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Park JS, Moon SJ, Park HS, Cho SH. Survival benefit of metformin use according to cancer diagnosis in diabetic patients with metabolic syndrome. Prev Med Rep 2024; 48:102928. [PMID: 39634282 PMCID: PMC11616528 DOI: 10.1016/j.pmedr.2024.102928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 11/05/2024] [Accepted: 11/06/2024] [Indexed: 12/07/2024] Open
Abstract
Background Metabolic syndrome (MetSyn) is a disease cluster causing cardiovascular disease, cancer, and high mortality. Metformin is the most common antidiabetic agent inhibiting the tumorigenesis and insulin resistance of MetSyn. We describe the association between metformin intake and survival of patients with type 2 diabetes mellitus (T2DM) and MetSyn, according to the presence of cancer. Methods We analyzed the clinical characteristics and all-cause mortality of patients with T2DM and MetSyn using a 5-year dataset between January 1, 2009 and December 31, 2013 derived from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). Cox proportional hazards regression models were used to investigate metformin effects adjusted for other potential confounding variables. Results Among a total of 43,043 patients with both MetSyn and T2DM, 24,725 patients (57.4 %) received metformin regularly. Female sex, high income, regular exercise, and metformin use were good prognostic factors, whereas hypertension, current smoking, cancer, and diabetes medication (except metformin) were poor prognostic factors. After adjustment for possible confounding variables, metformin showed a significant effect on patient survival (hazard ratio [HR], 0.68; 95 % confidence interval [CI], 0.63-0.75; p < 0.001). The effect of metformin was pronounced on the group of patients with liver, lung, colorectal, or prostate cancers (HR, 0.57; CI, 0.46-0.70). Conclusions Metformin intake may be related to favorable survival among patients with T2DM and MetSyn. The efficacy might be more remarkable in those with liver, lung, colorectal, and prostate cancers. The potential benefit of metformin in patients with these risk factors should be further investigated.
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Affiliation(s)
- Ji Soo Park
- Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
- Division of Medical Oncology, Department of Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Jin Moon
- Department of Statistics and Actuarial Science, Soongsil University, South Korea
| | - Hyung Seok Park
- Cancer Prevention Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang-Hoon Cho
- Department of Statistics and Actuarial Science, Soongsil University, South Korea
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Smiles WJ, Ovens AJ, Oakhill JS, Kofler B. The metabolic sensor AMPK: Twelve enzymes in one. Mol Metab 2024; 90:102042. [PMID: 39362600 PMCID: PMC11752127 DOI: 10.1016/j.molmet.2024.102042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/12/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of αβγ-subunits that in humans are encoded by seven individual genes (isoforms α1, α2, β1, β2, γ1, γ2 and γ3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined. SCOPE OF REVIEW Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the α-subunit), altogether highlighting opportunities for future and impactful research. MAJOR CONCLUSIONS Baseline activity of α1-AMPK is higher than its α2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. α2 complexes however, show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers α1 is a tumour promoter and α2 a suppressor. β1-AMPK activity is toggled by a 'myristoyl-switch' mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. β2-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the γ2 and γ3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in γ2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, γ3 complexes might be preferentially regulated by mTORC1 in response to physical exercise.
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Affiliation(s)
- William J Smiles
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria; Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia.
| | - Ashley J Ovens
- Protein Engineering in Immunity & Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia
| | - Jonathan S Oakhill
- Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia; Department of Medicine, University of Melbourne, Parkville, Australia
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
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Tan XD, Luo CF, Liang SY. Antihyperlipidemic drug rosuvastatin suppressed tumor progression and potentiated chemosensitivity by downregulating CCNA2 in lung adenocarcinoma. J Chemother 2024; 36:662-674. [PMID: 38288951 DOI: 10.1080/1120009x.2024.2308975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/13/2024] [Accepted: 01/15/2024] [Indexed: 11/22/2024]
Abstract
Rosuvastatin (RSV) is widely used to treat hyperlipidemia and hypercholesterolemia and is recommended for the primary and secondary prevention of cardiovascular diseases (CVD). In this study, we aimed to explore its action and mechanism in lung adenocarcinoma (LUAD) therapy. Lewis and CMT64 cell-based murine subcutaneous LUAD models were employed to explore the effects of RSV monotherapy combined with cisplatin and gemcitabine. Human lung fibroblasts and human LUAD cell lines were used to assess the effects of RSV on normal and LUAD cells. Bioinformatics and RNA interference were used to observe the contribution of cyclin A2 (CCNA2) knockdown to RSV inhibition and to improve chemosensitivity in LUAD. RSV significantly suppressed grafted tumor growth in a murine subcutaneous LUAD model and exhibited synergistic anti-tumor activity with cisplatin and gemcitabine. In vitro and in vivo experiments demonstrated that RSV impaired the proliferation and migration of cancer cells while showing little inhibition of normal lung cells. RNA interference and CCK8 detection preliminarily indicated that RSV inhibited tumor growth and enhanced the chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2. RSV suppressed LUAD progression and enhanced chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2, which should be prior consideration for the treatment of LUAD, especially for patients co-diagnosed with hyperlipidemia and hypercholesterolemia.
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Affiliation(s)
- Xiang-Di Tan
- The Fourth Affiliated Hospital, Guangzhou Medical University, Zengcheng, China
| | - Cui-Fang Luo
- The Fourth Affiliated Hospital, Guangzhou Medical University, Zengcheng, China
| | - Si-Yu Liang
- The Fourth Affiliated Hospital, Guangzhou Medical University, Zengcheng, China
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Sui Q, Yang H, Hu Z, Jin X, Chen Z, Jiang W, Sun F. The Research Progress of Metformin Regulation of Metabolic Reprogramming in Malignant Tumors. Pharm Res 2024; 41:2143-2159. [PMID: 39455505 DOI: 10.1007/s11095-024-03783-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrate enhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for their malignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus, has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits. METHODS This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors. RESULTS This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways. CONCLUSION In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment.
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Affiliation(s)
- Qihai Sui
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Huiqiang Yang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Zhengyang Hu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Xing Jin
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Zhencong Chen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Wei Jiang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Fenghao Sun
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
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Sahu P, Camarillo IG, Dettin M, Zamuner A, Teresa Conconi M, Barozzi M, Giri P, Sundararajan R, Sieni E. Electroporation enhances cell death in 3D scaffold-based MDA-MB-231 cells treated with metformin. Bioelectrochemistry 2024; 159:108734. [PMID: 38762949 DOI: 10.1016/j.bioelechem.2024.108734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/08/2024] [Accepted: 05/14/2024] [Indexed: 05/21/2024]
Abstract
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer lacks estrogen, progesterone, and HER2 receptors and hence, is therapeutically challenging. Towards this, we studied an alternate therapy by repurposing metformin (FDA-approved type-2 diabetic drug with anticancer properties) in a 3D-scaffold culture, with electrical pulses. 3D cell culture was used to simulate the tumor microenvironment more closely and MDA-MB-231, human TNBC cells, treated with both 5 mM metformin (Met) and 8 electrical pulses at 2500 V/cm, 10 µs (EP1) and 800 V/cm, 100 µs (EP2) at 1 Hz were studied in 3D and 2D. They were characterized using cell viability, reactive oxygen species (ROS), glucose uptake, and lactate production assays at 24 h. Cell viability, as low as 20 % was obtained with EP1 + 5 mM Met. They exhibited 1.65-fold lower cell viability than 2D with EP1 + 5 mM Met. ROS levels indicated a 2-fold increase in oxidative stress for EP1 + 5 mM Met, while the glucose uptake was limited to only 9 %. No significant change in the lactate production indicated glycolytic arrest and a non-conducive environment for MDA-MB-231 growth. Our results indicate that 3D cell culture, with a more realistic tumor environment that enhances cell death using metformin and electrical pulses could be a promising approach for TNBC therapeutic intervention studies.
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Affiliation(s)
- Praveen Sahu
- School of Engineering Technology, Purdue University, West Lafayette, IN 47907, USA
| | - Ignacio G Camarillo
- Deptartment of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, West Lafayette, IN 47907, USA
| | - Monica Dettin
- Department of Industrial Engineering, University of Padova, Padova 35122, Italy
| | - Annj Zamuner
- Department of Industrial Engineering, University of Padova, Padova 35122, Italy; Department of Civil, Environmental, and Architectural Engineering, University of Padova, Italy
| | - Maria Teresa Conconi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
| | - Marco Barozzi
- Department of Theoretical and Applied Sciences, University of Insubria, Varese 21100, Italy
| | - Pragatheiswar Giri
- School of Engineering Technology, Purdue University, West Lafayette, IN 47907, USA
| | - Raji Sundararajan
- School of Engineering Technology, Purdue University, West Lafayette, IN 47907, USA
| | - Elisabetta Sieni
- Department of Theoretical and Applied Sciences, University of Insubria, Varese 21100, Italy.
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Nemeth DV, Iannelli L, Gangitano E, D’Andrea V, Bellini MI. Energy Metabolism and Metformin: Effects on Ischemia-Reperfusion Injury in Kidney Transplantation. Biomedicines 2024; 12:1534. [PMID: 39062107 PMCID: PMC11275143 DOI: 10.3390/biomedicines12071534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/03/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Metformin (MTF) is the only biguanide included in the World Health Organization's list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of interest for many trying to find alternative treatments for varied pathologies. Over time, an increasing body of evidence has shown additional roles of MTF, with unexpected interactions of benefit in other diseases. Metformin (MTF) holds significant promise in mitigating ischemia-reperfusion injury (IRI), particularly in the realm of organ transplantation. As acceptance criteria for organ transplants expand, IRI during the preservation phase remain a major concern within the transplant community, prompting a keen interest in MTF's effects. Emerging evidence suggests that administering MTF during reperfusion may activate the reperfusion injury salvage kinase (RISK) pathway. This pathway is pivotal in alleviating IRI in transplant recipients, potentially leading to improved outcomes such as reduced rates of organ rejection. This review aims to contextualize MTF historically, explore its current uses, pharmacokinetics, and pharmacodynamics, and link these aspects to the pathophysiology of IRI to illuminate its potential future role in transplantation. A comprehensive survey of the current literature highlights MTF's potential to recondition and protect against IRI by attenuating free radical damage, activating AMP-activated protein kinase to preserve cellular energy and promote repair, as well as directly reducing inflammation and enhancing microcirculation.
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Affiliation(s)
- Denise V. Nemeth
- School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, TX 78235, USA
| | - Leonardo Iannelli
- Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy
| | - Elena Gangitano
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Vito D’Andrea
- Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy
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Sarkar A, Fanous KI, Marei I, Ding H, Ladjimi M, MacDonald R, Hollenberg MD, Anderson TJ, Hill MA, Triggle CR. Repurposing Metformin for the Treatment of Atrial Fibrillation: Current Insights. Vasc Health Risk Manag 2024; 20:255-288. [PMID: 38919471 PMCID: PMC11198029 DOI: 10.2147/vhrm.s391808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 06/05/2024] [Indexed: 06/27/2024] Open
Abstract
Metformin is an orally effective anti-hyperglycemic drug that despite being introduced over 60 years ago is still utilized by an estimated 120 to 150 million people worldwide for the treatment of type 2 diabetes (T2D). Metformin is used off-label for the treatment of polycystic ovary syndrome (PCOS) and for pre-diabetes and weight loss. Metformin is a safe, inexpensive drug with side effects mostly limited to gastrointestinal issues. Prospective clinical data from the United Kingdom Prospective Diabetes Study (UKPDS), completed in 1998, demonstrated that metformin not only has excellent therapeutic efficacy as an anti-diabetes drug but also that good glycemic control reduced the risk of micro- and macro-vascular complications, especially in obese patients and thereby reduced the risk of diabetes-associated cardiovascular disease (CVD). Based on a long history of clinical use and an excellent safety record metformin has been investigated to be repurposed for numerous other diseases including as an anti-aging agent, Alzheimer's disease and other dementias, cancer, COVID-19 and also atrial fibrillation (AF). AF is the most frequently diagnosed cardiac arrythmia and its prevalence is increasing globally as the population ages. The argument for repurposing metformin for AF is based on a combination of retrospective clinical data and in vivo and in vitro pre-clinical laboratory studies. In this review, we critically evaluate the evidence that metformin has cardioprotective actions and assess whether the clinical and pre-clinical evidence support the use of metformin to reduce the risk and treat AF.
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Affiliation(s)
- Aparajita Sarkar
- Department of Medical Education, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Kareem Imad Fanous
- Department of Medical Education, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Isra Marei
- Department of Pharmacology & Medical Education, Weill Cornell Medicine- Qatar, Doha, Qatar
| | - Hong Ding
- Department of Pharmacology & Medical Education, Weill Cornell Medicine- Qatar, Doha, Qatar
| | - Moncef Ladjimi
- Department of Biochemistry & Medical Education, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Ross MacDonald
- Health Sciences Library, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Morley D Hollenberg
- Department of Physiology & Pharmacology, and Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Todd J Anderson
- Department of Cardiac Sciences and Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Michael A Hill
- Dalton Cardiovascular Research Center & Department of Medical Pharmacology & Physiology, School of Medicine, University of Missouri, Columbia, Missouri, USA
| | - Chris R Triggle
- Department of Pharmacology & Medical Education, Weill Cornell Medicine- Qatar, Doha, Qatar
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8
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Xu JX, Zhu QL, Bi YM, Peng YC. New evidence: Metformin unsuitable as routine adjuvant for breast cancer: a drug-target mendelian randomization analysis. BMC Cancer 2024; 24:691. [PMID: 38844880 PMCID: PMC11155042 DOI: 10.1186/s12885-024-12453-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 05/30/2024] [Indexed: 06/10/2024] Open
Abstract
PURPOSE The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. METHODS Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. RESULTS The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. CONCLUSION The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.
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Affiliation(s)
- Jing-Xuan Xu
- Department of General Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
| | - Qi-Long Zhu
- Pharmacy Department, The Ninth People's Hospital of Chongqing, Chongqing, 400015, China
| | - Yu-Miao Bi
- Department of General Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China.
| | - Yu-Chong Peng
- Department of General Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China.
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Sun X, Ping J, Guo X, Long J, Cai Q, Shu XO, Shu X. Drug-target Mendelian randomization revealed a significant association of genetically proxied metformin effects with increased prostate cancer risk. Mol Carcinog 2024; 63:849-858. [PMID: 38517045 PMCID: PMC11014764 DOI: 10.1002/mc.23692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/04/2024] [Accepted: 01/16/2024] [Indexed: 03/23/2024]
Abstract
The association between metformin use and risk of prostate cancer remains controversial, while data from randomized trials is lacking. We aim to evaluate the association of genetically proxied metformin effects with prostate cancer risk using a drug-target Mendelian randomization (MR) approach. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium (79,148 cases and 61,106 controls). Cis-expression quantitative trait loci (cis-eQTL) variants in the gene targets of metformin were identified in the GTEx project and eQTLGen consortium. We also obtained male-specific genome-wide association study data for type 2 diabetes, body mass index (BMI), total testosterone, bioavailable testosterone, estradiol, and sex hormone binding globulin for mediation analysis. Inverse-variance weighted (IVW) regression, weighted median, MR-Egger regression, and MR-PRESSO were performed in the main MR analysis. Multivariable MR was used to identify potential mediators and genetic colocalization analysis was performed to assess any shared genetic basis between two traits of interest. We found that genetically proxied metformin effects (1-SD HbA1c reduction, equivalent to 6.75 mmol/mol) were associated with higher risk of prostate cancer (odds ratioIVW [ORIVW]: 1.55, 95% confidence interval, CI: 1.23-1.96, p = 3.0 × 10-3). Two metformin targets, mitochondrial complex I (ORIVW: 1.48, 95% CI: 1.07-2.03, p = 0.016) and gamma-secretase complex (ORIVW: 2.58, 95%CI :1.47-4.55, p = 0.001), showed robust associations with prostate cancer risk, and their effects were partly mediated through BMI (16.4%) and total testosterone levels (34.3%), respectively. These results were further supported by colocalization analysis that expressions of NDUFA13 and BMI, APH1A, and total testosterone may be influenced by shared genetic factors, respectively. In summary, our study indicated that genetically proxied metformin effects may be associated with an increased risk of prostate cancer. Repurposing metformin for prostate cancer prevention in general populations is not supported by our findings.
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Affiliation(s)
- Xiaohui Sun
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology, Zhejiang Chinese Medical University, Zhejiang, China
| | - Jie Ping
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Xingyi Guo
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jirong Long
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Xiao-ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Xiang Shu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Amengual-Cladera E, Morla-Barcelo PM, Morán-Costoya A, Sastre-Serra J, Pons DG, Valle A, Roca P, Nadal-Serrano M. Metformin: From Diabetes to Cancer-Unveiling Molecular Mechanisms and Therapeutic Strategies. BIOLOGY 2024; 13:302. [PMID: 38785784 PMCID: PMC11117706 DOI: 10.3390/biology13050302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/06/2024] [Accepted: 04/25/2024] [Indexed: 05/25/2024]
Abstract
Metformin, a widely used anti-diabetic drug, has garnered attention for its potential in cancer management, particularly in breast and colorectal cancer. It is established that metformin reduces mitochondrial respiration, but its specific molecular targets within mitochondria vary. Proposed mechanisms include inhibiting mitochondrial respiratory chain Complex I and/or Complex IV, and mitochondrial glycerophosphate dehydrogenase, among others. These actions lead to cellular energy deficits, redox state changes, and several molecular changes that reduce hyperglycemia in type 2 diabetic patients. Clinical evidence supports metformin's role in cancer prevention in type 2 diabetes mellitus patients. Moreover, in these patients with breast and colorectal cancer, metformin consumption leads to an improvement in survival outcomes and prognosis. The synergistic effects of metformin with chemotherapy and immunotherapy highlights its potential as an adjunctive therapy for breast and colorectal cancer. However, nuanced findings underscore the need for further research and stratification by molecular subtype, particularly for breast cancer. This comprehensive review integrates metformin-related findings from epidemiological, clinical, and preclinical studies in breast and colorectal cancer. Here, we discuss current research addressed to define metformin's bioavailability and efficacy, exploring novel metformin-based compounds and drug delivery systems, including derivatives targeting mitochondria, combination therapies, and novel nanoformulations, showing enhanced anticancer effects.
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Affiliation(s)
- Emilia Amengual-Cladera
- Grupo Metabolismo Energético y Nutrición, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain; (E.A.-C.); (A.M.-C.); (A.V.)
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain; (P.M.M.-B.); (J.S.-S.); (D.G.P.); (M.N.-S.)
| | - Pere Miquel Morla-Barcelo
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain; (P.M.M.-B.); (J.S.-S.); (D.G.P.); (M.N.-S.)
- Grupo Multidisciplinar de Oncología Traslacional, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain
| | - Andrea Morán-Costoya
- Grupo Metabolismo Energético y Nutrición, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain; (E.A.-C.); (A.M.-C.); (A.V.)
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain; (P.M.M.-B.); (J.S.-S.); (D.G.P.); (M.N.-S.)
| | - Jorge Sastre-Serra
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain; (P.M.M.-B.); (J.S.-S.); (D.G.P.); (M.N.-S.)
- Grupo Multidisciplinar de Oncología Traslacional, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Daniel Gabriel Pons
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain; (P.M.M.-B.); (J.S.-S.); (D.G.P.); (M.N.-S.)
- Grupo Multidisciplinar de Oncología Traslacional, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain
| | - Adamo Valle
- Grupo Metabolismo Energético y Nutrición, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain; (E.A.-C.); (A.M.-C.); (A.V.)
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain; (P.M.M.-B.); (J.S.-S.); (D.G.P.); (M.N.-S.)
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Pilar Roca
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain; (P.M.M.-B.); (J.S.-S.); (D.G.P.); (M.N.-S.)
- Grupo Multidisciplinar de Oncología Traslacional, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Mercedes Nadal-Serrano
- Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Illes Balears, Spain; (P.M.M.-B.); (J.S.-S.); (D.G.P.); (M.N.-S.)
- Grupo Multidisciplinar de Oncología Traslacional, Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universitat de les Illes Balears, Ctra. de Valldemossa, km 7.5, 07122 Palma, Illes Balears, Spain
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11
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Galal MA, Al-Rimawi M, Hajeer A, Dahman H, Alouch S, Aljada A. Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int J Mol Sci 2024; 25:4083. [PMID: 38612893 PMCID: PMC11012626 DOI: 10.3390/ijms25074083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Mohammed Al-Rimawi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | | | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Samhar Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
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12
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Sun Y, Cheng J, Nie D, Fang Q, Li C, Zhang Y. Metformin inhibits cell proliferation and ACTH secretion in AtT20 cells via regulating the MAPK pathway. Mol Cell Endocrinol 2024; 582:112140. [PMID: 38147953 DOI: 10.1016/j.mce.2023.112140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 12/17/2023] [Accepted: 12/19/2023] [Indexed: 12/28/2023]
Abstract
We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing's disease.
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Affiliation(s)
- Yingxuan Sun
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Jianhua Cheng
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Ding Nie
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Qiuyue Fang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Chuzhong Li
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
| | - Yazhuo Zhang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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13
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Teng M, Li Z, Gu Y, Fan Y, Wang D, Liu M, Li Y, Wei G, Huang Y. Real-time monitoring of glucose metabolism and effects of metformin on HepG2 cells using 13C in-cell NMR spectroscopy. Biochem Biophys Res Commun 2024; 694:149383. [PMID: 38150918 DOI: 10.1016/j.bbrc.2023.149383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 12/02/2023] [Accepted: 12/11/2023] [Indexed: 12/29/2023]
Abstract
Metformin is currently a strong candidate antitumor agent for multiple cancers, and has the potential to inhibit cancer cell viability, growth, and proliferation. Metabolic reprogramming is a critical feature of cancer cells. However, the effects of metformin which targets glucose metabolism on HepG2 cancer cells remain unclear. In this study, to explore the effects of metformin on glucose metabolism in HepG2 cells, we conducted real-time metabolomic monitoring of live HepG2 cells treated with metformin using 13C in-cell NMR spectroscopy. Metabolic tracing with U-13C6-glucose revealed that metformin significantly increased the production of 13C-G3P and 13C-glycerol, which were reported to attenuate liver cancer development, but decreased the production of potential oncogenesis-supportive metabolites, including 13C-lactate, 13C-alanine, 13C-glycine, and 13C-glutamate. Moreover, the expression levels of enzymes associated with the measured metabolites were carried out. The results showed that the levels of ALT1, MCT4, GPD2 and MPC1 were greatly reduced, which were consistent with the changes of measured metabolites in 13C in-cell NMR spectroscopy. Overall, our approach directly provides fundamental insights into the effects of metformin on glucose metabolism in live HepG2 cells, and highlights the potential mechanism of metformin, including the increase in production of G3P and glycerol derived from glucose, as well as the inhibition of glucose incorporation into lactate, alanine, glutamate, and glycine.
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Affiliation(s)
- Muzhou Teng
- Key Laboratory of the Digestive System Tumors of Gansu Province, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
| | - Zhijia Li
- Dermatology Hospital, Southern Medical University, Guangzhou, 510091, China
| | - Yanmei Gu
- Key Laboratory of the Digestive System Tumors of Gansu Province, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
| | - Yitao Fan
- Key Laboratory of the Digestive System Tumors of Gansu Province, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
| | - Daijun Wang
- Key Laboratory of the Digestive System Tumors of Gansu Province, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
| | - Meiyu Liu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China
| | - Yumin Li
- Key Laboratory of the Digestive System Tumors of Gansu Province, The Second Clinical Medical College of Lanzhou University, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China.
| | - Gang Wei
- Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
| | - Yanjie Huang
- Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, China; Engineering Technology Research Center for Comprehensive Development and Utilization of Authentic Medicinal Materials in Henan Province, Zhengzhou, Henan, 450046, China.
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14
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Gupta J, Jalil AT, Abd Alzahraa ZH, Aminov Z, Alsaikhan F, Ramírez-Coronel AA, Ramaiah P, Najafi M. The Metformin Immunoregulatory Actions in Tumor Suppression and Normal Tissues Protection. Curr Med Chem 2024; 31:5370-5396. [PMID: 37403391 DOI: 10.2174/0929867331666230703143907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/19/2023] [Accepted: 06/01/2023] [Indexed: 07/06/2023]
Abstract
The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor-promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, Pin Code 281406, U. P., India
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | | | - Zafar Aminov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, 103 Makhtumkuli Str., Tashkent, Uzbekistan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Cuenca, Ecuador
- Epidemiology and Biostatistics Research Group, CES University, Medellin, Colombia
- Educational Statistics Research Group (GIEE), National University of Education, Cuenca, Ecuador
| | | | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Bliss JM, Rastogi P, Rabaglio-Poretti M, Thompson AM, Rea DW, Stos PM, Shepherd LE, Stambolic V, Parulekar WR. Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer. J Clin Oncol 2023; 41:5356-5362. [PMID: 37695982 PMCID: PMC10713140 DOI: 10.1200/jco.23.00296] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/28/2023] [Accepted: 07/20/2023] [Indexed: 09/13/2023] Open
Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.
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Affiliation(s)
- Pamela J. Goodwin
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Bingshu E. Chen
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | - Karen A. Gelmon
- University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada
| | | | | | | | | | - Dawn L. Hershman
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY
| | | | | | - Judith M. Bliss
- ICR-CTSU, Institute of Cancer Research (UK), London, United Kingdom
| | - Priya Rastogi
- NRG Oncology and University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Manuela Rabaglio-Poretti
- IBCSG and Department of Oncology, Bern University Hospital, University of Bern, Berne, Switzerland
| | | | - Daniel W. Rea
- Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Paul M. Stos
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | - Lois E. Shepherd
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | - Vuk Stambolic
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
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16
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Zhong Y, Shen C, Xi X, Luo Y, Ding P, Luo L. Multitask joint learning with graph autoencoders for predicting potential MiRNA-drug associations. Artif Intell Med 2023; 145:102665. [PMID: 37925217 DOI: 10.1016/j.artmed.2023.102665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 06/14/2023] [Accepted: 09/14/2023] [Indexed: 11/06/2023]
Abstract
The occurrence of many diseases is associated with miRNA abnormalities. Predicting potential drug-miRNA associations is of great importance for both disease treatment and new drug discovery. Most computation-based approaches learn one task at a time, ignoring the information contained in other tasks in the same domain. Multitask learning can effectively enhance the prediction performance of a single task by extending the valid information of related tasks. In this paper, we presented a multitask joint learning framework (MTJL) with a graph autoencoder for predicting the associations between drugs and miRNAs. First, we combined multiple pieces of information to construct a high-quality similarity network of both drugs and miRNAs and then used a graph autoencoder (GAE) to learn their embedding representations separately. Second, to further improve the embedding quality of drugs, we added an auxiliary task to classify drugs using the learned representations. Finally, the embedding representations of drugs and miRNAs were linearly transformed to obtain the predictive association scores between them. A comparison with other state-of-the-art models shows that MTJL has the best prediction performance, and ablation experiments show that the auxiliary task can enhance the embedding quality and improve the robustness of the model. In addition, we show that MTJL has high utility in predicting potential associations between drugs and miRNAs by conducting two case studies.
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Affiliation(s)
- Yichen Zhong
- School of Computer Science, University of South China, Hengyang 421001, China
| | - Cong Shen
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410083, China
| | - Xiaoting Xi
- School of Computer Science, University of South China, Hengyang 421001, China
| | - Yuxun Luo
- School of Computer Science and Engineering, Hunan University of Science and Technology, Xiangtan 411105, China
| | - Pingjian Ding
- School of Computer Science, University of South China, Hengyang 421001, China
| | - Lingyun Luo
- School of Computer Science, University of South China, Hengyang 421001, China.
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17
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Halma MTJ, Tuszynski JA, Marik PE. Cancer Metabolism as a Therapeutic Target and Review of Interventions. Nutrients 2023; 15:4245. [PMID: 37836529 PMCID: PMC10574675 DOI: 10.3390/nu15194245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/20/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.
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Affiliation(s)
- Matthew T. J. Halma
- Department of Physics and Astronomy, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- EbMC Squared CIC, Bath BA2 4BL, UK
| | - Jack A. Tuszynski
- Department of Physics, University of Alberta, 11335 Saskatchewan Dr NW, Edmonton, AB T6G 2M9, Canada
- Department of Data Science and Engineering, The Silesian University of Technology, 44-100 Gliwice, Poland
- DIMEAS, Politecnico di Torino, Corso Duca degli Abruzzi 24, I-1029 Turin, Italy
| | - Paul E. Marik
- Frontline COVID-19 Critical Care Alliance, Washington, DC 20036, USA
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Cigrovski Berkovic M, Giovanardi F, Mrzljak A, Lai Q. Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma: A systematic review and meta-analysis. World J Diabetes 2023; 14:1289-1300. [PMID: 37664473 PMCID: PMC10473950 DOI: 10.4239/wjd.v14.i8.1289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/24/2023] [Accepted: 05/16/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the commonest malignancies associated with significant cancer-related death. The identification of chemo-preventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing. Metformin, a first-line agent used in the treatment of type 2 diabetes mellitus (T2DM), has been associated with inhibition of HCC growth. AIM To determine whether metformin can prevent adverse events (i.e., death, tumor progression, and recurrence) after any HCC treatment in T2DM patients. METHODS A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy. A search of the PubMed and Cochrane Central Register of Con-trolled Trials Databases was conducted. RESULTS A total of 13 studies (n = 14886 patients) were included in this review. With regard to the risk of death, a decreased risk was reported in cases receiving metformin, although this decrease was not statistically significant [odds ratio (OR) = 0.89, P = 0.42]. When only patients treated with curative strategies were considered, a more marked correlation between metformin and favorable cases was reported (OR = 0.70, P = 0.068). When analyzing palliative treatment, there was no statistical significance in terms of the correlation between metformin and favorable cases (OR = 0.74, P = 0.66). As for the risks of progressive disease and recurrence, no obvious correlation between metformin use and reduced risk was reported. When sub-analyses were performed for patients from different regions, the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin (OR = 0.69, P = 0.17), but the same was not seen in patients from Western countries (OR = 1.19, P = 0.31). CONCLUSION Metformin failed to show a marked impact in preventing adverse effects after HCC treatment. A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death, especially in patients from Eastern regions. Great heterogeneity was reported among the different studies. Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.
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Affiliation(s)
- Maja Cigrovski Berkovic
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb, Zagreb 10000, Croatia
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb 10000, Croatia
- Department of Medicine, School of Medicine, Zagreb 10000, Croatia
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
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Yang K, Lu HH, Zhao W, Zhao Q. Efficacy and safety of metformin in combination with chemotherapy in cancer patients without diabetes: systematic review and meta-analysis. Front Oncol 2023; 13:1176885. [PMID: 37546417 PMCID: PMC10402741 DOI: 10.3389/fonc.2023.1176885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/26/2023] [Indexed: 08/08/2023] Open
Abstract
Background The results of a meta-analysis of retrospective studies suggest that the use of metformin in cancer patients may prolong progression-free disease survival and overall survival. However, the studies included in the meta-analysis did not strictly distinguish between patients with or without type 2 diabetes mellitus. Therefore, further studies are needed to assess whether the use of adjuvant chemotherapy with metformin in cancer patients without diabetes improves prognosis. Method Systematic searches of Embase, Pubmed, and The Cochrane library were performed for the subject terms metformin and neoplasm and for free words. Data related to PFS, OS were extracted according to inclusion exclusion criteria. The data were combined and meta-analysis was performed using Review Manager 5.4 to confirm the efficacy and safety of metformin administration. Results There were 3228 publications retrieved from the database and a total of 13 publications with 955 patients were included in the meta-analysis after screening. All included studies were randomised controlled trials. Metformin combined with adjuvant chemotherapy did not improve progression-free survival (HR=1,95CI 0.79-1.25), overall survival (HR=0.91,95% CI 0.69-1.20) and did not improve objective disease response rates in patients. There was no significant difference in grade 3-4 adverse reactions compared to placebo. Conclusion In this meta-analysis of randomised controlled trial studies, we found that chemotherapy in combination with metformin in cancer patients without diabetes did not prolong progression-free survival and overall survival and improved disease control in patients, although there was no significant difference in terms of safety. More high-quality randomised controlled trials are needed in the future to confirm the in vivo anti-tumour activity and survival benefit of metformin.
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Affiliation(s)
- Kang Yang
- Department of Pharmacy, General Hospital of Northern Theater Command of PLA, Shenyang, China
- China Medical University, Shenyang, China
| | - Hao-hao Lu
- Department of Pharmacy, General Hospital of Northern Theater Command of PLA, Shenyang, China
- China Medical University, Shenyang, China
| | - Wei Zhao
- Department of Pharmacy, General Hospital of Northern Theater Command of PLA, Shenyang, China
| | - Qingchun Zhao
- Department of Pharmacy, General Hospital of Northern Theater Command of PLA, Shenyang, China
- China Medical University, Shenyang, China
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20
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Hua Y, Zheng Y, Yao Y, Jia R, Ge S, Zhuang A. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J Transl Med 2023; 21:403. [PMID: 37344841 DOI: 10.1186/s12967-023-04263-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 06/09/2023] [Indexed: 06/23/2023] Open
Abstract
Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.
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Affiliation(s)
- Yu Hua
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Yue Zheng
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Yiran Yao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Ai Zhuang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, No. 639 Zhizaoju Road, Shanghai, 200011, China.
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21
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Lange C, Brüggemann J, Thüner T, Jauckus J, Strowitzki T, Germeyer A. Changes in the expression of cancer- and metastasis-related genes and proteins after metformin treatment under different metabolic conditions in endometrial cancer cells. Heliyon 2023; 9:e16678. [PMID: 37313172 PMCID: PMC10258389 DOI: 10.1016/j.heliyon.2023.e16678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 05/20/2023] [Accepted: 05/24/2023] [Indexed: 06/15/2023] Open
Abstract
Research question Hyperinsulinemia and elevated estrogen levels are known risk factors for endometrial cancer (EC) development and are associated with obesity, type 2 diabetes mellitus (T2DM), insulin resistance, among others. Metformin, an insulin-sensitizing drug, displays anti-tumor effects in cancer patients, including EC, but the mechanism of action is still not completely understood. In the present study, the effects of metformin on gene and protein expression were investigated in pre- and postmenopausal EC in vitro models in order to identify candidates that are potentially involved in the drug's anti-cancer mechanism. Design After treating the cells with metformin (0.1 and 1.0 mmol/L), changes in the expression of >160 cancer- and metastasis-related gene transcripts were evaluated with RNA arrays. A total of 19 genes and 7 proteins were selected for a follow-up expression analysis, including further treatment conditions, in order to evaluate the influence of hyperinsulinemia and hyperglycemia on metformin-induced effects. Results Changes in the expression of BCL2L11, CDH1, CDKN1A, COL1A1, PTEN, MMP9 and TIMP2 were analyzed on gene and protein level. The consequences resulting from the detected expression changes as well as the influence of varying environmental influences are discussed in detail. With the presented data, we contribute to a better understanding of the direct anti-cancer activity of metformin as well as its underlying mechanism of action in EC cells. Conclusions Although further research will be necessary to confirm the data, the influence of different environmental settings on metformin-induced effects could be highlighted with the presented data. Additionally, gene and protein regulation were not similar in the pre- and postmenopausal in vitro models.
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22
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Yu OHY, Suissa S. Metformin and Cancer: Solutions to a Real-World Evidence Failure. Diabetes Care 2023; 46:904-912. [PMID: 37185680 DOI: 10.2337/dci22-0047] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/09/2023] [Indexed: 05/17/2023]
Abstract
The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.
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Affiliation(s)
- Oriana Hoi Yun Yu
- 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
- 2Division of Endocrinology, Jewish General Hospital, Montreal, Canada
- 3Department of Medicine, McGill University, Montreal, Canada
| | - Samy Suissa
- 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
- 3Department of Medicine, McGill University, Montreal, Canada
- 4Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
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23
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An injectable and pH-responsive hyaluronic acid hydrogel as metformin carrier for prevention of breast cancer recurrence. Carbohydr Polym 2023; 304:120493. [PMID: 36641175 DOI: 10.1016/j.carbpol.2022.120493] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 12/13/2022] [Accepted: 12/20/2022] [Indexed: 12/25/2022]
Abstract
To achieve the pH-responsive release of metformin in tumor acidic microenvironment, we prepared OHA-Met by covalently grafting metformin (Met) onto oxidized hyaluronic acid (OHA) through imine bonds, and then prepared carboxymethyl chitosan (CMCS)/OHA-Met drug loaded hydrogels. The CMCS/OHA-Met hydrogels showed the in-situ injection performance. At pH = 7.4, the cumulative release rate of metformin from CMCS/OHA-Met20 hydrogel was 42.7 ± 2.6 % in 6 h, and the release tended to balance after 72 h. At pH = 5.5, the release kept constant and the cumulative release rate was 79.3 ± 4.7 % at 6 h, showing good pH-responsive behavior. Metformin induced apoptosis of MCF-7 cells through the caspase 3/PARP pathway. CMCS/OHA-Met20 hydrogel could effectively kill MCF-7 cells, while reducing the cytotoxicity of free metformin to L929 cells. In vivo breast cancer recurrence experiments showed CMCS/OHA-Met20 hydrogel could achieve local injection and pH-responsive smart drug delivery at the tumor resection site, inhibiting breast cancer recurrence. Compared with direct administration, CMCS/OHA-Met20 hydrogel reduced the metformin dosage, frequency of administration and systemic side effects.
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24
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Li L, Huang J, Huang T, Yao J, Zhang Y, Chen M, Shentu H, Lou H. Effect of Metformin on the Prognosis of Gastric Cancer Patients with Type 2 Diabetes Mellitus: A Meta-Analysis Based on Retrospective Cohort Studies. Int J Endocrinol 2023; 2023:5892731. [PMID: 36915376 PMCID: PMC10008112 DOI: 10.1155/2023/5892731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/17/2023] [Accepted: 02/20/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Metformin is one of the most common drugs for type 2 diabetes mellitus (T2DM) treatment. In addition, metformin intends to have a positive effect on the prognosis of several cancers. However, the therapeutic effect of metformin on gastric cancer (GC) remains controversial. This study explores and updates the therapeutic effect of metformin in GC patients with T2DM. METHODS We searched through PubMed, Embase, Web of Science, and the Cochrane Library for relevant articles by July 2022. The relationship between metformin therapy and the prognosis of GC patients with T2DM was evaluated based on the hazard ratio (HR) at a 95% confidence interval (95% CI). Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) were the primary outcomes analyzed. RESULTS Seven retrospective cohort studies with a combined 2,858 patients met the inclusion criteria. OS and CSS were reported in six studies, and PFS was reported in four studies. Pooled results showed that, compared to the nonmetformin group, the prolonged OS (HR = 0.72, p = 0.001), CSS (HR = 0.81, p = 0.001), and PFS (HR = 0.70, p = 0.008) of the experimental group may be associated with the exposure to metformin. CONCLUSION Metformin may have a beneficial effect on the prognosis of GC patients with T2DM.
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Affiliation(s)
- Lingna Li
- Pharmacy Department, The Affiliated Hospital of Ningbo University, Li Huili Hospital, Ningbo, China
| | - Jianing Huang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Tongmin Huang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jie Yao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yeyuan Zhang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Meiling Chen
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Haojie Shentu
- School of Medical Imaging, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Haiying Lou
- Department of Endocrinology, Zhuji People's Hospital, Shaoxing, Zhejiang, China
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25
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Sanati M, Aminyavari S, Mollazadeh H, Motamed-Sanaye A, Bibak B, Mohtashami E, Teng Y, Afshari AR, Sahebkar A. The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme. Curr Med Chem 2023; 30:857-877. [PMID: 35796457 DOI: 10.2174/0929867329666220707103525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/13/2022] [Accepted: 04/16/2022] [Indexed: 02/08/2023]
Abstract
In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Samaneh Aminyavari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ali Motamed-Sanaye
- Student Research Committee, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Bahram Bibak
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA30322, USA
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Han K, Fyles A, Shek T, Croke J, Dhani N, D'Souza D, Lee TY, Chaudary N, Bruce J, Pintilie M, Cairns R, Vines D, Pakbaz S, Jaffray D, Metser U, Rouzbahman M, Milosevic M, Koritzinsky M. A Phase II Randomized Trial of Chemoradiation with or without Metformin in Locally Advanced Cervical Cancer. Clin Cancer Res 2022; 28:5263-5271. [PMID: 36037303 DOI: 10.1158/1078-0432.ccr-22-1665] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/13/2022] [Accepted: 08/25/2022] [Indexed: 01/24/2023]
Abstract
PURPOSE Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT. PATIENTS AND METHODS A window-of-opportunity, phase II randomized trial was performed in stage IB-IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was a change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic. RESULTS Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4%-34.2%) ± SD 16.9% after 1 week of metformin, compared with an average increase of 4.7% (29.1%-33.8%) ± 11.5% for the 3 controls (P = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival was 67% for the metformin arm versus 33% for controls (P = 0.09). CONCLUSIONS Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor. See related commentary by Lyng et al., p. 5233.
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Affiliation(s)
- Kathy Han
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Anthony Fyles
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Tina Shek
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Quantitative Imaging for Personalized Cancer Medicine, Techna Institute, University Health Network, Toronto, Ontario, Canada
| | - Jennifer Croke
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Neesha Dhani
- Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - David D'Souza
- London Regional Cancer Program, London Health Sciences Centre, Department of Oncology, Western University, London, Ontario, Canada
| | - Ting-Yim Lee
- London Regional Cancer Program, London Health Sciences Centre, Department of Oncology, Western University, London, Ontario, Canada
| | - Naz Chaudary
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jeffrey Bruce
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Melania Pintilie
- Department of Biostatistics, University Health Network, Toronto, Ontario, Canada
| | - Rob Cairns
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Douglass Vines
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - David Jaffray
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Ur Metser
- Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Marjan Rouzbahman
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Michael Milosevic
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Marianne Koritzinsky
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
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27
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Du Y, Zhang Z, Yang Y, Liu T, Chen T, Li X. Highly active selenium nanotherapeutics combined with metformin to achieve synergistic sensitizing effect on NK cells for osteosarcoma therapy. NANOPHOTONICS (BERLIN, GERMANY) 2022; 11:5101-5111. [PMID: 39634308 PMCID: PMC11501141 DOI: 10.1515/nanoph-2022-0289] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 06/12/2022] [Indexed: 12/07/2024]
Abstract
NK cells-based cancer therapy combined with chemotherapeutic drugs for the treatment of tumors can enhance the immunosensitivity of NK cells, increase the expression of NK cell receptors, and eventually boost the killing effect of NK cells on cancer cells. Selenium (Se) with different chemical structures can be metabolized into selenoproteins to regulate tumor and immune cells' fate and functions. Herein, we found that, functionalized Se nanoparticles (SeNPs) combining with metformin (met) could amply the immunotherapeutic effects of NK92 cells against osteosarcoma cancer. The results revealed that TW80-SeNPs combined with met had the optimum performance on NK92 cells for HepG2 cells, owing to the increased ROS in HepG2 cells and the augmented expression of cell surface receptor proteins ULBP-3/4, PD-L1, MICA, and NK92 cell surface receptor proteins PD-1 and FasL. Additionally, TW80-SeNPs were gradually metabolized into selenoproteins (Gpx4 and TR1) into human osteosarcoma MG63 cells to reinforce the anticancer effect of NK92 cells by regulating the redox balance in the tumor microenvironment. This study provides a therapeutic approach in treating cancer itself or diabetes coupled with cancer. Moreover, it provides a multidrug strategy to improve immune cell function in practical applications, especially for synergistic immunotherapy of osteosarcoma.
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Affiliation(s)
- Yanxin Du
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Zehang Zhang
- Department of Oncology, Department of Chemistry, The First Affiliated Hospital, Jinan University, Guangzhou510632, China
| | - Yu Yang
- Department of Oncology, Department of Chemistry, The First Affiliated Hospital, Jinan University, Guangzhou510632, China
| | - Ting Liu
- Department of Oncology, Department of Chemistry, The First Affiliated Hospital, Jinan University, Guangzhou510632, China
| | - Tianfeng Chen
- Department of Oncology, Department of Chemistry, The First Affiliated Hospital, Jinan University, Guangzhou510632, China
| | - Xiaoling Li
- Institute of Food Safety and Nutrition, Jinan University, Guangzhou510632, China
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28
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Jin P, Jiang J, Zhou L, Huang Z, Qin S, Chen H, Peng L, Zhang Z, Li B, Luo M, Zhang T, Ming H, Ding N, Li L, Xie N, Gao W, Zhang W, Nice EC, Wei Y, Huang C. Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis. EMBO Mol Med 2022; 14:e16082. [PMID: 36321555 PMCID: PMC9728056 DOI: 10.15252/emmm.202216082] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 09/23/2022] [Accepted: 10/12/2022] [Indexed: 12/12/2022] Open
Abstract
Metformin, a well-known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was upregulated to promote tumor metastasis in response to metformin-induced metabolic stress. Mechanistically, TOMM34 interacted with ATP5B to preserve F1 FO -ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preference for OXPHOS suggested a large requirement of energy supply by cancer cells to survive and spread in response to therapeutic stress. Notably, disturbing the interaction between TOMM34 and ATP5B using Gboxin, a specific OXPHOS inhibitor, increased sensitivity to metformin and suppressed tumor progression both in vitro and in vivo. Overall, this study demonstrates a molecular link of the TOMM34/ATP5B-ATP synthesis axis during metformin adaptation and provides promising therapeutic targets for metformin sensitization in cancer treatment.
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Affiliation(s)
- Ping Jin
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Hai‐Ning Chen
- Colorectal Cancer Center, State Key Laboratory of Biotherapy and Cancer Center, West China HospitalSichuan UniversityChengduChina
| | - Liyuan Peng
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Bowen Li
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Maochao Luo
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Tingting Zhang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
| | - Hui Ming
- West China School of Basic Medical Sciences & Forensic MedicineSichuan UniversityChengduChina
| | - Ning Ding
- School of Basic Medical SciencesChengdu University of Traditional Chinese MedicineChengduChina
| | - Lei Li
- School of Basic Medical SciencesChengdu University of Traditional Chinese MedicineChengduChina
| | - Na Xie
- West China School of Basic Medical Sciences & Forensic MedicineSichuan UniversityChengduChina
| | - Wei Gao
- Clinical Genetics LaboratoryAffiliated Hospital & Clinical Medical College of Chengdu UniversityChengduChina
| | - Wei Zhang
- Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Edouard C Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVicAustralia
| | - Yuquan Wei
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan UniversityChengduChina
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Effects of Slow-Acting Metformin Treatment on the Hormonal and Morphological Thyroid Profile in Patients with Insulin Resistance. Pharmaceutics 2022; 14:pharmaceutics14101987. [PMID: 36297423 PMCID: PMC9607242 DOI: 10.3390/pharmaceutics14101987] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/30/2022] [Accepted: 09/15/2022] [Indexed: 12/05/2022] Open
Abstract
Metformin appears to reduce TSH levels in untreated hypothyroid patients. In contrast, in euthyroid patients with type 2 diabetes mellitus (T2DM), metformin is initially devoid of effects on TSH. However, it is followed by a significant reduction in TSH level after twelve months of treatment. Additionally, some evidence suggests that metformin may also improve thyroid morphological abnormalities. This study aimed to evaluate the effects of metformin not only on TSH and thyroid hormone values, but also on thyroid volume and nodules. A total of 50 patients (mean age: 36.9 ± 12.8 years) with insulin resistance (homeostatic model assessment (HOMA) index ≥2.5) and with thyroid uninodular disease were recruited for this study. They were prescribed slow-acting metformin at a daily dose of 500 mg for six months. Treatment with metformin in euthyroid patients with uninodular thyroid disease and insulin resistance reduces TSH levels, increases FT4 and FT3 values, and decreases thyroid and nodule volumes. These data suggest that metformin may be an effective drug not only for the treatment of T2DM and metabolic syndrome, but also for thyroid disease.
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30
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Jin P, Jiang J, Zhou L, Huang Z, Nice EC, Huang C, Fu L. Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. J Hematol Oncol 2022; 15:97. [PMID: 35851420 PMCID: PMC9290242 DOI: 10.1186/s13045-022-01313-4] [Citation(s) in RCA: 96] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 02/08/2023] Open
Abstract
Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.
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Affiliation(s)
- Ping Jin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China.
| | - Li Fu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, People's Republic of China.
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31
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Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Bliss JM, Rastogi P, Rabaglio-Poretti M, Mukherjee SD, Mackey JR, Abramson VG, Oja C, Wesolowski R, Thompson AM, Rea DW, Stos PM, Shepherd LE, Stambolic V, Parulekar WR. Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA 2022; 327:1963-1973. [PMID: 35608580 PMCID: PMC9131745 DOI: 10.1001/jama.2022.6147] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 03/31/2022] [Indexed: 02/02/2023]
Abstract
Importance Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration ClinicalTrials.gov Identifier: NCT01101438.
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Affiliation(s)
- Pamela J. Goodwin
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Bingshu E. Chen
- Canadian Cancer Trials Group, Queen’s University, Kingston, Ontario, Canada
| | - Karen A. Gelmon
- Department of Medicine, University of British Columbia, BC Cancer Agency, Vancouver, Canada
| | - Timothy J. Whelan
- Department of Radiation Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, Ontario, Canada
| | | | - Julie Lemieux
- Department of Hematology Research, CHU de Québec-Université Laval, Québec, Québec, Canada
| | - Jennifer A. Ligibel
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Dawn L. Hershman
- Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Ingrid A. Mayer
- Department of Medicine, Vanderbilt University, Nashville, Tennessee
| | | | - Judith M. Bliss
- Division of Clinical Studies, ICR-CTSU, Institute of Cancer Research United Kingdom, London, United Kingdom
| | - Priya Rastogi
- Department of Medicine, NRG Oncology and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Manuela Rabaglio-Poretti
- Department of Medical Oncology, IBCSG and Department of Oncology, Bern University Hospital, University of Bern, Berne, Switzerland
| | - Som D. Mukherjee
- Department of Oncology, Juravinski Cancer Center, McMaster University, Hamilton, Ontario, Canada
| | - John R. Mackey
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada
| | | | - Conrad Oja
- Department of Medicine, University of British Columbia, BC Cancer Agency, Vancouver, Canada
| | - Robert Wesolowski
- Department of Internal Medicine, James Cancer Hospital, Ohio State Comprehensive Cancer Center, Columbus, Ohio
| | | | - Daniel W. Rea
- School of Cancer and Genomic Science, Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Paul M. Stos
- Canadian Cancer Trials Group, Queen’s University, Kingston, Ontario, Canada
| | - Lois E. Shepherd
- Canadian Cancer Trials Group, Queen’s University, Kingston, Ontario, Canada
| | - Vuk Stambolic
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Wendy R. Parulekar
- Canadian Cancer Trials Group, Queen’s University, Kingston, Ontario, Canada
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32
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Zhang T, Wang Y, Chen Y, Gao Y, Zhang D, Jin S, Yao W, Li L, Yang S, Wu Y. Metformin alleviates nickel-refining fumes-induced aerobic glycolysis via AMPK/GOLPH3 pathway in vitro and in vivo. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 236:113461. [PMID: 35405526 DOI: 10.1016/j.ecoenv.2022.113461] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/20/2022] [Accepted: 03/25/2022] [Indexed: 06/14/2023]
Abstract
Nickel (Ni) compounds is recognized industrial carcinogen, which could increase the risk of lung cancer in Ni refineries workers. However, the underlying carcinogenic mechanism still remains to elucidate. Metformin has shown the anticancer properties through suppressing aerobic glycolysis. In the present study, we evaluated the effect of Ni-refining fumes exposure on aerobic glycolysis and the role of AMPK/GOLPH3, as well as how metformin alleviated nickel-induced aerobic glycolysis in vitro and vivo. Firstly, Beas-2B cells were exposed to different concentrations of Ni-refining fumes and pretreated with metformin (activation of AMPK), compound C (AMPK inhibitor) in vitro. Our findings indicated that Ni fumes expose evoked aerobic glycolysis by AMPK/GOLPH3, while metformin attenuated Ni particles-promoted GOLPH3-mediated aerobic glycolysis by p-AMPK expression increase. Then Mito-TEMPT (a mitochondria-targeted antioxidant) and lipopolysaccharide (LPS, ROS activator) were pretreated to affect ROS production in Beas-2B cells. Ni-induced ROS prevented AMPK activation. Moreover, C57BL/6 mice were exposed to 2 mg/kg Ni by non-exposed endotracheal instillation and metformin (100, 200 and 300 mg/kg) via oral gavage for 4 weeks. The effects of AMPK/GOLPH3 axis on Ni-induced aerobic glycolysis were assessed. The results indicated that metformin decreased the protein levels of GOLPH3, LDHA, HK2, MCT-4 and improved p-AMPK expression. Thus, our findings demonstrated metformin antagonized Ni-refining fumes-caused aerobic glycolysis via AMPK/GOLPH3.
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Affiliation(s)
- Tong Zhang
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Yue Wang
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Yangyang Chen
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Ying Gao
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Dan Zhang
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Shuo Jin
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Wenxue Yao
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Lina Li
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Shikuan Yang
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China
| | - Yonghui Wu
- Department of Occupational Health, College of Public Health, Harbin Medical University, Harbin, Heilongjiang Province 150086, PR China.
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33
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Bilusic M, Toney NJ, Donahue RN, Wroblewski S, Zibelman M, Ghatalia P, Ross EA, Karzai F, Madan RA, Dahut WL, Gulley JL, Schlom J, Plimack ER, Geynisman DM. A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1). Prostate Cancer Prostatic Dis 2022; 25:735-740. [PMID: 35079115 PMCID: PMC9309187 DOI: 10.1038/s41391-022-00492-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/17/2021] [Accepted: 01/11/2022] [Indexed: 01/14/2023]
Abstract
BACKGROUND Metformin may have anticancer effects that are independent of its hypoglycemic effects. Retrospective studies have shown that metformin use is associated with decreased incidence of prostate cancer and prostate cancer-specific mortality. Preclinical studies suggesting additive anticancer effects of combining metformin and bicalutamide prompted this clinical trial (NCT02614859). METHODS This open-label, randomized, phase 2 trial enrolled non-diabetic patients with biochemically recurrent prostate cancer, a PSADT of 3-9 months, BMI > 25 and normal testosterone. Patients were randomized 1:2 to observation for an initial 8 weeks (Arm A) or metformin 1000 mg twice daily (Arm B). Bicalutamide 50 mg/day was added after 8 weeks to both arms. The primary objective was to evaluate the number of patients with undetectable PSA ( < 0.2 ng/mL) at the end of 32 weeks. Immune correlatives were assessed as exploratory endpoints. RESULTS A total of 29 patients were enrolled from March 2015 to January 2020. No difference was seen between the 2 arms in the proportion of patients with undetectable PSA. Modest PSA decrease ranging from 4% to 24% were seen in 40.0% (95% CI: 19.1-64.0%) of patients with metformin monotherapy, compared to 11.1% (95% CI: 0.3-48.3%) in the observation arm. Metformin monotherapy reduced PD-1+ NK cells, and increased NKG2D+ NK cells. The combination of metformin and bicalutamide led to greater reductions in PD-1 expressing NK, CD4+ T, and CD8+ T-cell subsets compared to bicalutamide alone. The trial was stopped early due to predicted inability to achieve its primary endpoint. CONCLUSIONS Although metformin plus bicalutamide was well tolerated, there was no improvement in rates of achieving undetectable PSA at 32 weeks. Metformin monotherapy induced modest PSA declines in 40% of patients after 8 weeks. Metformin, given alone and in combination with bicalutamide, displayed immune modifying effects, primarily within NK and T cells subsets. TRIAL REGISTRATION Trial Registration Number: NCT02614859.
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Affiliation(s)
- Marijo Bilusic
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
- Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, 33136, USA.
| | - Nicole J Toney
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Renee N Donahue
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Susan Wroblewski
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Matthew Zibelman
- Department of Hematology Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Pooja Ghatalia
- Department of Hematology Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Eric A Ross
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Fatima Karzai
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ravi A Madan
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - William L Dahut
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - James L Gulley
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Elizabeth R Plimack
- Department of Hematology Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Daniel M Geynisman
- Department of Hematology Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
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34
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Gan X, Cao C, He Y, Hu X, Peng X, Su Y. The metformin has no significant anticancer effect on patients with advanced or unresectable cancer: systematic review and meta-analysis. Curr Pharm Des 2022; 28:1351-1358. [PMID: 35352646 DOI: 10.2174/1381612828666220329113434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/14/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND At present, the antitumor effect of metformin is controversial. Previous meta-analyses included observational studies, of which the results can be influenced by many confounders, affecting the result of meta-analyses and weakening the strength of evidence. Therefore, we conducted a meta-analysis to confirm the effect of metformin use on patients with advanced or unresectable cancers, including randomized clinical trials (RCTs). METHODS We searched for RCTs in accordance with the inclusion and exclusion criteria. A meta-analysis was conducted to combine hazard ratios (HRs) or risk ratios (RRs) and their 95% confidence intervals (CIs), using a random-effects model. RESULTS Finally, 7 eligible RCTs were included in meta-analysis. Overall, the combined results revealed that treatment with metformin did not improve the overall survival (OS) of patients (HR, 1.12; 95%CI, 0.91-1.37, P>0.05), and there was no clear evidence that metformin use was related to improved progression-free survival (PFS) (HR,1.17; 95%CI, 0.97-1.40; P>0.05). The pooled RR for grade III or IV adverse events was 0.92 (95%CI, 0.52-1.60; P>0.05), indicating that the use of metformin was not significantly related to increased toxicity. CONCLUSION Metformin does not significantly improve the survival of patients with advanced or unresectable cancer, regardless of cancer type and region. Open Science Framework： DOI 10.17605/OSF.IO/SPKE8.
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Affiliation(s)
- Xinyan Gan
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Chang Cao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yan He
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaolin Hu
- Department of Nursing, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xingchen Peng
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yonglin Su
- Rehabilitation Medicine Center and Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, China；
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35
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Fu J, Liu S, Hu M, Liao X, Wang X, Xu Z, Li Q, Quan J. Biguanide MC001, a Dual Inhibitor of OXPHOS and Glycolysis, Shows Enhanced Antitumor Activity Without Increasing Lactate Production. ChemMedChem 2022; 17:e202100674. [PMID: 34984842 DOI: 10.1002/cmdc.202100674] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 12/29/2021] [Indexed: 11/12/2022]
Abstract
Metformin and other biguanides represent a new class of inhibitors of mitochondrial complex I that show promising antitumor effects. However, stronger inhibition of mitochondrial complex I is generally associated with upregulation of glycolysis and higher risk of lactic acidosis. Herein we report a novel biguanide derivative, N-cystaminylbiguanide (MC001), which was found to inhibit mitochondrial complex I with higher potency while inducing lactate production to a similar degree as metformin.Furthermore, MC001 was found to efficiently inhibit a panel of colorectal cancer (CRC) cells in vitro and to suppress tumor growth in a HCT116 xenograft nude mouse model, while not enhancing lactate production relative to metformin, exhibiting a superior safety profile to other potent biguanides such as phenformin. Mechanistically, MC001 efficiently inhibits mitochondrial complex I, activates AMPK, and represses mTOR, leading to cell-cycle arrest and apoptosis. Notably, MC001 inhibits both oxidative phosphorylation (OXPHOS) and glycolysis. We therefore propose that MC001 warrants further investigation in cancer treatment.
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Affiliation(s)
- Jiamiao Fu
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School, Shenzhen, 518055, China
| | - Siyu Liu
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School, Shenzhen, 518055, China
| | - Minqiang Hu
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School, Shenzhen, 518055, China
| | - Ximing Liao
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School, Shenzhen, 518055, China
| | - Xiaoquan Wang
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School, Shenzhen, 518055, China
| | - Zhengshuang Xu
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School, Shenzhen, 518055, China
| | - Qinkai Li
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School, Shenzhen, 518055, China
| | - Junmin Quan
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University, Shenzhen Graduate School, Shenzhen, 518055, China
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36
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Nitsche LJ, Mukherjee S, Cheruvu K, Krabak C, Rachala R, Ratnakaram K, Sharma P, Singh M, Yendamuri S. Exploring the Impact of the Obesity Paradox on Lung Cancer and Other Malignancies. Cancers (Basel) 2022; 14:cancers14061440. [PMID: 35326592 PMCID: PMC8946288 DOI: 10.3390/cancers14061440] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/01/2022] [Accepted: 03/09/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Studies have shown that obesity is associated with many adverse health effects, including worse cancer outcomes. Many studies paradoxically suggest a survival benefit for obesity in treatment outcomes of cancers such as non-small-cell lung cancer. This relationship is not seen in animal models. We hypothesize that this relationship is secondary to suboptimal quantification of adiposity, enhanced immunotherapy response, and variables such as sex, medications, and smoking status. There are many ways to measure and classify adiposity, but the ability to distinguish abdominal obesity is likely key in predicting accurate prognosis. There are many ways obesity impacts cancer treatment course from diagnosis to survivorship. In this paper, we aim to analyze the factors contributing to the obesity paradox and its effect on lung cancer. This can aid the treatment and prognosis of lung cancer and may support further research into obesity-specific impacts on this malignancy. Abstract There is a paradoxical relationship between obesity, as measured by BMI, and many types of cancer, including non-small-cell lung cancer. Obese non-small-cell lung cancer patients have been shown to fare better than their non-obese counterparts. To analyze the multifaceted effects of obesity on oncologic outcomes, we reviewed the literature on the obesity paradox, methods to measure adiposity, the obesity-related derangements in immunology and metabolism, and the oncologic impact of confounding variables such as gender, smoking, and concomitant medications such as statins and metformin. We analyzed how these aspects may contribute to the obesity paradox and cancer outcomes with a focus on lung cancer. We concluded that the use of BMI to measure adiposity is limited and should be replaced by a method that can differentiate abdominal obesity. We also concluded that the concomitant metabolic and immunologic derangements caused by obesity contribute to the obesity paradox. Medications, gender, and smoking are additional variables that impact oncologic outcomes, and further research needs to be performed to solidify the mechanisms.
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Affiliation(s)
- Lindsay Joyce Nitsche
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Sarbajit Mukherjee
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA;
| | - Kareena Cheruvu
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Cathleen Krabak
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Rohit Rachala
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Kalyan Ratnakaram
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Priyanka Sharma
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Maddy Singh
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
| | - Sai Yendamuri
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA; (L.J.N.); (K.C.); (C.K.); (R.R.); (K.R.); (P.S.); (M.S.)
- Correspondence: ; Tel.: +1-716-8458675
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Barakat HE, Hussein RRS, Elberry AA, Zaki MA, Elsherbiny Ramadan M. Factors influencing the anticancer effects of metformin on breast cancer outcomes: a systematic review and meta-analysis. Expert Rev Anticancer Ther 2022; 22:415-436. [PMID: 35259320 DOI: 10.1080/14737140.2022.2051482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Several clinical trials have attempted to find evidence that supports the use of metformin as an anticancer treatment. However, the observed effects on various breast cancer (BC) outcomes have been heterogeneous. AREAS COVERED Based on the outcomes of previous clinical trials, this review discusses the patients' characteristics, cancer intrinsic subtypes, cancer stage, and anticancer treatments that may influence the anticancer effect of metformin on BC outcomes. Additionally, the safety and tolerability of metformin addition to various anticancer regimens are reviewed. EXPERT OPINION Metformin is a challenging anticancer agent in BC cohorts, besides being safe and well-tolerated at antidiabetic doses. Survival benefits of metformin have been observed in BC patients with: hormone receptor-positive, human epidermal growth factor receptor-2 overexpression, and high insulin like growth factor-1 receptor expression on the tumor surface. Moreover, patients with diabetes receiving metformin experienced better survival outcomes compared to diabetic patients not receiving metformin. Additionally, metformin has anti-proliferative activity in patients with BC who have high insulin resistance and high body mass index. Besides, metformin has been shown to decrease metastatic events, and enhance the level of metabolic- and insulin-related biomarkers associated with carcinogenesis. Finally, most adverse events following metformin treatment were low-grade GIT toxicities.
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Feng J, Wang X, Ye X, Ares I, Lopez-Torres B, Martínez M, Martínez-Larrañaga MR, Wang X, Anadón A, Martínez MA. Mitochondria as an important target of metformin: The mechanism of action, toxic and side effects, and new therapeutic applications. Pharmacol Res 2022; 177:106114. [DOI: 10.1016/j.phrs.2022.106114] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/21/2022] [Accepted: 02/01/2022] [Indexed: 12/25/2022]
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Greene J, Segaran A, Lord S. Targeting OXPHOS and the electronic transport chain in cancer; molecular and therapeutic implications. Semin Cancer Biol 2022; 86:851-859. [PMID: 35122973 DOI: 10.1016/j.semcancer.2022.02.002] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/29/2022] [Accepted: 02/01/2022] [Indexed: 12/11/2022]
Abstract
Oxidative phosphorylation (OXPHOS) takes place in mitochondria and is the process whereby cells use carbon fuels and oxygen to generate ATP. Formerly OXPHOS was thought to be reduced in tumours and that glycolysis was the critical pathway for generation of ATP but it is now clear that OXPHOS, at least in many tumour types, plays a critical role in delivering the bioenergetic and macromolecular anabolic requirements of cancer cells. There is now great interest in targeting the OXPHOS and the electron transport chain for cancer therapy and in this review article we describe current therapeutic approaches and challenges.
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Affiliation(s)
- John Greene
- Department of Oncology, University of Oxford, Churchill Hospital, Oxford, United Kingdom
| | - Ashvina Segaran
- Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom
| | - Simon Lord
- Department of Oncology, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
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Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma. Cancers (Basel) 2021; 14:cancers14010112. [PMID: 35008275 PMCID: PMC8749852 DOI: 10.3390/cancers14010112] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/15/2021] [Accepted: 12/19/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Glioblastoma is the most aggressive primary brain tumor, with the highest incidence and the worst prognosis. Life expectancy from diagnosis remains dismal, at around 15 months, despite surgical resection and treatment with radiotherapy and chemotherapy. Given the aggressiveness of the tumor and the inefficiency of the treatments adopted to date, the scientific research investigates innovative therapeutic approaches. Importantly, angiogenesis represents one of the main features of glioblastoma, becoming in the last few years a major candidate for target therapy. Metformin, a well-established therapy for type 2 diabetes, offered excellent results in preventing and fighting tumor progression, particularly against angiogenic mechanisms. Therefore, the purpose of this review is to summarize and discuss experimental evidence of metformin anti-cancer efficacy, with the aim of proposing this totally safe and tolerable drug as add-on therapy against glioblastoma. Abstract Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.
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EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine. Sci Rep 2021; 11:22733. [PMID: 34815475 PMCID: PMC8611048 DOI: 10.1038/s41598-021-02181-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 11/10/2021] [Indexed: 12/13/2022] Open
Abstract
Small intestinal neuroendocrine tumors (SI-NETs) are slow-growing tumors that seem genetically quite stable without highly recurrent mutations, but are epigenetically dysregulated. In contrast to the undetectable expression of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase in the enterochromaffin cells of the small intestine, we found high and differential expression of EZH2 in primary SI-NETs and corresponding metastases. Silencing EZH2 in the SI-NET cell line CNDT2.5 reduced cell proliferation and induced apoptosis. Furthermore, EZH2 knockout inhibited tumor progression in a CNDT2.5 SI-NET xenograft mouse model, and treatment of SI-NET cell lines CNDT2.5 and GOT1 with the EZH2-specific inhibitor CPI-1205 decreased cell viability and promoted apoptosis. Moreover, CPI-1205 treatment reduced migration capacity of CNDT2.5 cells. The EZH2 inhibitor GSK126 also repressed proliferation of CNDT2.5 cells. Recently, metformin has received wide attention as a therapeutic option in diverse cancers. In CNDT2.5 and GOT1 cells, metformin suppressed EZH2 expression, and inhibited cell proliferation. Exposure of GOT1 three-dimensional cell spheroids to CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. These novel findings support a possible role of EZH2 as a candidate oncogene in SI-NETs, and suggest that CPI-1205 and metformin should be further evaluated as therapeutic options for patients with SI-NETs.
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Mamdouh AM, Khodeer DM, Tantawy MA, Moustafa YM. In-vitro and in-vivo investigation of amygdalin, metformin, and combination of both against doxorubicin on hepatocellular carcinoma. Life Sci 2021; 285:119961. [PMID: 34536497 DOI: 10.1016/j.lfs.2021.119961] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 12/27/2022]
Abstract
AIM Hepatocellular carcinoma (HCC) is a potentially life-threatening cancer. In the current study, anti-HCC efficacy of amygdalin, or metformin alone or in combination in comparison to doxorubicin was studied. MAIN METHODS Both in-vitro and in-vivo based models. HepG-2 and Huh-7 cell lines as established in-vitro model for HCC were treated with different concentrations of indicated drugs to evaluate the cytotoxicity and determine IC50 for 24, 48 and 72 h. Moreover, the effect of different treatments on apoptosis and cell cycle using flow cytometric analysis were studied. Hepatocellular carcinoma induced in rats by diethyl-nitrosamine and carbon tetrachloride was established, to further investigate the efficacy of indicated drugs. Aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase were measured by spectrophotometer, alpha-fetoprotein, cytochrome-c, caspase-3 and malondialdehyde were measured by ELISA, and liver biopsies were also evaluated histopathologically. KEY FINDINGS In-vitro results showed that the combination has a promising effect when compared to amygdalin or metformin alone as it is more cytotoxic and have higher ability for induction of apoptosis and arresting cell cycle. In-vivo doxorubicin has a good effect for treating HCC. Also, the combination showed a promising prognostic effect depending on the cytotoxic activity and tumor marker when compared to amygdalin or metformin alone. SIGNIFICANCE Based on the current data, it was hypothesized that amygdalin and metformin especially when used in combination will be a promising approach with low side effects for enhancement of HCC.
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Affiliation(s)
- Ahmed M Mamdouh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Horus University - Egypt, New Damietta 34518, Egypt
| | - Dina M Khodeer
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
| | - Mohamed A Tantawy
- Hormones Department, Medical Research Division, National Research Centre, Cairo, Egypt; Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, Egypt
| | - Yasser M Moustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Faculty of Pharmacy, BUC, Cairo, Egypt
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DeNicola GM, Shackelford DB. Metabolic Phenotypes, Dependencies, and Adaptation in Lung Cancer. Cold Spring Harb Perspect Med 2021; 11:a037838. [PMID: 34127512 PMCID: PMC8559540 DOI: 10.1101/cshperspect.a037838] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Lung cancer is a heterogeneous disease that is subdivided into histopathological subtypes with distinct behaviors. Each subtype is characterized by distinct features and molecular alterations that influence tumor metabolism. Alterations in tumor metabolism can be exploited by imaging modalities that use metabolite tracers for the detection and characterization of tumors. Microenvironmental factors, including nutrient and oxygen availability and the presence of stromal cells, are a critical influence on tumor metabolism. Recent technological advances facilitate the direct evaluation of metabolic alterations in patient tumors in this complex microenvironment. In addition, molecular alterations directly influence tumor cell metabolism and metabolic dependencies that influence response to therapy. Current therapeutic approaches to target tumor metabolism are currently being developed and translated into the clinic for patient therapy.
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Affiliation(s)
- Gina M DeNicola
- Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - David B Shackelford
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles, California 90095, USA
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Goodwin PJ, Dowling RJO, Ennis M, Chen BE, Parulekar WR, Shepherd LE, Gelmon KA, Whelan TJ, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Rastogi P, Rabaglio-Poretti M, Lemieux J, Thompson AM, Rea DW, Stambolic V. Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA.32: A Breast Cancer Randomized Trial of Metformin vs Placebo. JNCI Cancer Spectr 2021; 5:pkab066. [PMID: 34485814 PMCID: PMC8410139 DOI: 10.1093/jncics/pkab066] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/15/2021] [Accepted: 07/26/2021] [Indexed: 11/18/2022] Open
Abstract
Background Circulating levels of cancer antigen (CA) 15-3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15-3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer. Methods A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15-3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15-3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided. Results Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor-positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15-3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15-3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15-3 = 7.7% vs 2.0%, P < .001; relative metformin: placebo level of CA 15-3 [adjusted for age, baseline body mass index, and baseline CA 15-3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps > .11). Conclusions Our observation that metformin reduces CA 15-3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15-3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.
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Affiliation(s)
- Pamela J Goodwin
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Department of Medicine, University of Toronto, Toronto, ON, Canada
| | | | | | - Bingshu E Chen
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | - Wendy R Parulekar
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | - Lois E Shepherd
- Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada
| | - Karen A Gelmon
- University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada
| | - Timothy J Whelan
- McMaster University, Juravinski Cancer Centre, Hamilton, ON, Canada
| | | | - Dawn L Hershman
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, NY, USA
| | | | | | - Priya Rastogi
- NRG Oncology and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Manuela Rabaglio-Poretti
- IBCSG and Department of Oncology, Bern University Hospital, University of Bern, Bern, Switzerland
| | | | | | - Daniel W Rea
- Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Vuk Stambolic
- Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada and University of Toronto, Toronto, ON, Canada
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Zhang Z, Zeng D, Zhang W, Chen A, Lei J, Liu F, Deng B, Zhuo J, He B, Yan M, Lei X, Wang S, Lam EWF, Liu Q, Wang Z. Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition. Cell Death Dis 2021; 12:893. [PMID: 34593753 PMCID: PMC8484571 DOI: 10.1038/s41419-021-04190-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 09/06/2021] [Accepted: 09/17/2021] [Indexed: 02/08/2023]
Abstract
Uncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.
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Affiliation(s)
- Zijian Zhang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Deshun Zeng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Wei Zhang
- Department of Clinical Immunology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Ailin Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Jie Lei
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Fang Liu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Bing Deng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Junxiao Zhuo
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Bin He
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Min Yan
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Xinxing Lei
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Shulan Wang
- Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Eric W-F Lam
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Quentin Liu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.
| | - Zifeng Wang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
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Eyres M, Lanfredini S, Xu H, Burns A, Blake A, Willenbrock F, Goldin R, Hughes D, Hughes S, Thapa A, Vavoulis D, Hubert A, D'Costa Z, Sabbagh A, Abraham AG, Blancher C, Jones S, Verrill C, Silva M, Soonawalla Z, Maughan T, Schuh A, Mukherjee S, O'Neill E. TET2 Drives 5hmc Marking of GATA6 and Epigenetically Defines Pancreatic Ductal Adenocarcinoma Transcriptional Subtypes. Gastroenterology 2021; 161:653-668.e16. [PMID: 33915173 DOI: 10.1053/j.gastro.2021.04.044] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 03/12/2021] [Accepted: 04/07/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDAC) is characterized by advanced disease stage at presentation, aggressive disease biology, and resistance to therapy, resulting in an extremely poor 5-year survival rate of <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression, but exactly why is unclear and is hindered by the technical limitations of analyzing clinical samples. METHODS We performed genome-wide epigenetic mapping of DNA modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmc) using oxidative bisulfite sequencing from formalin-embedded sections. We identified overlap with transcriptional signatures in formalin-fixed, paraffin-embedded tissue from resected patients, via bioinformatics using iCluster and mutational profiling and confirmed them in vivo. RESULTS We found that aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci, including GATA6, which promote differentiated classical pancreatic subtypes. We showed that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5-methylcytosine hydroxylase TET2. Furthermore, we found that SMAD4 directly supports TET2 levels in classical pancreatic tumors, and loss of SMAD4 expression was associated with reduced 5hmc, GATA6, and squamous-like tumors. Importantly, enhancing TET2 stability using metformin and vitamin C/ascorbic acid restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo. CONCLUSIONS We identified epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data showed that restoring epigenetic control increases biomarkers of classical pancreatic tumors that are associated with improved therapeutic responses and survival.
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MESH Headings
- 5-Methylcytosine/analogs & derivatives
- 5-Methylcytosine/metabolism
- Animals
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Ascorbic Acid/pharmacology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/enzymology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Cell Differentiation
- Cell Line, Tumor
- DNA Methylation/drug effects
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Dioxygenases/genetics
- Dioxygenases/metabolism
- Epigenesis, Genetic/drug effects
- Epigenome
- Epigenomics
- GATA6 Transcription Factor/genetics
- GATA6 Transcription Factor/metabolism
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Metformin/pharmacology
- Mice, Nude
- Mice, Transgenic
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/enzymology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Retrospective Studies
- Smad4 Protein/genetics
- Smad4 Protein/metabolism
- Transcription, Genetic/drug effects
- Transcriptome
- Wnt Signaling Pathway/genetics
- Xenograft Model Antitumor Assays
- Mice
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Affiliation(s)
- Michael Eyres
- Department of Oncology, University of Oxford, Oxford, UK
| | | | - Haonan Xu
- Department of Oncology, University of Oxford, Oxford, UK
| | - Adam Burns
- Department of Oncology, University of Oxford, Oxford, UK
| | - Andrew Blake
- Department of Oncology, University of Oxford, Oxford, UK
| | | | - Robert Goldin
- Centre for Pathology, Imperial College, London, United Kingdom
| | - Daniel Hughes
- Department of Oncology, University of Oxford, Oxford, UK; Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom
| | - Sophie Hughes
- Department of Oncology, University of Oxford, Oxford, UK
| | - Asmita Thapa
- Department of Oncology, University of Oxford, Oxford, UK
| | | | - Aline Hubert
- Department of Oncology, University of Oxford, Oxford, UK
| | | | - Ahmad Sabbagh
- Department of Oncology, University of Oxford, Oxford, UK
| | | | - Christine Blancher
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Stephanie Jones
- Oxford Radcliffe Biobank, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Clare Verrill
- Nuffield Department of Surgical Sciences and Oxford National Institute for Health Research Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Michael Silva
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom
| | - Zahir Soonawalla
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom
| | | | - Anna Schuh
- Department of Oncology, University of Oxford, Oxford, UK
| | | | - Eric O'Neill
- Department of Oncology, University of Oxford, Oxford, UK.
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Shi B, Hu X, He H, Fang W. Metformin suppresses breast cancer growth via inhibition of cyclooxygenase-2. Oncol Lett 2021; 22:615. [PMID: 34257723 PMCID: PMC8243079 DOI: 10.3892/ol.2021.12876] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Pre-clinical and on-going trials have indicated the advantage of using metformin as an anticancer drug alone or in combination with other chemotherapeutics for the treatment of patients with breast cancer. However, the mechanisms by which metformin attenuates tumorigenesis remain to be further elucidated. The present study investigated the anticancer effects of metformin in breast cancer and identified potential molecular targets of metformin using western blotting and immunohistochemical analysis. Metformin significantly decreased tumor cell proliferation in vitro and suppressed tumor growth in vivo. Moreover, it induced the activation of AMP-induced protein kinase and suppression of phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1 (p-4E-BP1), a downstream effector of the mTOR signaling pathway, and decreased cyclin D1 levels in in vitro and in vivo experimental models. Additionally, metformin inhibited cyclooxygenase (COX)-2 expression. Clinically, high expression levels of COX-2 and p-4E-BP1 in tissues of patients with breast cancer were significantly associated with enhanced lymphatic metastasis and distant metastasis. Thus, the current data suggested that metformin may have potential value as a synergistic therapy targeting both the COX-2 and mTOR signaling pathways.
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Affiliation(s)
- Bin Shi
- Department of Medical Oncology, Fuzhou General Hospital of Fujian Medical University, East Hospital Affiliated to Xiamen University (The 900th Hospital of The Joint Logistics Support Force of The Chinese PLA), Dongfang Hospital, Xiamen University, Fuzhou, Fujian 350025, P.R. China
- Department of Medical Oncology, Longyan People's Hospital, Longyan, Fujian 364000, P.R. China
| | - Xinyu Hu
- Department of Medical Oncology, Fuzhou General Hospital of Fujian Medical University, East Hospital Affiliated to Xiamen University (The 900th Hospital of The Joint Logistics Support Force of The Chinese PLA), Dongfang Hospital, Xiamen University, Fuzhou, Fujian 350025, P.R. China
| | - Huimin He
- Department of Medical Oncology, Fuzhou General Hospital of Fujian Medical University, East Hospital Affiliated to Xiamen University (The 900th Hospital of The Joint Logistics Support Force of The Chinese PLA), Dongfang Hospital, Xiamen University, Fuzhou, Fujian 350025, P.R. China
| | - Wenzheng Fang
- Department of Medical Oncology, Fuzhou General Hospital of Fujian Medical University, East Hospital Affiliated to Xiamen University (The 900th Hospital of The Joint Logistics Support Force of The Chinese PLA), Dongfang Hospital, Xiamen University, Fuzhou, Fujian 350025, P.R. China
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Skinner H, Hu C, Tsakiridis T, Santana-Davila R, Lu B, Erasmus JJ, Doemer AJ, Videtic GMM, Coster J, Yang AX, Lee RY, Werner-Wasik M, Schaner PE, McCormack SE, Esparaz BT, McGarry RC, Bazan J, Struve T, Paulus R, Bradley JD. Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial. JAMA Oncol 2021; 7:1324-1332. [PMID: 34323922 DOI: 10.1001/jamaoncol.2021.2318] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Importance Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. Objective To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. Design, Setting, and Participants The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. Interventions Chemoradiation and consolidation chemotherapy with or without metformin. Main Outcomes and Measures The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. Results A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. Conclusions and Relevance In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. Trial Registration ClinicalTrials.gov Identifier: NCT02186847.
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Affiliation(s)
- Heath Skinner
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Chen Hu
- NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
| | | | | | - Bo Lu
- Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | | | | | | | | | | | | | | | | | - Steven E McCormack
- Metro-Minnesota Community Oncology Research Consortium, St Louis Park, Minnesota
| | | | | | - Jose Bazan
- Ohio State University Comprehensive Cancer Center, Columbus
| | - Timothy Struve
- University of Cincinnati/Barrett Cancer Center, Cincinnati, Ohio
| | - Rebecca Paulus
- NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
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Deng T, Shen P, Li A, Zhang Z, Yang H, Deng X, Peng X, Hu Z, Tang Z, Liu J, Hou R, Liu Z, Fang W. CCDC65 as a new potential tumor suppressor induced by metformin inhibits activation of AKT1 via ubiquitination of ENO1 in gastric cancer. Am J Cancer Res 2021; 11:8112-8128. [PMID: 34335983 PMCID: PMC8315052 DOI: 10.7150/thno.54961] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 05/16/2021] [Indexed: 12/14/2022] Open
Abstract
The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.
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Shi B, Hu X, He H, Fang W. Metformin suppresses breast cancer growth via inhibition of cyclooxygenase‑2. Oncol Lett 2021; 22:615. [DOI: https:/doi.org/10.3892/ol.2021.12876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025] Open
Affiliation(s)
- Bin Shi
- Department of Medical Oncology, Fuzhou General Hospital of Fujian Medical University, East Hospital Affiliated to Xiamen University (The 900th Hospital of The Joint Logistics Support Force of The Chinese PLA), Dongfang Hospital, Xiamen University, Fuzhou, Fujian 350025, P.R. China
| | - Xinyu Hu
- Department of Medical Oncology, Fuzhou General Hospital of Fujian Medical University, East Hospital Affiliated to Xiamen University (The 900th Hospital of The Joint Logistics Support Force of The Chinese PLA), Dongfang Hospital, Xiamen University, Fuzhou, Fujian 350025, P.R. China
| | - Huimin He
- Department of Medical Oncology, Fuzhou General Hospital of Fujian Medical University, East Hospital Affiliated to Xiamen University (The 900th Hospital of The Joint Logistics Support Force of The Chinese PLA), Dongfang Hospital, Xiamen University, Fuzhou, Fujian 350025, P.R. China
| | - Wenzheng Fang
- Department of Medical Oncology, Fuzhou General Hospital of Fujian Medical University, East Hospital Affiliated to Xiamen University (The 900th Hospital of The Joint Logistics Support Force of The Chinese PLA), Dongfang Hospital, Xiamen University, Fuzhou, Fujian 350025, P.R. China
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