4.7 Review

Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing

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Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides

Hannah R. Bridges et al.

Summary: We have characterized the molecular mode of action of biguanides by studying the drug-target interaction with cryo-electron microscopy and enzyme kinetics. Our results explain the selectivity of biguanide binding to different enzyme states and provide a structural basis for their action. This research also opens new opportunities for the rational design of medicinal biguanides.

SCIENCE (2023)

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Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions

Shan Liu et al.

Summary: This study examined the effects of metformin on cell growth, metabolic activities, and nutrient consumption under different oxygen and nutrient conditions. The results showed that the efficacy of metformin was influenced by cell types, oxygen conditions, and nutrient availability. Additionally, metformin was found to induce metabolic switch and may have potential as a combinational therapy.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Article Endocrinology & Metabolism

A behavioral weight-loss intervention, but not metformin, decreases a marker of gut barrier permeability: results from the SPIRIT randomized trial

Curtis Tilves et al.

Summary: This study aimed to investigate the effects of a behavioral weight-loss intervention and metformin treatment on plasma LBP. The results showed that only the behavioral weight-loss intervention reduced LBP compared to control, indicating that lifestyle weight-loss interventions that promote a DASH diet may effectively reduce gut barrier permeability to lipopolysaccharides.

INTERNATIONAL JOURNAL OF OBESITY (2022)

Article Oncology

Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives

Federica Barbieri et al.

Summary: Two novel CLIC1 blockers, Q48 and Q54, were identified as more potent antiproliferative agents for GSCs than metformin in vitro. Q48 and Q54 also showed inhibitory effects on GSC self-renewal, migration and invasion, with low systemic toxicity in vivo. These findings suggest that Q48 and Q54 may be potential CLIC1 blockers for the treatment of CLIC1-expressing glioblastomas.

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (2022)

Article Multidisciplinary Sciences

Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Teng Ma et al.

Summary: The molecular target of the antidiabetic medicine metformin is identified as PEN2, and the PEN2-ATP6AP1 axis activates the AMPK pathway, providing therapeutic effects without substantial adverse effects.

NATURE (2022)

Article Oncology

A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1)

Marijo Bilusic et al.

Summary: This study investigated the effects of metformin in prostate cancer treatment through a phase 2 trial. The results showed that metformin monotherapy induced modest declines in serum PSA levels in some patients and had an impact on immune cell subsets. However, the combination of metformin and bicalutamide did not improve the rate of achieving undetectable PSA at 32 weeks.

PROSTATE CANCER AND PROSTATIC DISEASES (2022)

Review Oncology

Hallmarks of Cancer: New Dimensions

Douglas Hanahan

Summary: The concept of the hallmarks of cancer is a tool for simplifying the complexity of cancer phenotypes and genotypes into basic principles. This article proposes phenotypic plasticity and disrupted differentiation as distinct hallmark capabilities, and discusses nonmutational epigenetic reprogramming and polymorphic microbiomes as enabling characteristics. Additionally, the importance of senescent cells in the tumor microenvironment is highlighted. The integrative concept of the hallmarks of cancer helps in understanding the mechanisms of cancer development and applying that knowledge to cancer medicine.

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Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma

Ai Zhuang et al.

Summary: This study revealed for the first time that metformin significantly inhibited the proliferation and migration of ocular melanoma cells in vitro and in vivo, acting as an autophagy inhibitor through histone deacetylation of OPTN. These findings provide novel insights into the potential use of metformin for ocular melanoma treatment and its dual role in autophagy regulation.

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Article Medicine, General & Internal

Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer The MA.32 Randomized Clinical Trial

Pamela J. Goodwin et al.

Summary: This study aimed to determine whether adjuvant metformin improves outcomes in breast cancer patients without diabetes. The results suggest that the addition of metformin to standard treatment did not significantly improve invasive disease-free survival in high-risk operable breast cancer patients.

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (2022)

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Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis

Eryun Zhang et al.

Summary: This study reveals that AMPK in the intestine modulates brown adipose tissue thermogenesis and affects energy balance and metabolic disorders. These findings provide important insights into the mechanism of metformin, a drug used to treat diabetes.

NATURE COMMUNICATIONS (2022)

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Metformin increases natural killer cell functions in head and neck squamous cell carcinoma through CXCL1 inhibition

McKenzie Crist et al.

Summary: The study demonstrates that metformin enhances the activation of peripheral NK cells and promotes NK cell-mediated cytotoxicity in HNSCC through downregulation of CXCL1.

JOURNAL FOR IMMUNOTHERAPY OF CANCER (2022)

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Impact of Concomitant Medications on Biochemical Outcome in Localised Prostate Cancer Treated with Radiotherapy and Androgen Deprivation Therapy

S. Roy et al.

Summary: The study evaluated the impact of commonly prescribed concomitant medications on biochemical relapse-free survival in patients with localized prostate cancer. It found that the use of metformin and sulfonamide-based alpha 1-receptor blockers was associated with inferior biochemical outcomes.

CLINICAL ONCOLOGY (2021)

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Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer

Hanyu Chen et al.

Summary: Metabolic syndrome is associated with increased risk of early-onset colorectal cancer, especially in relation to proximal and distal colon cancer.
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The Effect of Metformin in Treatment of Adenomas in Patients with Familial Adenomatous Polyposis

Jae Jun Park et al.

Summary: The study found that 7-month metformin treatment did not reduce the number or size of polyps in the colorectum or duodenum in FAP patients when compared to placebo. These results do not support the use of metformin to promote regression of intestinal adenomas in FAP patients.

CANCER PREVENTION RESEARCH (2021)

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Mechanisms of action of metformin and its regulatory effect on microRNAs related to angiogenesis

Gang Wang et al.

Summary: Angiogenesis plays a vital role in response to various pathological conditions, and anti-angiogenic therapy has emerged as an effective strategy for treating cancer and cardiovascular-related diseases. Metformin, as a first-line oral antidiabetic agent, not only benefits in diabetes but also shows positive effects on cancers, cardiovascular diseases, and angiogenesis regulation. MicroRNAs are crucial in controlling cardiovascular cell function and angiogenesis, with miR-21 being a key player in these processes.

PHARMACOLOGICAL RESEARCH (2021)

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Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas

Pooja Panwalkar et al.

Summary: Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and poor prognoses compared to group B ependymomas (PFBs). PFAs exhibit enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism, with high expression of glycolytic genes associated with a poor outcome. These tumors also show high EZHIP expression linked to a dismal prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Repurposing the antidiabetic drug metformin has shown therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts by targeting integrated metabolic/epigenetic pathways.

SCIENCE TRANSLATIONAL MEDICINE (2021)

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An epigenetic aging analysis of randomized metformin and weight loss interventions in overweight postmenopausal breast cancer survivors

Jamaji C. Nwanaji-Enwerem et al.

Summary: The study conducted a 6-month trial on breast cancer survivors and found limited effect of metformin on decelerating epigenetic age. Although there was a high correlation with chronological age, no significant association was observed between intervention arms and epigenetic age. Longer duration studies are needed to further characterize these relationships.

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Metformin Affects Gut Microbiome Composition and Function and Circulating Short-Chain Fatty Acids: A Randomized Trial

Noel T. Mueller et al.

Summary: The study found that metformin treatment significantly altered gut microbiota composition at both 6 months and 12 months, while behavioral weight loss did not have the same effect. Additionally, both metformin and behavioral weight loss changed circulating SCFAs at 6 months, with an increase in acetate correlating with lower fasting insulin levels. Further research is needed to explore whether the gut microbiome mediates or modifies the health effects of metformin.

DIABETES CARE (2021)

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Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial

Monika Janda et al.

Summary: This study examined the effectiveness of using LNG-IUD combined with M or WL in patients with EAC or EHA, and found that the pCR rates were high in all three groups at 6 months.

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Effects of Metformin on the virus/host cell crosstalk in human papillomavirus-positive cancer cells

Karin Hoppe-Seyler et al.

Summary: The study reveals that Metformin can effectively suppress the expression of HPV oncogenes in HPV-positive cancer cells, leading to a reversible proliferative halt without inducing senescence completely.

INTERNATIONAL JOURNAL OF CANCER (2021)

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Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment

Junjiro Yoshida et al.

Summary: The study demonstrated that a mitochondrial complex I inhibitor, intervenolin, can suppress tumor growth by modulating lactate metabolism and inducing cellular acidification, presenting a potential treatment strategy for solid tumors.

ISCIENCE (2021)

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A randomized controlled trial of metformin in women with components of metabolic syndrome: intervention feasibility and effects on adiposity and breast density

Edgar Tapia et al.

Summary: The study found that metformin intervention has a positive impact on obesity-related breast cancer risk, showing potential in primary breast cancer prevention and improving waist circumference and waist-to-hip ratio. However, more research is needed to understand the impact of this treatment on breast density and non-dense breast volume.

BREAST CANCER RESEARCH AND TREATMENT (2021)

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Metformin: review of epidemiology and mechanisms of action in pancreatic cancer

Guido Eibl et al.

Summary: Metformin has beneficial effects in pancreatic cancer, reducing the risk of developing the disease and improving survival in patients, mainly through its direct effects on transformed pancreatic epithelial cells and indirect effects on extra-pancreatic tissues.

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TAXOMET: A French Prospective Multicentric Randomized Phase II Study of Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in Metastatic Castration-Resistant Prostate Cancer

Marc Pujalte Martin et al.

Summary: In mCRPC patients, the addition of MET did not improve the standard DOCE regimen, although there were some trends in certain indicators. Therefore, further research targeting tumor cell metabolism should be conducted.

CLINICAL GENITOURINARY CANCER (2021)

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Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer

Jingjing Yang et al.

Summary: This study demonstrates that metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, metformin increases the intracellular Fe2+ and lipid ROS levels by targeting the UFMylation process of SLC7A11. Additionally, combining metformin with the x(c)(-) inhibitor sulfasalazine synergistically induces ferroptosis and inhibits the proliferation of breast cancer cells.

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (2021)

Article Multidisciplinary Sciences

PD-L1 degradation is regulated by electrostatic membrane association of its cytoplasmic domain

Maorong Wen et al.

Summary: The cytoplasmic domain of PD-L1 (PD-L1-CD) is involved in regulating PD-L1 stability and degradation. Here the authors show that membrane binding of PD-L1-CD mediates the cellular levels of PD-L1, while metformin can disrupt the interaction between PD-L1-CD and the membrane to reduce PD-L1 levels.

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Effects of a Behavioral Weight Loss Intervention and Metformin Treatment on Serum Urate: Results from a Randomized Clinical Trial

Jiun-Ruey Hu et al.

Summary: The study investigated the impact of weight loss and metformin treatment on serum urate in overweight/obese adult cancer survivors. While weight loss reduced BMI in the coach-directed and metformin groups, it unexpectedly increased serum urate in the coach-directed group. These findings suggest that BMI reduction may not necessarily lead to a decrease in serum urate levels. Long-term studies are needed to further investigate this relationship.

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Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer The NRG-LU001 Phase 2 Randomized Clinical Trial

Heath Skinner et al.

Summary: The addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC in this randomized clinical trial.

JAMA ONCOLOGY (2021)

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Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects

Ratna Veeramachaneni et al.

Summary: Metformin has complex systemic and local immune effects that vary depending on treatment duration. Acute metformin exposure does not show significant antitumor activity, but long-term treatment can reduce tumor growth velocity, increase the CD8+/T-reg ratio, and enhance tumor infiltrating lymphocyte levels. Combinatorial strategies with immune checkpoint inhibitors need to consider these effects in order to maximize antitumor activity in future clinical trials.

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Phase II study of liposomal doxorubicin, docetaxel and trastuzumab in combination with metformin as neoadjuvant therapy for HER2-positive breast cancer

Andrea Rocca et al.

Summary: The study aimed to improve the efficacy of neoadjuvant regimens for HER2-positive breast cancer by combining trastuzumab, liposomal doxorubicin, docetaxel, and metformin, but did not show superior activity compared to conventional sequential regimens.

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Metformin Effects on FOXP3+and CD8+T Cell Infiltrates of Head and Neck Squamous Cell Carcinoma

Dev Amin et al.

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Metformin-repressed miR-381-YAP-snail axis activity disrupts NSCLC growth and metastasis

Dan Jin et al.

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Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma

Bo Li et al.

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Long-Term Weight Loss With Metformin or Lifestyle Intervention in the Diabetes Prevention Program Outcomes Study

John W. Apolzan et al.

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Martin J. Spiering

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Antitumour effects of metformin and curcumin in human papillomavirus positive and negative head and neck cancer cells

Cameron Lindsay et al.

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Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity

Tien S. Dong et al.

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Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy

Rosina Pryor et al.

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Metformin targets a YAP1-TEAD4 complex via AMPKα to regulate CCNE1/2 in bladder cancer cells

Yanju Wu et al.

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Bioactivity and prostate tissue distribution of metformin in a preprostatectomy prostate cancer cohort

Mike M. Nguyen et al.

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Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism

E. Cuyas et al.

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Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Elisabet Cuyas et al.

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Ritwika Mallik et al.

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Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function

Lixin Wan et al.

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Effect of metformin on the survival of patients with ALL who express high levels of the ABCB1 drug resistance gene

Christian Ramos-Penafiel et al.

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Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1

Jong-Ho Cha et al.

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Metformin as an Anticancer Agent

Ales Vancura et al.

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Gut microbiota and intestinal FXR mediate the clinical benefits of metformin

Lulu Sun et al.

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Marc E. De Broe et al.

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Metformin alters DNA methylation genome-wide via the H19/SAHH axis

T. Zhong et al.

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Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia

Nicole E. Scharping et al.

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Metformin targets gastric cancer stem cells

Sarah Courtois et al.

EUROPEAN JOURNAL OF CANCER (2017)

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Ruth E. Farmer et al.

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Metformin Effects on Head and Neck Squamous Carcinoma Microenvironment: Window of Opportunity Trial

Joseph Curry et al.

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Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells

Wei Xie et al.

MEDICAL SCIENCE MONITOR (2017)

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Repurposing metformin for the prevention of cancer and cancer recurrence

Brandy M. Heckman-Stoddard et al.

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Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling

Kari Brown et al.

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Upasna Sharma et al.

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Carlos Lopez-Otin et al.

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An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer

Lianfeng Wu et al.

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Metformin: An anti-diabetic drug to fight cancer

Marie Daugan et al.

PHARMACOLOGICAL RESEARCH (2016)

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Metabolic control of epigenetics in cancer

Adam Kinnaird et al.

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p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells

Puyu Li et al.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2015)

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Metformin Does Not Reduce Markers of Cell Proliferation in Esophageal Tissues of Patients With Barrett's Esophagus

Amitabh Chak et al.

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NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin

Dong Suwei et al.

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Effect of Metformin vs Placebo on Weight and Metabolic Factors in NCIC CTG MA.32

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JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE (2015)

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Metformin and cancer: Between the bioenergetic disturbances and the antifolate activity

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Immune-mediated antitumor effect by type 2 diabetes drug, metformin

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Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo

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Cellular senescence: from physiology to pathology

Daniel Munoz-Espin et al.

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Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells

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Metformin Reduces Endogenous Reactive Oxygen Species and Associated DNA Damage

Carolyn Algire et al.

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Metformin in cancer: translational challenges

Ryan J. O. Dowling et al.

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AMPK: a nutrient and energy sensor that maintains energy homeostasis

D. Grahame Hardie et al.

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Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells

Chang W. Song et al.

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Metformin in prostate cancer: two for the price of one

A. Clements et al.

ANNALS OF ONCOLOGY (2011)

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Garry G. Graham et al.

CLINICAL PHARMACOKINETICS (2011)

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In vitro and in vivo anti-melanoma action of metformin

Kristina Janjetovic et al.

EUROPEAN JOURNAL OF PHARMACOLOGY (2011)

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Diabetes and Cancer: A Consensus Report

Edward Giovannucci et al.

CA-A CANCER JOURNAL FOR CLINICIANS (2010)

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Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis

Andrea DeCensi et al.

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Tamas A. Gonda et al.

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IGF and Insulin Receptor Signaling in Breast Cancer

Antonino Belfiore et al.

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AMPK phosphorylation of raptor mediates a metabolic checkpoint

Dana M. Gwinn et al.

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Rury R. Holman et al.

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Michael Pollak

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Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells

Mahvash Zakikhani et al.

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Milica Momcilovic et al.

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JMM Evans et al.

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