H. M., Anttila, J. M., Marques, E., Raatikainen, T., Ilander, M. M., Hakanen, H. H. E., Ala-Hongisto, H., Savelius, M., Balboa, D., von Eyß, B., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08541-2 · Cited by 73
Xie, J., Ye, J., Cai, Z., Luo, Y., Zhu, X., Deng, Y., Feng, Y., Liang, Y., Liu, R., Han, Z., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-2852 · Cited by 75
“Although the metformin concentration we used in our in vitro experiments was at mmol/L level, which was much higher than those used in vivo, but the concentrations we used are similar to other studies (42, 43).”
BackgroundMethodMetformin as a Therapeutic Target in Endometrial Cancers
Lee, T. Y., Martinez‐Outschoorn, U., Schilder, R. J., Kim, C. H., Richard, S. D., Rosenblum, N. G., & Johnson, J. M. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00341 · Cited by 76
“Several studies have now shown that higher doses ofmetformin are required inmice to have antitumor effects than those administered in clinical trials and this may be a reflection of pharmacokinetic differences between rodents and humans (86, 105, 106).”
BackgroundRico, M., Baglioni, M. V., Bondarenko, M., Laluce, N. C., Rozados, V. R., André, N., Carré, M., Scharovsky, O. G., & Menacho-Márquez, M. (2016) · Oncotarget · doi:10.18632/oncotarget.13760 · Cited by 73
“To date, there is not clear correlation between in vitro Met effective antitumoral doses and the concentration of this drug observed in patient’s plasma [35, 36].”
BackgroundMetformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
Postler, T. S., Peng, V., Bhatt, D. M., & Ghosh, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-97441-x · Cited by 73
A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer
Khan, A., & Frigo, D. E. (2017) · Nature Reviews Urology · doi:10.1038/nrurol.2016.272 · Cited by 74
Vara‐Ciruelos, D., Dandapani, M., Russell, F. M., Grzes, K. M., Atrih, A., Foretz, M., Viollet, B., Lamont, D. J., Cantrell, D. A., & Hardie, D. G. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.067 · Cited by 76
The Mechanism of Action of Biguanides: New Answers to a Complex Question
Magno, L. D., Pastena, F. D., Bordone, R., Coni, S., & Canettieri, G. (2022) · Cancers · doi:10.3390/cancers14133220 · Cited by 81
“35 g/Kg Oral 200–1500 μM 3 weeks Mouse [22]”
BackgroundInfluentialMetformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial
Curry, J., Johnson, J. M., Tassone, P. T., Domingo‐Vidal, M., Menezes, D. W., Sprandio, J. D., Mollaee, M., Cotzia, P., Birbe, R., Lin, Z., et al. (2017) · The Laryngoscope · doi:10.1002/lary.26489 · Cited by 72
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“05% FA in water, 100% MPA-0% MPA gradient run Flow rate: N/A Mouse Serum, Liver, tumor dose study No [55]”
BackgroundNew Insights Into the Anti-Diabetic Actions of Metformin: From the Liver to the Gut
Wu, T., Horowitz, M., & Rayner, C. K. (2017) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2017.1273769 · Cited by 64
“However, the doses of metformin commonly employed in murine models (~250–350 mg/kg) seem to result in comparable plasma metformin concentrations to those of patients with type 2 diabetes receiving a standard oral dose of metformin [31], thereby supporting the potential clinical relevance of these studies.”
BackgroundInhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome
Wang, P., Li, J., Walcott, F. L., Kang, J., Starost, M. F., Talagala, S. L., Zhuang, J., Park, J., Huffstutler, R. D., Bryla, C., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci88668 · Cited by 65
Metformin-induced reductions in tumor growth involves modulation of the gut microbiome
Broadfield, L. A., Saigal, A., Szamosi, J. C., Hammill, J. A., Bezverbnaya, K., Wang, D., Gautam, J., Tsakiridis, E. E., Pastena, F. D., McNicol, J. D., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101498 · Cited by 64
Metformin targets mitochondrial complex I to lower blood glucose levels
Reczek, C. R., Chakrabarty, R. P., D’Alessandro, K. B., Sebo, Z. L., Grant, R. A., Gao, P., Budinger, G. R. S., & Chandel, N. S. (2024) · Science Advances · doi:10.1126/sciadv.ads5466 · Cited by 67
Totten, S. P., Im, Y. K., Cañedo, E. C., Najyb, O., Nguyen, A., Hébert, S., Ahn, R., Lewis, K., Lebeau, B., Selva, R. L., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23396-2 · Cited by 63
Metformin Affects Cortical Bone Mass and Marrow Adiposity in Diet-Induced Obesity in Male Mice
Bornstein, S., Moschetta, M., Kawano, Y., Sacco, A., Huynh, D., Brooks, D. J., Manier, S., Fairfield, H. E., Falank, C. R., Roccaro, A. M., et al. (2017) · Endocrinology · doi:10.1210/en.2017-00299 · Cited by 63
Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance
Slater, R. E., Strom, J. G., Methawasin, M., Liss, M., Gotthardt, M., Sweitzer, N. K., & Granzier, H. L. M. (2018) · The Journal of General Physiology · doi:10.1085/jgp.201812259 · Cited by 60
“, 2016; Sun and Yang, 2017) and aligns with levels achieved in routine diabetes treatment (Chandel et al., 2016).”
BackgroundSeneviratne, A. N., Cave, L., Hyde, G. D., Moestrup, S. K., Carling, D., Mason, J. C., Haskard, D. O., & Boyle, J. J. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa171 · Cited by 57
“Metformin was administered under published conditions at an oral dose that approximated clinical concentrations in humans.(28) Metformin was administered in drinking water (1 mg mL) with saccharin (1 mg mL) to disguise its taste, or matched saccharin-only controls in drinking water (1 mg mL).”
MethodHardeman, K. N., Peng, C., Paudel, B. B., Meyer, C. T., Luong, T., Tyson, D. R., Young, J. D., Quaranta, V., & Fessel, J. P. (2017) · Scientific Reports · doi:10.1038/srep42604 · Cited by 52
Xie, W., Wang, L., Sheng, H., Qiu, J. Y., Zhang, D., Zhang, L., Yang, F., Tang, D., & Zhang, K. (2017) · Medical Science Monitor · doi:10.12659/msm.898710 · Cited by 50
Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria
Guo, Z., Sevrioukova, I. F., Denisov, I. G., Zhang, X., Chiu, T.-L., Thomas, D. G., Hanse, E. A., Cuellar, R. A. D., Grinkova, Y. V., Langenfeld, V. W., et al. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.009 · Cited by 54
The Impact of Metformin on Tumor-Infiltrated Immune Cells: Preclinical and Clinical Studies
Abdelmoneim, M., Aboalela, M. A., Naoe, Y., Matsumura, S., Eissa, I. R., Bustos‐Villalobos, I., Sibal, P. A., Takido, Y., Kodera, Y., & Kasuya, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713353 · Cited by 49
“In the tumor tissue from mouse models, oral metformin treatment led to a low concentration (micromolar range) [70].”
BackgroundTargeting liver stage malaria with metformin
Vera, I., Ruivo, M. T. G., Rocha, L. F. L., Marques, S., Bhatia, S. N., Mota, M. M., & Mâncio-Silva, L. (2019) · JCI Insight · doi:10.1172/jci.insight.127441 · Cited by 49
“Metformin treatment over a week resulted in plasma concentrations of 3–7 μM, which is comparable to levels previously reported in mice (21) and diabetic patients under treatment (26).”
Metformin and ovarian cancer: the evidence
Urpilainen, E., Puistola, U., Boussios, S., & Karihtala, P. (2020) · Annals of Translational Medicine · doi:10.21037/atm-20-1060 · Cited by 46
Daneshmandi, S., Choi, J. E., Qi, Y., MacDonald, C. R., Pandey, M. R., Goruganthu, M., Roberts, N. T., Singh, P. K., Higashi, R. M., Lane, A. N., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47096-9 · Cited by 45
“For metformin treatments, 1.5mg/ml of metformin was dissolved in drinking water refreshed every 48 h. (to obtain 300mg/kg dosage) in respective groups 67,71 .”
Troncone, M. J., Cargnelli, S., Villani, L. A., Isfahanian, N., Broadfield, L. A., Zychla, L., Wright, J., Pond, G. R., Steinberg, G. R., & Tsakiridis, T. K. (2017) · Oncotarget · doi:10.18632/oncotarget.17496 · Cited by 45
“The discrepancy between achievable doses of metformin in humans and the ones needed to mediate anti-tumor action in other tumors led groups to suggest that most of the antitumor activity of metformin may be due to the indirect hepatic action of the drug where, due to portal circulation, metformin reaches greater conce…”
BackgroundMetformin inhibits human non-small cell lung cancer by regulating AMPK–CEBPB–PDL1 signaling pathway
Lu, T., Li, M., Zhao, M., Huang, Y., Bi, G., Liang, J., Chen, Z., Zheng, Y., Xi, J., Lin, Z., et al. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-021-03116-x · Cited by 44
Guo, Z., Johnson, V., Barrera, J., Porras, M., Ugarte, D. H., Hernández, I., McGarrah, P. W., & Potter, D. A. (2018) · Cancer and Metastasis Reviews · doi:10.1007/s10555-018-9749-6 · Cited by 44
A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects
Aguilar-Recarte, D., Barroso, E., Zhang, M., Rada, P., Pizarro‐Delgado, J., Peña, L., Palomer, X., Valverde, Á. M., Wahli, W., & Vázquez‐Carrera, M. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106578 · Cited by 47
Li, Y., Gappy, S. S., Liu, X., Sassalos, T. M., Zhou, T., Hsu, A., Zhang, A., Edwards, P. A., Gao, H., & Qiao, X. (2022) · PLoS ONE · doi:10.1371/journal.pone.0268451 · Cited by 40
“In vitro culture conditions do not accurately replicate the in vivo microenvironment and contain excessive nutrients such as glucose, serine, and glutamine, all of which reduce metformin sensitivity [46, 47].”
BackgroundTargeting Hypoxia-Inducible Factor-1α for the Management of Hepatocellular Carcinoma
Huynh, K. N., Rao, S. S., Roth, B. J., Bryan, T., Fernando, D. M., Dayyani, F., Imagawa, D. K., & Abi‐Jaoudeh, N. (2023) · Cancers · doi:10.3390/cancers15102738 · Cited by 36
“Indirectly, metformin suppresses HIF-1α translation, and also reduces intracellular oxygen demand, leading to decreased HIF-1α protein levels and decreased stabilization of HIFs under hypoxic conditions [81,82].”
BackgroundThe Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin
Henriksson, E., Huber, A., Soto, E., Kriebs, A., Vaughan, M. E., Duglan, D., Chan, A. B., Papp, S. J., Nguyen, M., Afetian, M. E., et al. (2017) · Journal of Biological Rhythms · doi:10.1177/0748730417710348 · Cited by 37
Pyridine Dinucleotides from Molecules to Man
Fessel, J. P., & Oldham, W. M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7120 · Cited by 35
“, phenformin) have been suggested to exert their beneficial effects through inhibition of mitochondrial Complex I (NADH:ubiquinone oxidoreductase) at concentrations achieved with standard therapeutic doses (31, 256).”
Song, X., Tsakiridis, E. E., Steinberg, G. R., & Pei, Y. (2020) · Cellular Signalling · doi:10.1016/j.cellsig.2020.109704 · Cited by 36
Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment
Anselmino, L., Baglioni, M. V., Malizia, F., Laluce, N. C., Etichetti, C. B., Marignac, V. L. M., Rozados, V. R., Scharovsky, O. G., Girardini, J. E., Rico, M. J., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-87525-z · Cited by 35
Mitochondrial targets of metformin—Are they physiologically relevant?
Pecinová, A., Brázdová, A., Drahota, Z., Houštěk, J., & Mráček, T. (2019) · BioFactors · doi:10.1002/biof.1548 · Cited by 33
“One possible explanation lies in the excess availability of nutrients in the cell culture media, as it is known that sensitivity to metformin decreases when nutrients are not limiting.(23,28) Under the limiting conditions, 1 mmol/L metformin in culture media led to intracellular concentration of 131 μmol/L, which is a…”
BackgroundInfluentialMitochondria and CancerPreprint
Kenny, T. C., & Birsoy, K. (2024) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041534 · Cited by 40
Hansel, C., Barr, S., Schemann, A. V., Lauber, K., Hess, J., Unger, K., Zitzelsberger, H., Jendrossek, V., & Klein, D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137064 · Cited by 33
“However, it is important to determine metformin preclinical concentrations in animal models in order to determine if these levels could be achieved in patients [77].”
BackgroundMATE2 Expression Is Associated With Cancer Cell Response to Metformin
Chowdhury, S., Yung, E., Pintilie, M., Muaddi, H., Chaib, S., Yeung, M., Fusciello, M., Sykes, J., Pitcher, B., Hagenkort, A., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0165214 · Cited by 33
Strekalova, E., Malin, D., Rajanala, S. H., & Cryns, V. L. (2017) · Breast Cancer Research and Treatment · doi:10.1007/s10549-017-4201-0 · Cited by 33
Shi, H., Sun, Y., He, M., Yang, X. W., Hamada, M., Fukunaga, T., Zhang, X., & Chang, C. (2019) · Oncogene · doi:10.1038/s41388-019-0962-8 · Cited by 32
Metformin Is a Pyridoxal-5′-phosphate (PLP)-Competitive Inhibitor of SHMT2
Tramonti, A., Cuyàs, E., Encinar, J. A., Pietzke, M., Paone, A., Verdura, S., Arbusà, A., Martı́n-Castillo, B., Giardina, G., Joven, J., et al. (2021) · Cancers · doi:10.3390/cancers13164009 · Cited by 31
“Treatment with typi‐ cally used concentrations of metformin required to induce anti‐cancer effects in in vitro studies (5–10 mmol/L)—a range of concentrations that might be achieved in the mitochon‐ drial matrix upon heavy accumulation of metformin due to the mitochondrial membrane potential [16,48,49]—notably reduced…”
BackgroundSekino, N., Kano, M., Matsumoto, Y., Sakata, H., Akutsu, Y., Hanari, N., Murakami, K., Toyozumi, T., Takahashi, M., Otsuka, R., et al. (2018) · Cancer Science · doi:10.1111/cas.13523 · Cited by 33
“We reported that 5 mg/mouse (250 mg/kg) of metformin was given to mice, giving a blood concentration of metformin of 5 lmol/L.(38) The blood concentration of metformin in patients taking metformin is reported to be 10 lmol/L.”
BackgroundWindow of opportunity clinical trial designs to study cancer metabolism
Aroldi, F., & Lord, S. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0621-4 · Cited by 32
Li, R., 杨凌712100，中国, 西., Zhu, Z., Zheng, Y., Lv, Y., Tian, X., Wu, D., Wang, Y., Zeng, W., & 成都611100，中国, 四. (2020) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2020.074 · Cited by 33
Sodium–glucose cotransporter inhibition in polycystic kidney disease: fact or fiction
Afşar, B., Afşar, R. E., Demiray, A., Altay, S., Korkmaz, H., Yıldız, A., Covic, A. C., Ortíz, A., & Kanbay, M. (2022) · Clinical Kidney Journal · doi:10.1093/ckj/sfac029 · Cited by 35
“0 g/day) may still not be sufficient for AMPK activation in the kidney [19, 20].”
Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease
Gupta, S., Ozimek-Kulik, J. E., & Phillips, J. K. (2021) · Genes · doi:10.3390/genes12111762 · Cited by 35
Iversen, A. B. B., Horsman, M. R., Jakobsen, S., Jensen, J., Garm, C., Jessen, N., Breining, P., Frøkiær, J., & Busk, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-10010-z · Cited by 29
Metformin: (future) best friend of the radiation oncologist?
Chevalier, B., Pasquier, D., Lartigau, E. F., Chargari, C., Schernberg, A., Jannin, A., Mirabel, X., Vantyghem, M., & Escande, A. (2020) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2020.06.030 · Cited by 27
Guarnaccia, L., Navone, S. E., Masseroli, M. M., Balsamo, M., Caroli, M., Valtorta, S., Moresco, R. M., Campanella, R., Garzia, E., Riboni, L., et al. (2021) · Cancers · doi:10.3390/cancers14010112 · Cited by 30
Metformin as a Treatment Strategy for Sjögren’s Syndrome
Kim, J., Kim, Y.-S., & Park, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137231 · Cited by 26
“Metformin inhibits mitochondrial respiratory chain complex Idirectly and, as a result, causes depletion of ATP and an increase of adenosine mono-phosphate (AMP) [10,12].”
BackgroundCuyàs, E., Buxó, M., Iglesias, M. J. F., Verdura, S., Pernas, S., Dorca, J., Álvarez, I., Torres‐Martínez, S., Pérez-García, J. M., Batista-López, N., et al. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00193 · Cited by 25
The Antitumor Effects of Metformin on Gastric Cancer In Vitro and on Peritoneal Metastasis
Sekino, N., Kano, M., Matsumoto, Y., Sakata, H., Murakami, K., Toyozumi, T., Otsuka, R., Yokoyama, M., Shiraishi, T., Okada, K., et al. (2018) · Anticancer Research · doi:10.21873/anticanres.12982 · Cited by 24
Bruycker, S. D., Vangestel, C., WYNGAERT, T. V. D., Pauwels, P., Wyffels, L., Staelens, S. G., & Stroobants, S. G. (2018) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.212225 · Cited by 23
“It has been hypothesized that metformin can accumulate up to 500-fold in the mitochondria, resulting in mitochondrial concentrations in the millimolar range (20,21), which should be adequate for inhibiting the respiratory chain complex I (11,20,22) and consequently improving tumor oxygenation.”
BackgroundLet-7 underlies metformin-induced inhibition of hepatic glucose production
Xie, D., Chen, F., Zhang, Y., Shi, B., Song, J., Chaudhari, K., Yang, S., Zhang, G. J., Sun, X., Taylor, H. S., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2122217119 · Cited by 24
“In recent years, repurposing metformin for the prevention and/or treatment of other illnesses including cancer, cardiovascular disease, and aging has received increased attention (3, 7, 8).”
BackgroundChao, R., Nishida, M., Yamashita, N., Tokumasu, M., Zhao, W., Kudo, I., & Udono, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.864225 · Cited by 23
Kalyanaraman, B., Cheng, G., Hardy, M., Ouari, O., Sikora, A., Zielonka, J., & Dwinell, M. B. (2017) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-017-0796-3 · Cited by 22
Alhajala, H. S., Markley, J. L., Kim, J. H., Al-Gizawiy, M. M., Schmainda, K. M., Kuo, J. S., & Chitambar, C. R. (2020) · Oncotarget · doi:10.18632/oncotarget.27567 · Cited by 21
“One of the challenges to the success of metformin as an anticancer drug in the clinic is that the concentrations of metformin used to inhibit the growth of malignant cells in vitro is far greater than the plasma levels attained in diabetic patients treated with this drug [12].”
BackgroundPeng, M., Deng, J., Zhou, S., Xiao, D., Long, J., Zhang, N., He, C., Mo, M., & Yang, X. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01159 · Cited by 21
“However, its drawbacks, particularly, unavailable high concentration on targeting tumor locations for its anticancer activity, have been reported (Menendez et al., 2014; Chandel et al., 2016).”
BackgroundMetformin Disrupts Signaling and Metabolism in Fetal Hepatocytes
Swenson, K. S., Wang, D., Jones, A. K., Nash, M. J., O’Rourke, R., Takahashi, D. L., Kievit, P., Hennebold, J. D., Aagaard, K. M., Friedman, J. E., et al. (2023) · Diabetes · doi:10.2337/db23-0089 · Cited by 22
Biguanides enhance antifungal activity against Candida glabrata
Xu, S., Feliu, M., Lord, A. K., Lukason, D. P., Negoro, P. E., Khan, N. S., Dagher, Z., Feldman, M. B., Reedy, J. L., Steiger, S. N., et al. (2018) · Virulence · doi:10.1080/21505594.2018.1475798 · Cited by 21
“in cancer cells, that lack OCT1 expression, often require concentrations similar to those used in our study [23,33].”
BackgroundMethodLiu, S., Polsdofer, E., Zhou, L., Ruan, S., Lyu, H., Hou, D., Liu, H., Thor, A. D., He, Z., & Liu, B. (2021) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2021.04.012 · Cited by 19
“Moreover, Chandel et al.54 propose that when assessing the efficacy of metformin, both pharmacokinetic and tumor-related biologic factors need to be considered.”
BackgroundKim, H. S., Kim, J. H., Jang, H. J., & Lee, J. Y. (2020) · International Journal of Medical Sciences · doi:10.7150/ijms.50338 · Cited by 19
Szkudelski, T., Konieczna, K., & Szkudelska, K. (2022) · Molecules · doi:10.3390/molecules27165250 · Cited by 18
“AMPK induction is also associated with reduced glucose uptake and oxidation in isolated adipocytes [37,57,58].”
BackgroundCalza, G., Nyberg, E., Mäkinen, M., Soliymani, R., Cascone, A., Lindholm, D., Barborini, E., Baumann, M., Lalowski, M. M., & Eriksson, O. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00141 · Cited by 19
“Metformin can penetrate into certain tumors, and concentrations reaching 100 μM have been measured in xenograft-bearing mice following oral administration (Chandel et al., 2016; Dowling et al., 2016).”
BackgroundInfluential
Metadata
- 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.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 23
- Issue
- 4
- Pages
- 569-570
- ISSN
- 1550-4131 (ISSN-L)
- 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
- 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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