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.
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Previous studies reported synergism of the metformin/low glucose combination.
“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
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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× · see citing works
“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 · see citing works
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Aslakson, C. J., & Miller, F. R. (1992) · PubMed · Cited by 1,234 · see citing works
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 · see citing works
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 923 · see citing works
Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus
Salpeter, S. R., Greyber, E., Pasternak, G. A., & Salpeter (posthumous), E. E. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002967.pub4 · Cited by 893 · see citing works
Marsin, A.-S., Bertrand, L., Rider, M. H., Deprez, J., Beauloye, C., Vincent, M. F., den Berghe, G. V., Carling, D., & Hue, L. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00742-9 · Cited by 818 · see citing works
Marroquin, L. D., Hynes, J., Dykens, J. A., Jamieson, J. D., & Will, Y. (2007) · Toxicological Sciences · doi:10.1093/toxsci/kfm052 · Cited by 626 · see citing works
Shackelford, D. B., Abt, E., Gerken, L., Vasquez, D. S., Seki, A., Leblanc, M., Wei, L., Fishbein, M. C., Czernin, J., Mischel, P. S., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.12.008 · Cited by 585 · see citing works
Sahra, I. B., Laurent, K., Giuliano, S., Larbret, F., Ponzio, G., Gounon, P., MARCHAND‐BRUSTEL, Y. L., Giorgetti‐Peraldi, S., Cormont, M., Bertolotto, C., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-2782 · Cited by 536 · see citing works
Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus
Salpeter, S. R., Greyber, E., Pasternak, G. A., & Salpeter, E. E. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002967.pub3 · Cited by 435 · see citing works
Batandier, C., Guigas, B., Détaille, D., El-Mir, M. Y. A., Fontaine, E. M., Rigoulet, M., & Leverve, X. M. (2006) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-006-9003-8 · Cited by 306 · see citing works
Lee, C., & Longo, V. D. (2011) · Oncogene · doi:10.1038/onc.2011.91 · Cited by 305 · see citing works
Zhou, W., Mukherjee, P., Kiebish, M. A., Markis, W. T., Mantis, J. G., & Seyfried, T. N. (2007) · Nutrition & Metabolism · doi:10.1186/1743-7075-4-5 · Cited by 299 · see citing works
In vitro metformin anti-neoplastic activity in epithelial ovarian cancer
Gotlieb, W. H., Saumet, J., Beauchamp, M.-C., Gu, J., Lau, S. K., Pollak, M., & Bruchim, I. (2008) · Gynecologic Oncology · doi:10.1016/j.ygyno.2008.04.008 · Cited by 267 · see citing works
Vazquez-Martin, A., Oliveras-Ferraros, C., & Menendez, J. A. (2009) · Cell Cycle · doi:10.4161/cc.8.1.7499 · Cited by 250 · cited 1× · see citing works
“Many groups have demonstrated metformin’s action in vitro in a variety of cancer types [10–14].”
BackgroundZhuang, Y., & Miskimins, W. K. (2008) · Journal of Molecular Signaling · doi:10.1186/1750-2187-3-18 · Cited by 247 · see citing works
Self-citationWu, S., & Wei, Y. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.09.014 · Cited by 182 · see citing works
Han, L., Ma, Q., Li, J., Liu, H., Li, W., Ma, G., Xu, Q., Zhou, S. Y., & Wu, E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027074 · Cited by 162 · see citing works
Saito, S., Furuno, A., Sakurai, J., Sakamoto, A., Park, H.-R., Shin‐ya, K., Tsuruo, T., & Tomida, A. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2689 · Cited by 160 · see citing works
Metabolic management of brain cancer
Seyfried, T. N., Kiebish, M. A., Marsh, J., Shelton, L. M., Huysentruyt, L. C., & Mukherjee, P. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.08.009 · Cited by 146 · see citing works
Sandulache, V. C., Ow, T. J., Pickering, C. R., Frederick, M. J., Zhou, G., Fokt, I., Davis‐Malesevich, M., Priebe, W., & Myers, J. N. (2011) · Cancer · doi:10.1002/cncr.25868 · Cited by 143 · see citing works
Central role of lactic acidosis in cancer cell resistance to glucose deprivation‐induced cell death
Wu, H., Ding, Z., Hu, D., Sun, F., Dai, C., Xie, J., & Hu, X. (2011) · The Journal of Pathology · doi:10.1002/path.3978 · Cited by 130 · see citing works
Metformin is synthetically lethal with glucose withdrawal in cancer cells
Menéndez, J. A., Oliveras‐Ferraros, C., Cufí, S., Corominas-Faja, B., Joven, J., Martı́n-Castillo, B., & Vázquez‐Martín, A. (2012) · Cell Cycle · doi:10.4161/cc.20948 · Cited by 129 · see citing works
Zhuang, Y., & Miskimins, W. K. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0343 · Cited by 109 · see citing works
Self-citationCaloric restriction reduces growth of mammary tumors and metastases
Lorenzo, M. S. D., Baljinnyam, E., Vatner, D. E., Abarzúa, P., Vatner, S. F., & Rabson, A. B. (2011) · Carcinogenesis · doi:10.1093/carcin/bgr107 · Cited by 109 · see citing works
Sinnett‐Smith, J. W., Kisfalvi, K., Kui, R. K., & Rozengurt, E. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.11.010 · Cited by 106 · see citing works
Metformin as an energy restriction mimetic agent for breast cancer prevention
Thompson, H. J., Zhu, Z., Thompson, M., Jiang, W., & McGinley, J. N. (2011) · Journal of Carcinogenesis · doi:10.4103/1477-3163.83043 · Cited by 51 · see citing works
Bonini, M. G., & Gantner, B. N. (2013) · IUBMB Life · doi:10.1002/iub.1213 · Cited by 47 · see citing works
Lea, M. A., Chacko, J., Bolikal, S., Hong, J. Y., Chung, R., Ortega, A., & desBordes, C. (2011) · PubMed · Cited by 47 · see citing works
Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin
Javeshghani, S., Zakikhani, M., Austin, S., Bazile, M., Blouin, M., Topisirović, I., St‐Pierre, J., & Pollak, M. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2907 · Cited by 47 · see citing works
Andrade, B. M., Cazarin, J., Zancan, P., & de Carvalho, D. P. (2012) · Thyroid · doi:10.1089/thy.2012.0041 · Cited by 25 · see citing works
Smith, T., Zanda, M., & Fleming, I. N. (2013) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2013.05.006 · Cited by 25 · see citing works
Habibollahi, P., van den Berg, N. S., Kuruppu, D., Loda, M. F., & Mahmood, U. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.112.107011 · Cited by 24 · see citing works
Oleksyszyn, J. (2011) · Medical Hypotheses · doi:10.1016/j.mehy.2011.04.001 · Cited by 23 · see citing works
Rizkalla, S. W., Elgrably, F., Tchobroutsky, G., & Slama, G. (1986) · PubMed · Cited by 19 · see citing works
Matsuo, J., Tsukumo, Y., Saito, S., Tsukahara, S., Sakurai, J., Sato, S., Kondo, H., Ushijima, M., Matsuura, M., Watanabe, T., et al. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0871 · Cited by 17 · see citing works
Flagged first, then by citations
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- [31]Sandulache VC, Ow TJ, Pickering CR, Frederick MJ, Zhou G, et al (2011) Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells. Cancer 117: 2926– 2938. 21692052 PMC3135768
Cited by
Sorted by citations
Metabolites and the Tumour Microenvironment: From Cellular Mechanisms to Systemic Metabolism
Elia, I., & Haigis, M. C. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00317-z · Cited by 651 · see citing works
Ketogenic diet in the treatment of cancer – Where do we stand?
Weber, D. D., Aminzadeh-Gohari, S., Tulipan, J., Catalano, L., Feichtinger, R. G., & Kofler, B. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.06.026 · Cited by 464 · see citing works
Elgendy, M., Cirò, M., Hosseini, A., Weiszmann, J., Mazzarella, L., Ferrari, E., Cazzoli, R., Curigliano, G., DeCensi, A., Bonanni, B., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.03.007 · Cited by 299 · see citing works
Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma
Poff, A. M., Koutnik, A. P., Egan, K. M., Sahebjam, S., D’Agostino, D. P., & Kumar, N. B. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.12.011 · Cited by 203 · see citing works
Klement, R. J. (2017) · Medical Oncology · doi:10.1007/s12032-017-0991-5 · Cited by 140 · see citing works
The Potential Effect of Metformin on Cancer: An Umbrella Review
Yu, H., Zhong, X. Z., Gao, P., Shi, J., Wu, Z., Guo, Z., Wang, Z., & Song, Y. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00617 · Cited by 133 · see citing works
Metformin in breast cancer: preclinical and clinical evidence
De, A., & Kuppusamy, G. (2019) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2019.06.003 · Cited by 124 · see citing works
Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities
Talib, W. H., Mahmod, A. I., Kamal, A., Rashid, H. M., Alashqar, A. M. D., Khater, S. H., Jamal, D., & Waly, M. I. (2021) · Current Issues in Molecular Biology · doi:10.3390/cimb43020042 · Cited by 126 · see citing works
Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis
Klement, R. J., Champ, C. E., Otto, C., & Kämmerer, U. (2016) · PLoS ONE · doi:10.1371/journal.pone.0155050 · Cited by 123 · see citing works
The Role of Diet in Cancer Prevention and Chemotherapy Efficacy
Mittelman, S. D. (2020) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-013120-041149 · Cited by 111 · see citing works
Saber, M. M., Al-mahallawi, A. M., Nassar, N. N., Stork, B., & Shouman, S. A. (2018) · BMC Cancer · doi:10.1186/s12885-018-4727-5 · Cited by 98 · see citing works
Falah, R. R., Talib, W. H., & Shbailat, S. J. (2017) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834016687482 · Cited by 92 · see citing works
Ma, L., Wei, J., Wan, J., Wang, W., Wang, L., Yuan, Y., Yang, Z., Liu, X., & Ming, L. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1090-6 · Cited by 91 · see citing works
O’Brien, A. J., Villani, L. A., Broadfield, L. A., Houde, V. P., Galić, S., Blandino, G., Kemp, B. E., Tsakiridis, T. K., Muti, P. C., & Steinberg, G. R. (2015) · Biochemical Journal · doi:10.1042/bj20150122 · Cited by 89 · see citing works
Press-pulse: a novel therapeutic strategy for the metabolic management of cancer
Seyfried, T. N., Yu, G. W., Maroon, J. C., & D’Agostino, D. P. (2017) · Nutrition & Metabolism · doi:10.1186/s12986-017-0178-2 · Cited by 86 · see citing works
Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer
Boukalová, Š., Štursa, J., Werner, L., Ezrova, Z., Černý, J., Bezawork‐Geleta, A., Pecinová, A., Dong, L., Drahota, Z., & Neužil, J. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-1021 · Cited by 73 · see citing works
Targeting the Wnt/β-catenin pathway in human osteosarcoma cells
Fang, F., VanCleave, A. M., Helmuth, R., de Oliveira, H. T., Rickel, K., Wollenzien, H., Sun, H., Zeng, E., Zhao, J., & Tao, J. (2018) · Oncotarget · doi:10.18632/oncotarget.26377 · Cited by 71 · see citing works
High glucose levels promote the proliferation of breast cancer cells through GTPases
Hou, Y., Zhou, M., Xie, J., Chao, P., Feng, Q., & Wu, J. (2017) · Breast Cancer Targets and Therapy · doi:10.2147/bctt.s135665 · Cited by 68 · see citing works
Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation
Tang, G., Guo, J., Zhu, Y., Huang, Z., Liu, T., Cai, J., Yu, L., & Wang, Z. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4343 · Cited by 65 · see citing works
Cdc42: A Novel Regulator of Insulin Secretion and Diabetes-Associated Diseases
Huang, Q.-Y., Lai, X., Qian, X., Lv, L., Li, J., Duan, J., Xiao, X., & Xiong, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20010179 · Cited by 67 · see citing works
On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer
Penkert, J., Ripperger, T., Schieck, M., Schlegelberger, B., Steinemann, D., & Illig, T. (2016) · Oncotarget · doi:10.18632/oncotarget.11759 · Cited by 62 · see citing works
Bizjak, M., Malavašič, P., Dolinar, K., Pohar, J., Pirkmajer, S., & Pavlin, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-01801-5 · Cited by 63 · see citing works
Metformin: A Dual-Role Player in Cancer Treatment and Prevention
Galal, M. A., Al-Rimawi, M., Hajeer, A., Dahman, H., Alouch, S. S., & Aljada, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25074083 · Cited by 68 · see citing works
Glucose-deprivation increases thyroid cancer cells sensitivity to metformin
Bikas, A., Jensen, K. E., Patel, A. D., Costello, J. M., McDaniel, D. P., Kłubo-Gwieździńska, J., Ларін, О. С., Hoperia, V., Burman, K. D., Boyle, L., et al. (2015) · Endocrine Related Cancer · doi:10.1530/erc-15-0402 · Cited by 59 · see citing works
Porper, K., Shpatz, Y., Плоткин, Л. Л., Pechthold, R. G., Talianski, A., Champ, C. E., Furman, O., Shimoni-Sebag, A., Symon, Z., Amit, U., et al. (2021) · Journal of Neuro-Oncology · doi:10.1007/s11060-021-03786-8 · Cited by 58 · see citing works
Metabolic dependencies and targets in ovarian cancer
Zhang, Y., Wang, Y., Zhao, G., Oršulić, S., & Matei, D. E. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108413 · Cited by 59 · see citing works
Gong, J., Kelekar, G., Shen, J., Shen, J., Kaur, S., & Mita, M. M. (2016) · Targeted Oncology · doi:10.1007/s11523-016-0423-z · Cited by 55 · see citing works
The influence of ketogenic therapy on the 5 R’s of radiobiology
Klement, R. J. (2017) · International Journal of Radiation Biology · doi:10.1080/09553002.2017.1380330 · Cited by 54 · see citing works
Reversal of obesity-driven aggressiveness of endometrial cancer by metformin.
Guo, H., Kong, W., Zhang, L., Han, J., Clark, L. H., Yin, Y., Fang, Z., Sun, W., Wang, J., Gilliam, T. P., et al. (2019) · PubMed Central · Cited by 54 · see citing works
Ariaans, G., Jalving, M., Vries, E. G. E. D., & Jong, S. D. (2017) · BMC Cancer · doi:10.1186/s12885-017-3230-8 · Cited by 51 · see citing works
Metformin and cancer: Between the bioenergetic disturbances and the antifolate activity
Jara, J. A., & López‐Muñoz, R. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.06.014 · Cited by 50 · see citing works
Silvestri, A., Palumbo, F., Rasi, I., Posca, D., Pavlidou, T., Paoluzi, S., Castagnoli, L., & Cesareni, G. (2015) · PLoS ONE · doi:10.1371/journal.pone.0136250 · Cited by 49 · see citing works
Valaee, S., Yaghoobi, M. M., & Shamsara, M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174486 · Cited by 47 · see citing works
Morscher, R. J., Aminzadeh-Gohari, S., Hauser‐Kronberger, C., Feichtinger, R. G., Sperl, W., & Kofler, B. (2016) · Oncotarget · doi:10.18632/oncotarget.7929 · Cited by 46 · see citing works
Cancer Treatment With the Ketogenic Diet: A Systematic Review and Meta-analysis of Animal Studies
Li, J., Zhang, H., & Dai, Z. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.594408 · Cited by 45 · see citing works
Corleto, K. A., Strandmo, J. L., & Giles, E. D. (2024) · Pharmaceuticals · doi:10.3390/ph17030396 · Cited by 44 · see citing works
Orlicka-Płocka, M., Gurda, D., Fedoruk‐Wyszomirska, A., & Wyszko, E. (2020) · APOPTOSIS · doi:10.1007/s10495-020-01637-x · Cited by 44 · see citing works
Xu, Y., Yang, X., Wang, T., Yang, L., He, Y., Miskimins, K. W., & Qian, S. Y. (2018) · BMC Cancer · doi:10.1186/s12885-018-4250-8 · Cited by 42 · see citing works
Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer
Litchfield, L. M., Mukherjee, A., Eckert, M. A., Johnson, A., Mills, K. A., Pan, S., Shridhar, V., Lengyel, E. R., & Romero, I. L. (2015) · Oncotarget · doi:10.18632/oncotarget.4556 · Cited by 41 · see citing works
Di, Y., Silva, F. D., Krol, E. S., & Alcorn, J. (2018) · Nutrition and Cancer · doi:10.1080/01635581.2018.1421677 · Cited by 38 · see citing works
Yang, W., Shin, H., Cho, H., Chung, J., Lee, E., Kim, J., & Kang, E. (2020) · Cancers · doi:10.3390/cancers12051329 · Cited by 37 · see citing works
Licha, D., Vidali, S., Aminzadeh-Gohari, S., Alka, O., Breitkreuz, L., Kohlbacher, O., Reischl, R., Feichtinger, R. G., Kofler, B., & Huber, C. G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20163873 · Cited by 34 · see citing works
Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin
Sivalingam, V. N., Latif, A., Kitson, S., McVey, R. J., Finegan, K. G., Marshall, K. M., Lisanti, M. P., Sotgia, F., Stratford, I. J., & Crosbie, E. J. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0627-y · Cited by 35 · see citing works
Nutrition Intervention and Microbiome Modulation in the Management of Breast Cancer
Jiang, Y., & Li, Y. (2024) · Nutrients · doi:10.3390/nu16162644 · Cited by 32 · see citing works
Sandoval-Acuña, C., Fuentes-Retamal, S., Guzmán‐Rivera, D., Peredo-Silva, L., Madrid-Rojas, M., Rebolledo, S., Castro-Castillo, V., Pavani, M., Catalán, M., Maya, J. D., et al. (2016) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2016.08.018 · Cited by 31 · see citing works
Sabnis, H. S., Bradley, H. L., Tripathi, S., Yu, W., Tse, W. T., Qu, C., & Bunting, K. D. (2016) · Leukemia Research · doi:10.1016/j.leukres.2016.10.004 · Cited by 31 · see citing works
Schroll, M. M., Liu, X., Herzog, S. K., Skube, S. B., & Hummon, A. B. (2016) · Nutrition Research · doi:10.1016/j.nutres.2016.08.002 · Cited by 30 · see citing works
Tran, L., Kichenadasse, G., Butler, L. M., Centenera, M. M., Morel, K. L., Ormsby, R. J., Michael, M., Lower, K. M., & Sykes, P. J. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0074 · Cited by 30 · see citing works
Caveolin‐1 in oncogenic metabolic symbiosis
Raudenská, M., Gumulec, J., Balvan, J., & Masařík, M. (2020) · International Journal of Cancer · doi:10.1002/ijc.32987 · Cited by 32 · see citing works
Use of metformin and risk of breast and colorectal cancer
Rennert, G., Rennert, H. S., Gronich, N., Pinchev, M., & Gruber, S. B. (2020) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2020.108232 · Cited by 30 · see citing works
Orlicka-Płocka, M., Fedoruk‐Wyszomirska, A., Gurda, D., Pawelczak, P., Krawczyk, P., Giel-Pietraszuk, M., Framski, G., Ostrowski, T., & Wyszko, E. (2021) · Antioxidants · doi:10.3390/antiox10060950 · Cited by 30 · see citing works
Osama, H., Sayed, O. M., Hussein, R. R. S., Abdelrahim, M. E. A., & Elberry, A. A. (2019) · Journal of Liposome Research · doi:10.1080/08982104.2019.1610434 · Cited by 28 · see citing works
Gkionis, L., Kavetsou, E., Kalospyros, A., Manousakis, D., Sanz, M. G., Butterworth, S., Detsi, A., & Tirella, A. (2020) · Molecular Diversity · doi:10.1007/s11030-020-10082-6 · Cited by 28 · see citing works
Hoyle, H. W., Stenger, C. M. L., & Przyborski, S. A. (2022) · Biomaterials and Biosystems · doi:10.1016/j.bbiosy.2022.100063 · Cited by 30 · see citing works
Ward, N. P., Poff, A. M., Koutnik, A. P., & D’Agostino, D. P. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180061 · Cited by 28 · see citing works
Drugs acting on homeostasis: challenging cancer cell adaptation
Moschovi, M. A., Critselis, E., Çen, O., Adamaki, M., Lambrou, G. Ι., Chrousos, G. P., & Vlahopoulos, S. (2015) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.2015.1095095 · Cited by 28 · see citing works
Monocarboxylate transporter 4 involves in energy metabolism and drug sensitivity in hypoxia
Yamaguchi, A., Mukai, Y., Sakuma, T., Narumi, K., Furugen, A., Yamada, Y., & Kobayashi, M. (2023) · Scientific Reports · doi:10.1038/s41598-023-28558-4 · Cited by 28 · see citing works
Wen, K., Sung, P., Wu, A. T. H., Chou, P., Lin, J.-H., Huang, C. F., Yeung, S. J., & Lee, M. (2020) · Journal of Ovarian Research · doi:10.1186/s13048-020-00703-x · Cited by 26 · see citing works
Ketogenic Diets and their Therapeutic Potential on Breast Cancer: A Systemic Review
Jemal, M., Shibabaw, T., & Dejenie, T. A. (2021) · Cancer Management and Research · doi:10.2147/cmar.s339970 · Cited by 26 · see citing works
Pennanen, P. T., Syvälä, H., Bläuer, M., Savinainen, K., Ylikomi, T. J., Tammela, T. L. J., & Murtola, T. J. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.06.036 · Cited by 26 · see citing works
Koobotse, M. O., Schmidt, D., Holly, J. M. P., & Perks, C. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228674 · Cited by 25 · see citing works
Maradagi, T., Kumar, R., & Ponesakki, G. (2021) · Diabetic Medicine · doi:10.1111/dme.14713 · Cited by 25 · see citing works
Klose, K., Packeiser, E., Müller, P., Granados-Soler, J. L., Schille, J. T., Goericke‐Pesch, S., Kietzmann, M., Escobar, H. M., & Nolte, I. J. A. (2021) · PLoS ONE · doi:10.1371/journal.pone.0257403 · Cited by 24 · see citing works
High Glucose Increases DNA Damage and Elevates the Expression of Multiple DDR Genes
Rahmoon, M. A., Elghaish, R. A., Ibrahim, A. A., Alaswad, Z., Gad, M. Z., El‐Khamisy, S. F., & Elserafy, M. (2023) · Genes · doi:10.3390/genes14010144 · Cited by 25 · see citing works
Tumor metabolism rewiring in epithelial ovarian cancer
Wang, M., Zhang, J., & Wu, Y. (2023) · Journal of Ovarian Research · doi:10.1186/s13048-023-01196-0 · Cited by 23 · see citing works
Lamichhane, S., Bastola, T., Pariyar, R., Lee, E.-S., Lee, H.-S., Lee, D., & Seo, J. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18030674 · Cited by 24 · see citing works
Machado, A. D. B., dos Reis, V. M. S. F., Weber, S. F., Jauckus, J., Brum, I. S., Corleta, H. V. E., Strowitzki, T., Capp, E., & Germeyer, A. (2016) · Oncology Letters · doi:10.3892/ol.2016.5041 · Cited by 22 · see citing works
Metformin inhibits tumor growth and affects intestinal flora in diabetic tumor-bearing mice
Kang, J., Li, C., Gao, X., Liu, Z., Chen, C., & Luo, D. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174605 · Cited by 22 · see citing works
Yenmiş, G., Beşli, N., Saraç, E. Y., Emre, F. S. H., Şenol, K., & SULTUYBEK, G. K. (2020) · TURKISH JOURNAL OF MEDICAL SCIENCES · doi:10.3906/sag-1908-112 · Cited by 21 · see citing works
Gou, S., Qiu, L., Yang, Q., Li, P., Zhou, X., Sun, Y., Zhou, X., Zhao, W., Zhai, W., Li, G., et al. (2021) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2021.115523 · Cited by 21 · see citing works
Shirian, F. I., Karimi, M., Alipour, M., Salami, S., Nourbakhsh, M., Nekufar, S., Safari‐Alighiarloo, N., & Tavakoli‐Yaraki, M. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09501-w · Cited by 20 · see citing works
Targeting HIF-1α is a prerequisite for cell sensitivity to dichloroacetate (DCA) and metformin
Hong, S.-E., Jin, H., Kim, H., Seong, M.-K., Kim, E., Ye, S., Choe, T., Lee, J. K., Kim, J., Park, I., et al. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.11.088 · Cited by 20 · see citing works
Ketogenic diet as a treatment and prevention strategy for cancer: A therapeutic alternative
Neha, N., & Chaudhary, R. (2024) · Nutrition · doi:10.1016/j.nut.2024.112427 · Cited by 20 · see citing works
Rajh, M., Dolinar, K., Miš, K., Pavlin, M., & Pirkmajer, S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0154747 · Cited by 20 · see citing works
Melatonin May Increase Anticancer Potential of Pleiotropic Drugs
Bojková, B., Kubatka, P., Qaradakhi, T., Zulli, A., & Kajo, K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123910 · Cited by 21 · see citing works
Loos, J. A., Coccimiglio, M., Nicolao, M. C., Rodrígues, C. R., & Cumino, A. C. (2021) · Parasitology · doi:10.1017/s0031182021001633 · Cited by 17 · see citing works
Taftian, M., Beigrezaei, S., Arabi, V., & Salehi‐Abargouei, A. (2022) · Nutrition and Cancer · doi:10.1080/01635581.2021.1942081 · Cited by 16 · see citing works
Chukkapalli, V., Gordon, L. I., Venugopal, P., Borgia, J. A., & Karmali, R. (2018) · Oncotarget · doi:10.18632/oncotarget.24989 · Cited by 16 · see citing works
Rogalska, A., Forma, E., Bryś, M., Śliwińska, A., & Marczak, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092750 · Cited by 15 · see citing works
In vitro quantification: Long-term effect of glucose deprivation on various cancer cell lines
Mathews, E. H., Visagie, M. H., Meyer, A. A., Joubert, A. M., & Mathews, G. E. (2020) · Nutrition · doi:10.1016/j.nut.2020.110748 · Cited by 15 · see citing works
Zylla, J. L. S., Hoffman, M., Plesselova, S., Bhattacharya, S., Calar, K., Tecleab, Y. A., de la Puente, P., Gnimpiéba, E. Z., Miskimins, W. K., & Messerli, S. M. (2022) · Cancers · doi:10.3390/cancers14071753 · Cited by 14 · see citing works
Self-citationMebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death
da Silva, E. L., Mesquita, F. P., Aragão, D. R., Portilho, A. J. D. S., Marinho, A. D., de Oliveira, L. L. B., Lima, L. B., de Moraes, M. E. A., Souza, P. F. N., & Montenegro, R. C. (2023) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2023.116630 · Cited by 13 · see citing works
Kinomic profiling of glioblastoma cells reveals PLCG1 as a target in restricted glucose
Walker, K. D., Boyd, N., Anderson, J. C., Willey, C. D., & Hjelmeland, A. B. (2018) · Biomarker Research · doi:10.1186/s40364-018-0136-9 · Cited by 13 · see citing works
Li, Y., Zhang, Q.-Q., Yang, J., He, W., Jiang, Y., Chen, Y., & Wang, Y. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.07.029 · Cited by 13 · see citing works
The Dual Role of Metformin: Repurposing an Antidiabetic Drug for Cancer Therapy
Barbosa, F., Cunha, A., Barbosa, J., Faria, J., & Queirós, O. (2025) · Applied Sciences · doi:10.3390/app152111576 · Cited by 13 · see citing works
Grube, M., Dimmler, A. W., Schmaus, A., Saup, R., Wagner, T., Garvalov, B. K., Sleeman, J. P., & Thiele, W. (2023) · Clinical & Experimental Metastasis · doi:10.1007/s10585-023-10249-z · Cited by 12 · see citing works
Sahu, P., Camarillo, I. G., & Sundararajan, R. (2021) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-021-03723-5 · Cited by 12 · see citing works
The Role of the Microbiome and of Radiotherapy-Derived Metabolites in Breast Cancer
Herrera‐Quintana, L., Vázquez‐Lorente, H., Silva, R. C. M. C., Arancibia, J. E. O., Reyes-Amigo, T., Pires, B. R. B., & Plaza‐Díaz, J. (2024) · Cancers · doi:10.3390/cancers16213671 · Cited by 11 · see citing works
Time-dependent cytotoxicity of dichloroacetate and metformin against Lewis lung carcinoma
Kolesnik, D. L., Pyaskovskaya, O. N., Yakshibaeva, Y. R., & Solyanik, G. I. (2019) · Experimental Oncology · doi:10.32471/exp-oncology.2312-8852.vol-41-no-1.12432 · Cited by 11 · see citing works
The Role of Ketogenic Diet in the Treatment of Neuroblastoma
Makuku, R., Far, Z. S., Khalili, N., Moyo, A., Razi, S., Keshavarz‐Fathi, M., Mahmoudi, M., & Rezaei, N. (2023) · Integrative Cancer Therapies · doi:10.1177/15347354221150787 · Cited by 10 · see citing works
Loos, J. A., Coccimiglio, M. B., Nicolao, M. C., Rodrígues, C. R., & Cumino, A. C. (2022) · CONICET Digital (CONICET) · Cited by 10 · see citing works
Sorokin, D. V., Shchegolev, Y. Y., Scherbakov, A. M., Ryabaya, O. O., Gudkova, M. V., Berstein, L. M., & Ma, K. (2020) · Pharmaceuticals · doi:10.3390/ph13090206 · Cited by 10 · see citing works
Islam, S. R., & Manna, S. K. (2024) · Metabolomics · doi:10.1007/s11306-024-02096-0 · Cited by 9 · see citing works
Novel cytotoxic amphiphilic nitro-compounds derived from a synthetic route for paraconic acids
Ribeiro, T. A., Machado-Ferreira, E., Guimarães, L. F., Cavaleiro, J., Britto, A. M. A., Redua, N., Souza, L. M. P., Pimentel, A. S., Picciani, P. H. S., Oliveira, O. N., et al. (2021) · Colloids and Surfaces A Physicochemical and Engineering Aspects · doi:10.1016/j.colsurfa.2021.126984 · Cited by 9 · see citing works
Elisia, I., Yeung, M., Wong, J., Kowalski, S., Larsen, M., Shyp, T., Sorensen, P. H. B., & Krystal, G. (2021) · Carcinogenesis · doi:10.1093/carcin/bgab106 · Cited by 9 · see citing works
Duan, C., Evison, A., Taylor, L., Onur, S., Morten, K., & Townley, H. E. (2020) · Phytotherapy Research · doi:10.1002/ptr.6898 · Cited by 9 · see citing works
Schmidt, K., Thatcher, A., Grobe, A. C., Broussard, P., Hicks, L. D., Gu, H., Ellies, L. G., Sears, D. D., Kalachev, L. V., & Kroll, E. (2024) · Translational Medicine Communications · doi:10.1186/s41231-024-00178-8 · Cited by 8 · see citing works
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 · see citing works
Nekoufar, S., Ghorbani, M., Safaei, S., Khosroushahi, G. A., Shirian, F. I., Baradaran, B., & Tavakoli‐Yaraki, M. (2025) · BMC Cancer · doi:10.1186/s12885-024-13397-x · Cited by 7 · see citing works
Qin, Z., Li, Y., Shao, X., Li, K., Bai, Y., Wang, B., Ma, F., Shi, W., Song, L., Zhuang, A., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217732 · Cited by 6 · see citing works
- 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
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