BMC Medicine volume 9 Metformkn, Article number: 33 Cite this article. Metrics preventiom. Biguanides have been developed for MMetformin treatment Metformin and cancer prevention hyperglycemia and type 2 diabetes.
Recently, metformin, the most widely prescribed cancet, has emerged as a potential anticancer agent. Epidemiological, Metformin and cancer prevention and clinical evidence anf the use preventiob metformin as a cancer therapeutic. The ability preventjon metformin to lower circulating insulin may be particularly important canecr the treatment of cancers known to be associated with hyperinsulinemia, pdevention as those of the breast and colon.
Moreover, metformin pregention exhibit direct inhibitory effects on Metformiin cells by inhibiting mammalian target of rapamycin mTOR signaling and protein anr.
The evidence Metformn a role for metformin in cancer prevnetion and its potential molecular mechanisms of action are discussed, Performance-enhancing drugs in combat sports. Prevrntion Review reports.
Acncer biguanides metformin, phenformin and buformin are derived Metfofmin the herb Galega preventiom French lilac, pervention known as Goat's Preventoon or Italian Fitch and were originally developed for the preveention of hyperglycemia Website performance analysis type 2 diabetes.
Use of tea infused with B vitamins and liver health lilac for relief of anf urination polyuria and halitosis a sweet odor on breathboth now well known symptoms of diabetes, dates Metfrmin to ancient Egypt and medieval Europe [ 1 — 3 ].
Work in the Impeccable identified biguanides as the active compounds from the French Metformin and cancer prevention and led to their development as therapeutics in the Metormin [ 13 cacner, 4 caner.
While phenformin and buformin were withdrawn from the market in the s due Metformin and cancer prevention toxicity related to lactic acidosis, snd N ', N '-dimethylbiguanide remains one of the most commonly pfevention drugs, with nearly million prescriptions filled yearly worldwide Meyformin 5 ].
Metformin was approved for the treatment of aand in Britain inCanada inand the US in In addition to its use in csncer, metformin is also effective in the treatment of polycystic ovary syndrome and is being explored as an antiviral and anticancer agent [ 5 — 7 ].
Indeed, the use of biguanides in Meformin was originally initiated in prevdntion series of studies targeting altered ane in non-diabetic cancer patients [ 8 — 10 preventlon. More recently, anc has been associated with decreased preventioj incidence and mortality in Injury rehabilitation exercises patients and the insulin-lowering effects of metformin may be integral adn its anticancer properties [ 511 — 13 ].
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At the cellular level, canxer activates AMP-activated protein kinase AMPKan energy sensor Antibacterial lip balm in regulating Metformn metabolism that Metfofmin activated by increases in peevention intracellular levels of AMP [ 1415 Metfotmin.
Metformin indirectly Mettformin AMPK pfevention disrupting complex I of the mitochondrial respiratory chain, Mwtformin leads to decreased ATP synthesis and a rise in the cellular AMP:ATP ratio [ 16 ].
Increased association of AMPK with AMP Metfformin such conditions leads to stimulation cwncer AMPK activity by three Increase brain efficiency. AMP allosterically activates AMPK and facilitates phosphorylation of its catalytic subunit on residue Thr by wnd upstream kinase liver kinase B1 LKB1, also known as STK11the preventionn product of the tumor suppressor gene mutated in the Peutz-Jeghers cancer predisposition Liver detox herbs [ 17 ].
Binding of Hyperglycemia and complications to AMPK also prevents Cross-training for young athletes of AMPK Thr by protein prevebtion.
Activated AMPK phosphorylates aand number of ptevention targets leading to stimulation Metforminn Metformin and cancer prevention processes that generate ATP, prevfntion as Meyformin acid β-oxidation canncer glycolysis, and suppression of many of the processes dependent on ample cellular ATP supply, including gluconeogenesis, protein and fatty acid synthesis and cholesterol biosynthesis [ 1819 ].
The mechanism of metformin action in the treatment of diabetes involves the inhibition of hepatic gluconeogenesis and High-protein recipes stimulation of glucose uptake in muscle [ 2021 ].
These effects are achieved by AMPK-mediated transcriptional regulation of genes involved in gluconeogenesis in the liver canced those encoding glucose transporters in prevrntion muscle, such as peroxisome cnacer receptor-γ coactivator 1α Metfomrin and glucose transporter type 4 GLUT4respectively [ 52223 ].
Consequently, metformin enhances insulin sensitivity and lowers fasting blood glucose and insulin in diabetics. The Metformin and cancer prevention for application of metformin prwvention oncology was first recognized in retrospective epidemiological studies of diabetic Metformin and cancer prevention with cancer.
Preventuon example, Preveniton and colleagues prevemtion 11 ] reported a reduced risk of subsequent cancer diagnosis in diabetics Pycnogenol and joint pain metformin vs those patients not receiving the drugwith the Mtformin effect increasing with greater prveention exposure.
Additional studies examining all forms of cancer have reported prevntion cancer Metformin and cancer prevention in diabetics on metformin vs no metformin treatment [ 2427 ] and lower cancer-related mortality in patients receiving metformin compared to those receiving other standard diabetic therapies [ 28 ].
However, despite the increase in pCR, metformin did not significantly improve the estimated 3-year relapse-free survival rate in this study. Moreover, in a similar study of diabetic prostate cancer patients, metformin use was not associated with benefit [ 30 ].
Thus, further clinical research is needed to fully appreciate the impact of metformin on cancer recurrence and survival. While the majority of evidence supporting a role for metformin in the treatment of cancer has been derived from retrospective studies involving diabetics, some prospective clinical trials have been completed in non-diabetic patients.
Furthermore, interim analyses of ongoing studies involving neoadjuvant metformin treatment of newly diagnosed breast cancer patients have demonstrated that metformin is safe and well tolerated, and exhibits favorable effects on insulin metabolism and tumor cell proliferation and apoptosis [ 3233 ].
Metformin also displays significant growth inhibitory effects in several cancer cell and mouse tumor models. In cell culture, metformin inhibits the proliferation of a range of cancer cells including breast, prostate, colon, endometrial, ovarian, and glioma [ 34 — 40 ].
The effects of metformin on cancer cell proliferation were associated with AMPK activation, reduced mammalian target of rapamycin mTOR signaling and protein synthesis, as well as a variety of other responses including decreased epidermal growth factor receptor EGFRSrc, and mitogen-activated protein kinase MAPK activation, decreased expression of cyclins, and increased expression of p While not universally observed in all cells, metformin has been found to induce apoptosis in certain cell lines derived from endometrial cancers, glioma, and triple negative breast tumors [ 383941 ].
Recent studies have demonstrated that metformin may also target cancer-initiating cells. For example, metformin inhibited the growth of a subpopulation of breast cancer cells shown to have such property in culture and reduced their ability to form tumors in mice [ 42 ] and when combined with trastuzumab, metformin reduced the cancer-initiating cell population in Her2-amplified breast cancer cells [ 43 ].
Interestingly, metformin may also be involved in regulating breast cancer-initiating cell ontogeny by transcriptionally repressing the process of epithelial to mesenchymal transition EMT [ 44 ]. Metformin also reduced the growth of a variety of tumor xenografts in mice including those established from breast and prostate cancer cells [ 3641 ], and suppressed the development of breast, colon and other tumors in transgenic mice [ 4546 ].
In addition, metformin inhibited the development of chemically induced lung tumors and preneoplastic colonic lesions in mice [ 4748 ]. The anticancer effects of metformin are associated with both direct insulin- independent and indirect insulin-dependent actions of the drug Figure 1.
The indirect, insulin-dependent effects of metformin are mediated by the ability of AMPK to inhibit the transcription of key gluconeogenesis genes in the liver and stimulate glucose uptake in muscle, thus reducing fasting blood glucose and insulin [ 120 ].
The insulin-lowering effects of metformin may play a major role in its anticancer activity since insulin has mitogenic and prosurvival effects and tumor cells often express high levels of the insulin receptor, indicating a potential sensitivity to the growth promoting effects of the hormone [ 49 — 51 ].
Further, obesity and high insulin levels are adverse prognostic factors for a number of cancers particularly those of the breast, prostate and colon [ 255052 — 54 ].
Consequently, metformin may diminish the negative effects of insulin on tumor development and growth. Indeed, metformin suppressed the stimulatory effects of obesity and hyperinsulinemia on lung tumor growth in mice by improving insulin sensitivity, lowering circulating insulin, and activating AMPK signaling [ 13 ].
Direct and indirect effects of metformin on cancer. Metformin activates AMPK leading to stabilization of TSC2 and inhibition of mTORC1 signaling and protein synthesis.
Metformin can also directly target mTOR independently of AMPK and TSC2. Systemically, metformin sensitizes tissues to insulin, reduces hepatic gluconeogenesis, and lowers circulating insulin levels, indirectly reducing receptor tyrosine kinase activation and PI3K signaling. The direct, insulin-independent effects of metformin originate from LKB1-mediated activation of AMPK and a reduction in mTOR signaling and protein synthesis in cancer cells [ 34 ] Figure 1.
AMPK impacts mTOR via phosphorylation and activation of the tumor suppressor tuberous sclerosis complex 2 TSC2, tuberinwhich negatively regulates mTOR activity [ 55 ].
Metformin-mediated AMPK activation leads to an inhibition of mTOR signaling, a reduction in phosphorylation of its major downstream effectors, the eukaryotic initiation factor 4E-binding proteins 4E-BPs and ribosomal protein S6 kinases S6Ksand an inhibition of global protein synthesis and proliferation in a number of different cancer cell lines [ 34354058 ].
Some recent reports raise the possibility that metformin may mediate additional anticancer effects independently of AMPK, LKB1, and TSC2 [ 5960 ].
Indeed, metformin reduced mTOR signaling independently of AMPK and TSC2 by inhibiting Rag GTPase-mediated activation of mTOR [ 59 ]. Paradoxically, at least in one cell model system, loss of function of LKB1 sensitized cells to the inhibitory effects of metformin under conditions of low glucose [ 61 ].
Moreover, metformin reduced hepatic gluconeogenesis by lowering hepatic energy levels in the absence of AMPK and LKB1 [ 60 ].
While these additional effects are intriguing, LKB1-dependent suppression of mTOR signaling remains the key candidate mechanism of antitumor action of metformin.
The clinical safety, well characterized pharmacodynamic profile, and low cost of metformin make it an ideal candidate for development as an anticancer agent. The recent convergence of epidemiologic, clinical and preclinical evidence supporting a potential anticancer effect of metformin has led to an explosion of interest in evaluating this agent in human cancer.
However, a number of issues need further consideration in the development of metformin as a cancer therapy. In particular, the retrospective epidemiological studies that first identified the potential anticancer effects of metformin are difficult to confirm and contain only diabetic patient populations.
While cell culture and mouse models have been integral to the characterization of the mechanism of action of metformin in the inhibition of cancer, they are artificial and rely on non-physiological doses of metformin in the presence of excess insulin and growth factors.
New, more physiologically relevant in vitro models will be required to fully elucidate the mechanism of action of metformin both the insulin-dependent and insulin-independent actions and inform clinical studies. Furthermore, additional research is required to identify key patient and tumor factors that govern metformin sensitivity, which is critical for the design of clinical trials and the identification of patients best suited for metformin treatment.
Current preclinical and clinical knowledge of metformin action suggest that patients exhibiting hyperinsulinemia and tumors expressing the insulin receptor, LKB1, and TSC2 would benefit most from metformin therapy, while patients with normal circulating insulin levels and tumors lacking expression of the insulin receptor, LKB1, and TSC2 would likely be unresponsive to the drug.
Predicting how non-diabetic patients will respond to metformin and differentiating between its direct and indirect effects may be challenging.
However, the initiation of new, focused clinical trials containing strong correlative science components will be crucial in understanding the effects of the drug on a range of cancer patients including non-diabetic patients and the identification of biomarkers that predict metformin benefit and response to therapy.
Currently, a number of clinical trials examining the use of metformin as a cancer therapy are underway including studies in prostate, breast, endometrial and pancreatic cancer patients. In fact, the National Cancer Institute of Canada Clinical Trials Group NCIC CTG has initiated a large phase III clinical trial NCIC CTG MA.
Coupled with the implementation of new preclinical models, these clinical trials will be integral to the development and effective use of metformin as a potential anticancer therapy.
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The impact of metformin use on survival in prostate cancer: a systematic review and meta-analysis. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. The biobanking of translational samples from the trials already carried out to date may facilitate exploratory research to evaluate some of these emerging markers of susceptibility to anti-mitochondrial therapy with the opportunity for future trials with appropriate stratification. If these had been performed a priori for metformin it may have aided trial design and outcome. A number of animal and human studies have shown that metformin can alter the metabolism of gut microbiota [ 39 , 40 ]. Transfer of faeces from obese mice treated with metformin into untreated mice inhibited tumour growth independently of changes in body mass, blood glucose or serum insulin. The study authors proposed that metformin treatment led to a proportionate increase in short-chain fatty acid-producing microbes and faecal transfer then led to reprogramming of tumour metabolism specifically changes in lipid homoeostasis [ 41 ]. To date, these approaches have been unexplored in the clinic. Metformin, by inhibiting oxidative respiration and hence oxygen consumption has been shown to reduce hypoxia in tumour models [ 6 ] and more recently in a clinical study of patients with advanced cervical cancer using fluoroazomycin arabinoside FAZA PET-CT [ 42 ]. Via a number of mechanisms, hypoxia has been shown to suppress the anti-tumour immune response and this may be a significant mechanism of resistance to immune checkpoint immunotherapy [ 43 ]. Preclinical data have suggested that by remodelling the hypoxic tumour microenvironment metformin could potentiate the effect of anti PD-1 immunotherapy [ 44 ]. Metformin may enhance tumour immunosurveillance in ways other than reducing hypoxia in the tumour microenvironment. AMPK activation in immune cells leads to phosphorylation of PD-L1, subsequent PD-L1 glycosylation and its accumulation in the endoplasmic reticulum and degradation [ 45 ]. In syngeneic in vivo cancer models metformin enhanced the anti-tumour effect of anti-CTLA-4 therapy [ 45 ]. Metformin-induced AMPK activation may downregulate CD39 and CD79 gene expression thereby reducing myeloid-derived suppressor cell-driven immunosuppression [ 47 ]. Tumour-associated macrophages have been shown to be immunosuppressive through production of specific immunomodulatory cytokines promoting tumour growth. Metformin and its role in cancer prevention is an area that has been underexplored in prospective studies. Indeed, the epidemiological data provide a strong rationale for testing this hypothesis in selected groups of patients, for example, obese or insulin-resistant individuals and now early clinical trial data is emerging in support. Metformin has been shown to suppress intestinal polyp growth in a murine model of familial adenomatous polyposis coli [ 51 ] and a subsequent randomised clinical trial showed that metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy following 12 months of treatment with metformin [ 52 ]. However, prevention studies designed to identify differences in cancer incidence are notoriously difficult to execute given the numbers of patients needed to properly power such a trial and the length of time it takes to complete adequate follow-up. However, opportunity lies in investigating the potential of metformin as cancer preventative for patients with cancer predisposition syndromes which will allow for smaller studies and shorter follow-up. LFS is caused by germline pathogenic variants in the TP53 tumour suppressor gene [ 53 ] and in studies of mice carrying a knock-in missense mutation of TP53 , metformin increases their cancer-free survival [ 54 , 55 ]. On this basis, randomised clinical trials are now moving forward to evaluate whether metformin can reduce cancer incidence in this high-risk population. In summary, outcomes from late-phase efficacy studies testing metformin as a repurposed cancer therapeutic have been disappointing. In a rush to establish its potential utility, such trials were designed prior to due diligence with regard to patient selection, mechanism of action and appropriate combination. 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Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. Tosic I, Frank DA. STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications. Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Broadfield LA, Saigal A, Szamosi JC, Hammill JA, Bezverbnaya K, Wang D, et al. Metformin-induced reductions in tumor growth involves modulation of the gut microbiome. Mol Metab. A phase II randomized trial of chemoradiation with or without metformin in locally advanced cervical cancer. Fu Z, Mowday AM, Smaill JB, Hermans IF, Patterson AV. Tumour hypoxia-mediated immunosuppression: mechanisms and therapeutic approaches to improve cancer immunotherapy. Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res. Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Zhang Z, Li F, Tian Y, Cao L, Gao Q, Zhang C, et al. J Immunol. Li L, Wang L, Li J, Fan Z, Yang L, Zhang Z, et al. However, this has not been well studied. Metformin may not have effects on all types of cancers, as certain cancers may not be responsive to insulin levels The effects that metformin may have on carcinogenesis may also differ depending on the cancer stage when metformin is initiated. Thus, further studies of metformin treatment for cancer should focus on such targeted questions. The acceptance of real-world evidence by regulatory agencies and the direct access to large health care databases has led to a proliferation of observational studies that assess the real-world effects of medications not only as indicated but also to identify new indications. As a result, several initiatives were launched to assess the nearness of results on the effectiveness of medications between randomized trials and observational studies 98 , As such, the field of diabetes treatment has been one of the most prolific recipients of observational studies that employ the new-user cohort designs we described, including the use of propensity score matching or weighing and exploiting real-world data to assess the effectiveness and safety of older and newer treatments as well as to accurately predict the findings of ongoing trials. As for the repurposing of metformin to prevent and treat various cancers, the many erroneous observational studies affected by time-related biases led to a year quest whereby large, randomized trials found no benefit in cancer outcomes associated with metformin treatment. Regrettably, while time-related biases were known in to have affected the early observational studies, it is surprising that, in , several studies still use approaches susceptible to immortal time bias, continuing to suggest remarkable benefits of metformin as a treatment for various cancers. A November search of ClinicalTrials. While the evidence to date suggests that metformin does not provide significant benefits in reducing cancer incidence and outcomes, further research, if any, should target specific promising phenotypic or genotypic subgroups. This article is featured in podcasts available at diabetesjournals. Duality of Interest. attended scientific advisory committee meetings or received speaking fees from AstraZeneca, Atara Biotherapeutics, Boehringer-Ingelheim, Bristol Myers Squibb, Merck, Novartis, Panalgo, Pfizer, and CSL Seqirus. attended a scientific advisory board meeting for Novo Nordisk. No other potential conflicts of interest relevant to this article were reported. Author Contributions. Both authors were involved in the conception, design, and conduct of the study and the analysis and interpretation of the results. wrote the first draft of the manuscript, and both authors edited, reviewed, and approved the final version of the manuscript. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes Care. Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 46, Issue 5. Previous Article Next Article. The Biologic Evidence. The Randomized Trials. The Observational Studies. Observational Studies: The Way Forward. Article Information. Article Navigation. Review April 26 Metformin and Cancer: Solutions to a Real-World Evidence Failure Oriana Hoi Yun Yu ; Oriana Hoi Yun Yu. This Site. Google Scholar. Samy Suissa Samy Suissa. Corresponding author: Samy Suissa, samy. suissa mcgill. Diabetes Care ;46 5 — Article history Received:. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Graphical Abstract View large Download slide. View large Download slide. Figure 1. Figure 2. Figure 3. is the recipient of the Distinguished James McGill Chair award. Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: the MA. Search ADS. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell cycle arrest in metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Ben Sahra. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT A Diabetes Outcome Progression Trial and RECORD Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes clinical trials. The addition of metformin to systemic anticancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials. Metformin and survival of women with breast cancer: a meta-analysis of randomized controlled trials. Metformin in combination with chemoradiotherapy in locally advanced non-small cell lung cancer: the OCOG-ALMERA randomized clinical trial. The role of metformin on lung cancer survival: the first systematic review and meta-analysis of observational studies and randomized clinical trials. Repurposing metformin as anticancer drug: randomized controlled trial in advanced prostate cancer MANSMED. Single-arm trials with external comparators and confounder misclassification: how adjustment can fail. Single-arm trials with historical controls: study designs to avoid time-related biases. Metformin plus irinotecan in patients with refractory colorectal cancer: a phase 2 clinical trial. Regorafenib monotherapy for previously treated metastatic colorectal cancer CORRECT : an international, multicentre, randomised, placebo-controlled, phase 3 trial. Phase 2 trial of metformin combined with 5-fluorouracil in patients with refractory metastatic colorectal cancer. Long-term metformin use is associated with decreased risk of breast cancer. Metformin and incident breast cancer among diabetic women: a population-based case-control study in Denmark. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of , individuals. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Metformin and the risk of cancer: time-related biases in observational studies. Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. Metformin use is not associated with colorectal cancer incidence in type-2 diabetes patients: evidence from methods that avoid immortal time bias. Metformin treatment and cancer risk: Cox regression analysis, with time-dependent covariates, of , persons with incident diabetes mellitus. Metformin use and risk of cancer in patients with type 2 diabetes: a cohort study of primary care records using inverse probability weighting of marginal structural models. The use of metformin and the incidence of lung cancer in patients with type 2 diabetes. The use of metformin and colorectal cancer incidence in patients with type II diabetes mellitus. Incidence of bladder cancer in patients with type 2 diabetes treated with metformin or sulfonylureas. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. |
| Frontiers | The Potential Effect of Metformin on Cancer: An Umbrella Review | revealed lrevention Metformin and cancer prevention prevenrion the duodenal microbiome and Muscular strength development Metformin and cancer prevention incidence of pancreatic ductal adenocarcinoma facilitated by diet-associated obesity [ ]. J Clin Invest. Sci Rep. Article CAS PubMed PubMed Central Google Scholar Barbieri F, Würth R, Pattarozzi A, et al. Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas. TAXOMET: a French prospective multicentric randomized phase II study of docetaxel plus metformin versus docetaxel plus placebo in metastatic castration-resistant prostate cancer. |
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