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Metformin and Other Biguanides in Oncology: Advancing the Research Agenda
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Abstract
Retrospective studies that may be impractical to confirm prospectively suggest that diabetics treated with metformin have a substantially reduced cancer burden compared with other diabetics. It is unclear if this reflects a chemopreventive effect, an effect on transformed cells, or both. It also remains to be established if these data have relevance to people without diabetes. Laboratory models, however, provide independent impressive evidence for the activity of metformin and other biguanides in both cancer treatment and chemoprevention. Investigations of mechanisms of action of biguanides have revealed considerable complexity and have identified important gaps in knowledge that should be addressed to ensure the optimal design of clinical trials of these agents. Such trials may define important new indications for biguanides in the prevention and/or treatment of many common cancers. Cancer Prev Res; 3(9); 1060–5. ©2010 AACR.
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“However, our results indicate that PTEN-negative tumors seem resistant to the anticancer effect of metformin, which may be related to another anticancer mechanism of metformin involving adenosine monophosphate-activated protein kinase (AMPK) [3,18].”
From Enzalutamide Plus Metformin Versus Enzalutamide Alone in Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 2 Trial (SAKK 08/14). (2026) · cites this paper as [18]
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Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis
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Lehraiki, A., Abbe, P., Cerezo, M., Rouaud, F., Regazzetti, C., Chignon‐Sicard, B., Passeron, T., Bertolotto, C., Ballotti, R., & Rocchi, S. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.202 · Cited by 86
“Recent studies indicate that metformin can potentially be used as an efficient anticancer drug in various tumors (Ben Sahra et al., 2010; Pollak, 2010).”
BackgroundMetformin prevents cell tumorigenesis through autophagy-related cell death
Santi, M. D., Baldelli, G., Diotallevi, A., Galluzzi, L., Schiavano, G. F., & Brandi, G. (2019) · Scientific Reports · doi:10.1038/s41598-018-37247-6 · Cited by 79
lncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1
Liu, X., & Gan, B. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1249545 · Cited by 77
“been increasing interest to re-examine phenformin as a potential agent in cancer prevention and treatment.(1-3,14)”
BackgroundMetformin impairs the growth of liver kinase B1-intact cervical cancer cells
Xiao, X., He, Q., Lu, C., Werle, K. D., Zhao, R.-X., Chen, J., Davis, B. C., Cui, R., Liang, J., & Xu, Z.-X. (2012) · Gynecologic Oncology · doi:10.1016/j.ygyno.2012.06.032 · Cited by 75
“Metformin is a biguanide derivative that has been widely used for treating diabetes mellitus [48].”
BackgroundRedaniel, M. T., Jeffreys, M., May, M., Ben‐Shlomo, Y., & Martin, R. M. (2012) · Cancer Causes & Control · doi:10.1007/s10552-012-0057-0 · Cited by 76
“We were not able to control for stage, tumor grade, and morphology, but our results are consistent with existing literature [13, 19, 23].”
BackgroundResultInhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions
Gutkind, J. S., Molinolo, A., Wu, X., Wang, Z., Nachmanson, D., Harismendy, O., Alexandrov, L. B., Wuertz, B. R. K., Ondrey, F. G., Laronde, D. M., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.147096 · 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
Metformin as an antitumor agent in cancer prevention and treatment
Li, D. (2011) · Journal of Diabetes · doi:10.1111/j.1753-0407.2011.00119.x · Cited by 68
“However, there are several key questions that need to be addressed before clinical trials can be optimally designed.(54) For example, how do we identify high-risk individuals who are most likely to benefit from metformin treatment? What are the optimal doses that should be used? What biomarkers could predict responses…”
BackgroundVrachnis, N., Iavazzo, C. R., Iliodromiti, Z., Sifakis, S., Alexandrou, A. P., Siristatidis, C. S., Grigoriadis, C., Botsis, D. S., & Creatsas, G. C. (2015) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-015-3858-z · Cited by 68
“cancer risk, while metformin seems to lower the risk [1].”
BackgroundTherapeutic aspects of AMPK in breast cancer: Progress, challenges, and future directions
Ponnusamy, L., Natarajan, S. R., Thangaraj, K., & Manoharan, R. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188379 · Cited by 68
Hawkes, A. L., Quinn, M. A., Gebski, V., Armes, J. E., Brennan, D. J., Janda, M., & Obermair, A. (2014) · Contemporary Clinical Trials · doi:10.1016/j.cct.2014.06.014 · Cited by 67
“There is an association between diabetes and cancer [19,20] and clinical observations have highlighted metformin as a potential anti-cancer therapy [21].”
BackgroundBocci, F., Jolly, M. K., George, J. T., Levine, H., & Onuchic, J. N. (2018) · Oncotarget · doi:10.18632/oncotarget.25692 · Cited by 67
Vazquez-Martin, A., López-Bonetc, E., Cufí, S., Oliveras-Ferraros, C., Del Barco, S., Martin-Castillo, B., & Menendez, J. A. (2011) · Drug Resistance Updates · doi:10.1016/j.drup.2011.04.003 · Cited by 66
“…molecular explanations for the effects of metformin on the proliferation and survival of fully transformed BC cells (Ben Sahra et al., 2010b; Berstein, 2010; GonzalezAngulo and Meric-Bernstam, 2010; Jalving et al., 2010; Martin-Castillo et al., 2010b; Pollak, 2010; Vazquez-Martin et al., 2010a,b).”
BackgroundInfluentialTherapeutic Repurposing of Biguanides in Cancer
Zhao, H., Swanson, K. D., & Zheng, B. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.03.001 · Cited by 69
Campagnoli, C., Pasanisi, P., Abbà, C., Ambroggio, S., Biglia, N., Brucato, T., Colombero, R., Danese, S., Donadio, M., Venturelli, E., et al. (2012) · Clinical Breast Cancer · doi:10.1016/j.clbc.2012.03.004 · Cited by 66
The Use of Metformin and Colorectal Cancer Incidence in Patients with Type II Diabetes Mellitus
Smiechowski, B., Azoulay, L., Yin, H., Pollak, M., & Suissa, S. (2013) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-13-0196 · Cited by 64
“making it a safe andpromising chemopreventive agent for colorectal cancer (2, 23), it is unclear whether such results can be extrapolated at the populational level.”
BackgroundSelf-citationChaudhary, S. C., Kurundkar, D., Elmets, C. A., Kopelovich, L., & Athar, M. (2012) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2012.01165.x · Cited by 65
Targeting the LKB1 Tumor Suppressor
Zhao, R., & Xu, Z. (2014) · Current Drug Targets · doi:10.2174/1389450114666140106095811 · Cited by 64
Cufí, S., Vázquez‐Martín, A., Oliveras‐Ferraros, C., Quirantes‐Piné, R., Segura‐Carretero, A., Micol, V., Joven, J., Bosch‐Barrera, J., Barco, S. D., Martı́n-Castillo, B., et al. (2012) · Cell Cycle · doi:10.4161/cc.11.6.19665 · Cited by 62
“because it may not have significant (if any) effects in non-diabetics individuals.(12-15) Because there is still a lack of retrospective clinical evidence for antitumor activity of metformin in nondiabetic individuals, strict criteria specifying high-risk populations in which metformin is expected to provide a greater…”
BackgroundDrug repurposing: Clinical practices and regulatory pathways
Saranraj, K., & Kiran, P. U. (2024) · Perspectives in Clinical Research · doi:10.4103/picr.picr_70_24 · Cited by 66
“…Sildenafil [40] Hypertension, angina Erectile dysfunction* Thalidomide [41] Sedative Multiple myeloma*, lepra reaction*, Behcet’s disease Metformin [42] Type 2 diabetes mellitus PCOS, anticancer, psoriasis Ivermectin [43] Antiparasitic Antiviral (COVID‑19), scabies Clozapine Schizophrenia…”
Westley, R., & May, F. E. B. (2013) · International Journal of Endocrinology · doi:10.1155/2013/632461 · Cited by 60
“Nonetheless, data are encouraging and suggest that further research into biguanides and their role in cancer protection is warranted [283].”
BackgroundMetformin Decreases Circulating Androgen and Estrogen Levels in Nondiabetic Women With Breast Cancer
Campagnoli, C., Berrino, F., Venturelli, E., Abbà, C., Biglia, N., Brucato, T., Cogliati, P., Danese, S., Donadio, M., Zito, G., et al. (2013) · Clinical Breast Cancer · doi:10.1016/j.clbc.2013.08.012 · Cited by 59
Repurposing old drugs to chemoprevention: the case of metformin
Heckman‐Stoddard, B. M., Gandini, S., Puntoni, M., Dunn, B. K., DeCensi, A., & Szabo, E. M. (2015) · Seminars in Oncology · doi:10.1053/j.seminoncol.2015.09.009 · Cited by 61
“In cancer cells, the consequences of this process include decreased protein synthesis, which correlates with reduced energy expenditure, and a decrease in cell proliferation [7,19].”
BackgroundInfluentialGerosuppressant Metformin: less is more
Menéndez, J. A., Cufí, S., Oliveras‐Ferraros, C., Vellón, L., Joven, J., & Vázquez‐Martín, A. (2011) · Aging · doi:10.18632/aging.100316 · Cited by 57
“Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report.”
BackgroundResultInfluentialChemoprevention Meets Glucose Control
Engelman, J. A., & Cantley, L. C. (2010) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-10-0178 · Cited by 58
Taghizadehghalehjoughi, A., Hacımüftüoğlu, A., Çetin, M., Kaplan, A. B. U., Gălățeanu, B., Mezhuev, Y. O., Okkay, U., Taşpınar, N., Taşpınar, M., Uyanık, A., et al. (2018) · Nanomedicine · doi:10.2217/nnm-2017-0386 · Cited by 54
Exenatide inhibits the growth of endometrial cancer Ishikawa xenografts in nude mice
Zhang, Y., Xu, F. L., Liang, H., Cai, M., Wen, X., Li, X., & Weng, J. (2015) · Oncology Reports · doi:10.3892/or.2015.4476 · Cited by 57
“Thus, we preliminarily conclude that exenatide (exendin-4) inhibits endometrial cancer Ishikawa growth through phosphorylating AMPK through GLP-1R signaling, which is similar to the mechanism of metformin on endometrial cancer cells (7-9).”
Richards, K. A., Liou, J., Cryns, V. L., Downs, T. M., Abel, E. J., & Jarrard, D. F. (2018) · The Journal of Urology · doi:10.1016/j.juro.2018.06.031 · Cited by 52
NCI's provocative questions on cancer: some answers to ignite discussion
Blagosklonny, M. V. (2011) · Oncotarget · doi:10.18632/oncotarget.432 · Cited by 51
“Also metformin decreases the risk of cancer in humans [206, 211-220].”
BackgroundMetformin and Cancer Stem Cells: Old Drug, New Targets
Bednar, F., & Simeone, D. M. (2012) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-12-0026 · Cited by 51
“Metformin belongs to the biguanide class of antidiabetic drugs and is of emerging interest for cancer prevention and therapy (17).”
BackgroundMetformin 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
“As such, this work provides information about the potential use of metformin for breast cancer prevention in a population of women who do not experience either condition.[42,46] Nonetheless, the data reported may not adequately reflect the potential for metformin to prevent breast cancer in obese and/or diabetic women.”
BackgroundInfluentialLiu, Z., Ren, L., Liu, C., Xia, T., Zha, X., & Wang, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0131207 · Cited by 50
“Biguanides, such as metformin and phenformin, are commonly used as therapeutics for type 2 diabetes[3].”
BackgroundMetformin: review of epidemiology and mechanisms of action in pancreatic cancer
Eibl, G., & Rozengurt, E. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09977-z · Cited by 51
AMPK: opposing the metabolic changes in both tumour cells and inflammatory cells?
Dandapani, M., & Hardie, D. G. (2013) · Biochemical Society Transactions · doi:10.1042/bst20120351 · Cited by 47
Singhal, J., Nagaprashantha, L. D., Vatsyayan, R., Awasthi, S., & Singhal, S. S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024688 · Cited by 48
“Metformin (Glucophage) is a biguanide-class hypoglycemic agent that operates primarily through inhibition of AMPK (which regulates the rate of endocytosis), but is also linked with PPARc through PGC1a (PPARc-receptor co-activator) [22].”
BackgroundLea, M. A., Chacko, J., Bolikal, S., Hong, J. Y., Chung, R., Ortega, A., & desBordes, C. (2011) · PubMed · Cited by 47
Metadata
- Authors
- Pollak, M.
- Affiliations
- Author's Affiliation: Department of Oncology, McGill University and Jewish General Hospital, Montreal, Quebec, Canada
- Venue
- Cancer Prevention Research
- Published
- 2010-09-01
- Volume
- 3
- Issue
- 9
- Pages
- 1060-1065
- ISSN
- 1940-6207 (ISSN-L)
- 1940-6215
- PMC
- PMC2954412
- OpenAlex
- W2165189414
- Cited by
- 240
- References
- 56
- Citations by year
- 2026: 12 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 9 · 2020: 5 · 2019: 12 · 2018: 11 · 2017: 11 · 2016: 8 · 2015: 23 · 2014: 14 · 2013: 23 · 2012: 44
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Prevention Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Prostate Cancer Foundation
- McGill University
- Prostate Cancer Canada
- National Institutes of Health (5r01ca101008-02)
- Canadian Cancer Society Research Institute
- National Cancer Institute (R01 CA101008)
- 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, biguanides, chemoprevention, cancer therapy, diabetes mellitus, mechanism of action, clinical trial design, laboratory model
- MeSH terms
- Animals, Antineoplastic Agents, Biguanides, Humans, Hypoglycemic Agents, Medical Oncology, Metformin, Neoplasms, Biomedical Research
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