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Li D, Jin P, Cai Y, Wu S, Guo X, Zhang Z, Liu K, Li P, Hu Y, Zhou Y. Clinical significance of lipid pathway-targeted therapy in breast cancer. Front Pharmacol 2025; 15:1514811. [PMID: 39834807 PMCID: PMC11743736 DOI: 10.3389/fphar.2024.1514811] [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: 10/21/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025] Open
Abstract
Globally, breast cancer represents the most common cancer and the primary cause of death by cancer in women. Lipids are crucial in human physiology, serving as vital energy reserves, structural elements of biological membranes, and essential signaling molecules. The metabolic reprogramming of lipid pathways has emerged as a critical factor in breast cancer progression, drug resistance, and patient prognosis. In this study, we delve into the clinical implications of lipid pathway-targeted therapy in breast cancer. We highlight key enzymes and potential therapeutic targets involved in lipid metabolism reprogramming, and their associations with cancer progression and treatment outcomes. Furthermore, we detail the clinical trials exploring the anticancer and cancer chemopreventive activity of therapies targeting these molecules. However, the clinical efficacy of these therapies remains controversial, highlighting the urgent need for predictive biomarkers to identify patient subpopulations likely to benefit from such treatment. We propose the Selective Lipid Metabolism Therapy Benefit Hypothesis, emphasizing the importance of personalized medicine in optimizing lipid pathway-targeted therapy for breast cancer patients.
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Affiliation(s)
- Dan Li
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Pengcheng Jin
- Department of Surgical Oncology, Linhai Branch, The Second Affiliated Hospital, Zhejiang University School of Medicine, Taizhou, Zhejiang, China
| | - Yiqi Cai
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shijie Wu
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianan Guo
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhiyun Zhang
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kexin Liu
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Panni Li
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yue Hu
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yunxiang Zhou
- Department of Breast Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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De-Leon-Covarrubias UE, Perez-Trujillo JJ, Villa-Cedillo SA, Martinez-Perez AG, Montes-de-Oca-Saucedo CR, Loera-Arias MDJ, Garcia-Garcia A, Saucedo-Cardenas O, Montes-de-Oca-Luna R. Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment. Metabolites 2024; 14:418. [PMID: 39195514 DOI: 10.3390/metabo14080418] [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: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 08/29/2024] Open
Abstract
Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies.
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Affiliation(s)
| | - Jose Juan Perez-Trujillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Sheila Adela Villa-Cedillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | | | | | - Maria de Jesus Loera-Arias
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Aracely Garcia-Garcia
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Odila Saucedo-Cardenas
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Roberto Montes-de-Oca-Luna
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
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Pujalte‐Martin M, Belaïd A, Bost S, Kahi M, Peraldi P, Rouleau M, Mazure NM, Bost F. Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759. Mol Oncol 2024; 18:1719-1738. [PMID: 38214418 PMCID: PMC11223609 DOI: 10.1002/1878-0261.13583] [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: 08/16/2023] [Revised: 11/15/2023] [Accepted: 12/29/2023] [Indexed: 01/13/2024] Open
Abstract
Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.
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Affiliation(s)
- Marc Pujalte‐Martin
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Amine Belaïd
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Simon Bost
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Michel Kahi
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Pascal Peraldi
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Matthieu Rouleau
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
- CNRS UMR7370, LP2MNiceFrance
| | - Nathalie M. Mazure
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
| | - Frédéric Bost
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)NiceFrance
- Equipe Labellisée Ligue Nationale Contre le Cancer
- Faculté de MédecineUniversité Côte d'AzurNiceFrance
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Jalali F, Fakhari F, Sepehr A, Zafari J, Sarajar BO, Sarihi P, Jafarzadeh E. Synergistic anticancer effects of doxorubicin and metformin combination therapy: A systematic review. Transl Oncol 2024; 45:101946. [PMID: 38636389 PMCID: PMC11040171 DOI: 10.1016/j.tranon.2024.101946] [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: 12/20/2023] [Revised: 03/05/2024] [Accepted: 03/24/2024] [Indexed: 04/20/2024] Open
Abstract
INTRODUCTION Doxorubicin (DOX) a chemotherapy drug often leads to the development of resistance, in cancer cells after prolonged treatment. Recent studies have suggested that using metformin plus doxorubicin could result in synergic effects. This study focuses on exploring the co-treat treatment of doxorubicin and metformin for various cancers. METHOD Following the PRISMA guidelines we conducted a literature search using different databases such as Embase, Scopus, Web of Sciences, PubMed, Science Direct and Google Scholar until July 2023. We selected search terms based on the objectives of this study. After screening a total of 30 articles were included. RESULTS The combination of doxorubicin and metformin demonstrated robust anticancer effects, surpassing the outcomes of monotherapy drug treatment. In vitro experiments consistently demonstrated inhibition of cancer cell growth and increased rates of cell death. Animal studies confirmed substantial reductions in tumor growth and improved survival rates, emphasizing the synergistic impact of the combined therapy. The research' discoveries collectively emphasize the capability of the co-treat doxorubicin-metformin as a compelling approach in cancer treatment, highlighting its potential to address medicate resistance and upgrade generally helpful results. CONCLUSION The findings of this study show that the combined treatment regimen including doxorubicin and metformin has significant promise in fighting cancer. The observed synergistic effects suggest that this combination therapy could be valuable, in a setting. This study highlights the need for clinical research to validate and enhance the application of the doxorubicin metformin regimen.
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Affiliation(s)
- Fereshtehsadat Jalali
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Fakhari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Afrah Sepehr
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Jaber Zafari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Behnam Omidi Sarajar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Pouria Sarihi
- Research Institute of Bioscience and Biotechnology, University of Tabriz, Tabriz, Iran.
| | - Emad Jafarzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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Kawakita E, Kanasaki K. Cancer biology in diabetes update: Focusing on antidiabetic drugs. J Diabetes Investig 2024; 15:525-540. [PMID: 38456597 PMCID: PMC11060166 DOI: 10.1111/jdi.14152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 03/09/2024] Open
Abstract
The association of type 2 diabetes with certain cancer risk has been of great interest for years. However, the effect of diabetic medications on cancer development is not fully understood. Prospective clinical trials have not elucidated the long-term influence of hypoglycemic drugs on cancer incidence and the safety for cancer-bearing patients with diabetes, whereas numerous preclinical studies have shown that antidiabetic drugs could have an impact on carcinogenesis processes beyond the glycemic control effect. Because there is no evidence of the safety profile of antidiabetic agents on cancer biology, careful consideration would be required when prescribing any medicines to patients with diabetes and existing tumor. In this review, we discuss the potential influence of each diabetes therapy in cancer 'initiation', 'promotion' and 'progression'.
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Affiliation(s)
- Emi Kawakita
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
| | - Keizo Kanasaki
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
- The Center for Integrated Kidney Research and Advance, Faculty of MedicineShimane UniversityIzumoJapan
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Goglia U, Hasballa I, Teti C, Boschetti M, Ferone D, Albertelli M. Ianus Bifrons: The Two Faces of Metformin. Cancers (Basel) 2024; 16:1287. [PMID: 38610965 PMCID: PMC11011026 DOI: 10.3390/cancers16071287] [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: 01/18/2024] [Revised: 03/10/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open?
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Affiliation(s)
- Umberto Goglia
- Endocrinology and Diabetology Unit, Local Health Authority CN1, 12100 Cuneo, Italy
| | - Iderina Hasballa
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Claudia Teti
- Endocrinology and Diabetology Unit, Local Health Autorithy Imperia 1, 18100 Imperia, Italy;
| | - Mara Boschetti
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Diego Ferone
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Manuela Albertelli
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
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Corleto KA, Strandmo JL, Giles ED. Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies. Pharmaceuticals (Basel) 2024; 17:396. [PMID: 38543182 PMCID: PMC10974219 DOI: 10.3390/ph17030396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/11/2024] [Accepted: 03/12/2024] [Indexed: 04/01/2024] Open
Abstract
Over the last several decades, a growing body of research has investigated the potential to repurpose the anti-diabetic drug metformin for breast cancer prevention and/or treatment. Observational studies in the early 2000s demonstrated that patients with diabetes taking metformin had decreased cancer risk, providing the first evidence supporting the potential role of metformin as an anti-cancer agent. Despite substantial efforts, two decades later, the exact mechanisms and clinical efficacy of metformin for breast cancer remain ambiguous. Here, we have summarized key findings from studies examining the effect of metformin on breast cancer across the translational spectrum including in vitro, in vivo, and human studies. Importantly, we discuss critical factors that may help explain the significant heterogeneity in study outcomes, highlighting how metformin dose, underlying metabolic health, menopausal status, tumor subtype, membrane transporter expression, diet, and other factors may play a role in modulating metformin's anti-cancer effects. We hope that these insights will help with interpreting data from completed studies, improve the design of future studies, and aid in the identification of patient subsets with breast cancer or at high risk for the disease who are most likely to benefit from metformin treatment.
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Affiliation(s)
- Karen A. Corleto
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (K.A.C.)
- School of Kinesiology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jenna L. Strandmo
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (K.A.C.)
| | - Erin D. Giles
- School of Kinesiology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
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Benjamin DJ, Haslam A, Prasad V. Cardiovascular/anti-inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta-analysis of randomized trials. Cancer Med 2024; 13:e7049. [PMID: 38491813 PMCID: PMC10943275 DOI: 10.1002/cam4.7049] [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: 07/15/2023] [Revised: 01/09/2024] [Accepted: 02/08/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Due to encouraging pre-clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin-converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer. We sought to investigate the anti-cancer effects of drugs repurposed from cardiology or anti-inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG-CoA reductase inhibitors (statins), cyclo-oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors. We also included non-steroidal anti-inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer. METHODS We performed a systematic literature review using PubMed and Web of Science with search terms including "aspirin," "NSAID," "statin" (including specific statin drug names), "metformin," "ACE inhibitors," and "ARBs" (including specific anti-hypertensive drug names) in combination with "cancer." Searches were limited to human studies published between 2000 and 2023. MAIN OUTCOMES AND MEASURES The number and percentage of studies reported positive results and pooled estimates of overall survival, progression-free survival, response, and disease-free survival. RESULTS We reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non-small-cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first-line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression-free survival (86.1% of studies testing progression-free survival) or in overall survival (94.3% of studies testing overall survival). Progression-free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression-free survival was worse in one study (2.8% of studies testing progression-free survival). CONCLUSIONS AND RELEVANCE Despite promising pre-clinical and population-based data, cardiovascular drugs and anti-inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.
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Affiliation(s)
| | - Alyson Haslam
- Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoCaliforniaUnited States
| | - Vinay Prasad
- Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoCaliforniaUnited States
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Garczorz W, Kosowska A, Francuz T. Antidiabetic Drugs in Breast Cancer Patients. Cancers (Basel) 2024; 16:299. [PMID: 38254789 PMCID: PMC10813754 DOI: 10.3390/cancers16020299] [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: 11/29/2023] [Revised: 01/06/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Diabetes is one of the leading chronic conditions worldwide, and breast cancer is the most prevalent cancer in women worldwide. The linkage between diabetes and its ability to increase the risk of breast cancer should always be analyzed in patients. This review focuses on the impact of antihyperglycemic therapy in breast cancer patients. Patients with diabetes have a higher risk of developing cancer than the general population. Moreover, diabetes patients have a higher incidence and mortality of breast cancer. In this review, we describe the influence of antidiabetic drugs from insulin and metformin to the current and emerging therapies, incretins and SGLT-2 inhibitors, on breast cancer prognosis. We also emphasize the role of obesity and the metastasis process in breast cancer patients who are treated with antidiabetic drugs.
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Affiliation(s)
- Wojciech Garczorz
- Department of Biochemistry, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 18, 40-055 Katowice, Poland; (A.K.); (T.F.)
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Chen Y, Bai B, Ye S, Gao X, Zheng X, Ying K, Pan H, Xie B. Genetic effect of metformin use on risk of cancers: evidence from Mendelian randomization analysis. Diabetol Metab Syndr 2023; 15:252. [PMID: 38057926 DOI: 10.1186/s13098-023-01218-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 11/13/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Increasing number of studies reported the positive effect of metformin on the prevention and treatment of cancers. However, the genetic causal effect of metformin utilization on the risk of common cancers was not completely demonstrated. METHODS Two-sample Mendelian Randomization (two-sample MR) analysis was conducted to uncover the genetically predicted causal association between metformin use and 26 kinds of cancers. Besides, two-step Mendelian Randomization (two-step MR) assessment was applied to clarify the mediators which mediated the causal effect of metformin on certain cancer. We utilized five robust analytical methods, in which the inverse variance weighting (IVW) method served as the major one. Sensitivity, pleiotropy, and heterogeneity were assessed. The genetic statistics of exposure, outcomes, and mediators were downloaded from publicly available datasets, including the Open Genome-Wide Association Study (GWAS), FinnGen consortium (FinnGen), and UK Biobank (UKB). RESULTS Among 26 kinds of common cancers, HER-positive breast cancer was presented with a significant causal relationship with metformin use [Beta: - 4.0982; OR: 0.0166 (95% CI: 0.0008, 0.3376); P value: 0.0077], which indicated metformin could prevent people from HER-positive breast cancer. Other cancers only showed modest associations with metformin use. Potential mediators were included in two-step MR, among which total testosterone levels (mediating effect: 24.52%) displayed significant mediating roles. Leave-one-out, MR-Egger, and MR-PRESSO analyses produced consistent outcomes. CONCLUSION Metformin use exhibited a genetically protective effect on HER-positive breast cancer, which was partially mediated by total testosterone levels.
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Affiliation(s)
- Yao Chen
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, 310016, Zhejiang, People's Republic of China
| | - Bingjun Bai
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
| | - Shuchang Ye
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
| | - Xing Gao
- Department of Oncology, The Second Affiliated Hospital, Soochow University, Suzhou, 215004, People's Republic of China
| | - Xinnan Zheng
- Department of Radiation Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, People's Republic of China
| | - Kangkang Ying
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, 310016, Zhejiang, People's Republic of China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, 310016, Zhejiang, People's Republic of China.
| | - Binbin Xie
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, 310016, Zhejiang, People's Republic of China.
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Wu Z, Wang W, Wei L, Zhu S. Current status and frontier tracking of clinical trials on Metformin for cancer treatment. J Cancer Res Clin Oncol 2023; 149:16931-16946. [PMID: 37698682 DOI: 10.1007/s00432-023-05391-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 09/01/2023] [Indexed: 09/13/2023]
Abstract
PURPOSE Metformin has been used clinically for more than six decades. Over time, numerous remarkable effects of metformin beyond the clinic have been discovered and discussed. Metformin has been shown to have a favorable impact on cancer therapy in addition to its clinically recognized hypoglycemic effect. However, the antitumor efficacy of metformin in humans has not been clearly demonstrated yet. Hence, a systematic analysis of the existing trials is necessary. METHODS Here, we retrieved clinical trials from the Clinical Trials.gov database to overview the clinical development of metformin for the treatment of cancer, analyze existing clinical results, and summarize some promising applications for specific cancer therapies. RESULTS The potential application of metformin contains three directions: Firstly, improvement of metabolic factors associated with treatment effects, such as insulin resistance and peripheral neuropathy. Secondly, in combination with immune checkpoint blockade effects. Finally, use it for the endocrine treatment of hormone-dependent cancers. CONCLUSION Although the outcomes of metformin as a repurposed agent in some trials have been unsatisfactory, it still has the potential to be used in select cancer therapy settings.
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Affiliation(s)
- Zhipeng Wu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Wei Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lengyun Wei
- School of Life Science, Anhui Medical University, Hefei, China.
| | - Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.
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12
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Kim JS, Kim MY, Hong S. Synergistic Effects of Metformin and Trastuzumab on HER2 Positive Gastroesophageal Adenocarcinoma Cells In Vitro and In Vivo. Cancers (Basel) 2023; 15:4768. [PMID: 37835462 PMCID: PMC10571931 DOI: 10.3390/cancers15194768] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/16/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
The incidence of HER2 amplification in advanced gastroesophageal adenocarcinoma (GC) reportedly ranges between 10% and 20%, depending on the population studied and the geographical region. Trastuzumab (Tmab) is the standard treatment for GCs with HER2 amplification. Metformin, a widely used antidiabetic drug, is an activator of AMP kinase that can affect the mTOR signaling pathway. The following GC cells were evaluated: HER2+ NCI-N87, YCC-19, YCC-38, OE19, OE33, and HER2- AGS. The effects of Tmab and metformin on these cell lines were assessed as single agents and in combination using cell viability assays, Western blotting, and xenograft models. Metformin induced phosphorylation of AMP kinase in all tested GC cells and dephosphorylation of mTOR in Tmab-sensitive GC cells. We observed that treatment with Tmab in combination with metformin induced a significant decrease in the number of colonies formed on soft agar by N87, YCC-19, YCC-38, and OE19 cells (88%, 95%, 73%, and 98%, respectively), in comparison to the number formed by control cells or cells in the single-treatment groups. No growth inhibition was detected in OE33 cells treated with Tmab alone. Combination with metformin resulted in decreased phosphorylation of HER2 and its downstream targets, AKT and ERK, in Tmab-sensitive HER2+ cells. Phospho-receptor tyrosine kinase (RTK) arrays were used to profile the phospho-proteome, which demonstrated a synergistic decrease in phosphorylation of EGFR, HER2, and HER3. Furthermore, the combination of Tmab and metformin exhibited enhanced antitumor effects in a xenograft model. Collectively, these data suggest that Tmab and metformin act synergistically in HER2+ GC cells. Since metformin is widely used and relatively non-toxic, its addition to the therapeutic regimen along with Tmab could enhance the clinical efficacy in patients with HER2+ GC.
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Affiliation(s)
- Jin-Soo Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea;
| | - Mi Young Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea;
| | - Sungyoul Hong
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;
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13
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Kawakita E, Yang F, Shi S, Takagaki Y, Koya D, Kanasaki K. Inhibition of Dipeptidyl Peptidase-4 Activates Autophagy to Promote Survival of Breast Cancer Cells via the mTOR/HIF-1α Pathway. Cancers (Basel) 2023; 15:4529. [PMID: 37760498 PMCID: PMC10526496 DOI: 10.3390/cancers15184529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 07/21/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Autophagy plays a complex role in breast cancer cell survival, metastasis, and chemotherapeutic resistance. Dipeptidyl peptidase (DPP)-4, a therapeutic target for type 2 diabetes mellitus, is also involved in autophagic flux. The potential influence of DPP-4 suppression on cancer biology remains unknown. Here, we report that DPP-4 deficiency promotes breast cancer cell survival via the induction of autophagy by the C-X-C motif chemokine 12 (CXCL12)/C-X-C receptor 4 (CXCR4)/mammalian target of rapamycin (mTOR)/hypoxia inducible factor (HIF)-1α axis. DPP-4 knockdown and DPP-4 inhibitor KR62436 (KR) treatment both increased the levels of LC3II and HIF-1α in cultured human breast and mouse mammary cancer cells. The KR-induced autophagic phenotype in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 and rapamycin. HIF-1α knockdown also suppressed breast cancer autophagy induced by KR. The autophagy inhibitor 3-methyladenine significantly blocked the KR-mediated suppression of cleaved caspase-3 levels and apoptosis in breast cancer cell lines. Finally, we found that the metformin-induced apoptosis of DPP-4-deficient 4T1 mammary cancer cells was associated with the suppression of autophagy. Our findings identify a novel role for DPP-4 inhibition in the promotion of breast cancer survival by inducing CXCL12/CXCR4/mTOR/HIF-1α axis-dependent autophagy. Metformin is a potential drug that counteracts the breast cancer cell survival system.
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Affiliation(s)
- Emi Kawakita
- Department of Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
- Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
| | - Fan Yang
- Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
- Department of Emergency Medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Sen Shi
- Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
- Division of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Yuta Takagaki
- Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
| | - Daisuke Koya
- Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
| | - Keizo Kanasaki
- Department of Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
- Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
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14
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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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15
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Sollfrank L, Linn SC, Hauptmann M, Jóźwiak K. A scoping review of statistical methods in studies of biomarker-related treatment heterogeneity for breast cancer. BMC Med Res Methodol 2023; 23:154. [PMID: 37386356 PMCID: PMC10308726 DOI: 10.1186/s12874-023-01982-w] [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: 11/08/2022] [Accepted: 06/19/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Many scientific papers are published each year and substantial resources are spent to develop biomarker-based tests for precision oncology. However, only a handful of tests is currently used in daily clinical practice, since development is challenging. In this situation, the application of adequate statistical methods is essential, but little is known about the scope of methods used. METHODS A PubMed search identified clinical studies among women with breast cancer comparing at least two different treatment groups, one of which chemotherapy or endocrine treatment, by levels of at least one biomarker. Studies presenting original data published in 2019 in one of 15 selected journals were eligible for this review. Clinical and statistical characteristics were extracted by three reviewers and a selection of characteristics for each study was reported. RESULTS Of 164 studies identified by the query, 31 were eligible. Over 70 different biomarkers were evaluated. Twenty-two studies (71%) evaluated multiplicative interaction between treatment and biomarker. Twenty-eight studies (90%) evaluated either the treatment effect in biomarker subgroups or the biomarker effect in treatment subgroups. Eight studies (26%) reported results for one predictive biomarker analysis, while the majority performed multiple evaluations, either for several biomarkers, outcomes and/or subpopulations. Twenty-one studies (68%) claimed to have found significant differences in treatment effects by biomarker level. Fourteen studies (45%) mentioned that the study was not designed to evaluate treatment effect heterogeneity. CONCLUSIONS Most studies evaluated treatment heterogeneity via separate analyses of biomarker-specific treatment effects and/or multiplicative interaction analysis. There is a need for the application of more efficient statistical methods to evaluate treatment heterogeneity in clinical studies.
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Affiliation(s)
- L Sollfrank
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Fehrbelliner Straße 39, Neuruppin, 16816, Germany
| | - S C Linn
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Pathology, University Medical Center, Utrecht, The Netherlands
| | - M Hauptmann
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Fehrbelliner Straße 39, Neuruppin, 16816, Germany
| | - K Jóźwiak
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Fehrbelliner Straße 39, Neuruppin, 16816, Germany.
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16
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Savva C, Copson E, Johnson PWM, Cutress RI, Beers SA. Obesity Is Associated with Immunometabolic Changes in Adipose Tissue That May Drive Treatment Resistance in Breast Cancer: Immune-Metabolic Reprogramming and Novel Therapeutic Strategies. Cancers (Basel) 2023; 15:cancers15092440. [PMID: 37173907 PMCID: PMC10177091 DOI: 10.3390/cancers15092440] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
White adipose tissue (WAT) represents an endocrinologically and immunologically active tissue whose primary role is energy storage and homeostasis. Breast WAT is involved in the secretion of hormones and proinflammatory molecules that are associated with breast cancer development and progression. The role of adiposity and systemic inflammation in immune responses and resistance to anti-cancer treatment in breast cancer (BC) patients is still not clear. Metformin has demonstrated antitumorigenic properties both in pre-clinical and clinical studies. Nevertheless, its immunomodulating properties in BC are largely unknown. This review aims to evaluate the emerging evidence on the crosstalk between adiposity and the immune-tumour microenvironment in BC, its progression and treatment resistance, and the immunometabolic role of metformin in BC. Adiposity, and by extension subclinical inflammation, are associated with metabolic dysfunction and changes in the immune-tumour microenvironment in BC. In oestrogen receptor positive (ER+) breast tumours, it is proposed that these changes are mediated via a paracrine interaction between macrophages and preadipocytes, leading to elevated aromatase expression and secretion of pro-inflammatory cytokines and adipokines in the breast tissue in patients who are obese or overweight. In HER2+ breast tumours, WAT inflammation has been shown to be associated with resistance to trastuzumab mediated via MAPK or PI3K pathways. Furthermore, adipose tissue in patients with obesity is associated with upregulation of immune checkpoints on T-cells that is partially mediated via immunomodulatory effects of leptin and has been paradoxically associated with improved responses to immunotherapy in several cancers. Metformin may play a role in the metabolic reprogramming of tumour-infiltrating immune cells that are dysregulated by systemic inflammation. In conclusion, evidence suggests that body composition and metabolic status are associated with patient outcomes. To optimise patient stratification and personalisation of treatment, prospective studies are required to evaluate the role of body composition and metabolic parameters in metabolic immune reprogramming with and without immunotherapy in patients with BC.
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Affiliation(s)
- Constantinos Savva
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Ellen Copson
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- Southampton Experimental Cancer Medicine Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Peter W M Johnson
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- Southampton Experimental Cancer Medicine Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Ramsey I Cutress
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- Southampton Experimental Cancer Medicine Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Stephen A Beers
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
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17
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Lord SR, Harris AL. Is it still worth pursuing the repurposing of metformin as a cancer therapeutic? Br J Cancer 2023; 128:958-966. [PMID: 36823364 PMCID: PMC10006178 DOI: 10.1038/s41416-023-02204-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Over the past 15 years, there has been great interest in the potential to repurpose the diabetes drug, metformin, as a cancer treatment. However, despite considerable efforts being made to investigate its efficacy in a number of large randomised clinical trials in different tumour types, results have been disappointing to date. This perspective article summarises how interest initially developed in the oncological potential of metformin and the diverse clinical programme of work to date including our contribution to establishing the intra-tumoral pharmacodynamic effects of metformin in the clinic. We also discuss the lessons that can be learnt from this experience and whether a further clinical investigation of metformin in cancer is warranted.
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Affiliation(s)
- Simon R Lord
- Department of Oncology, University of Oxford, Oxford, UK.
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18
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Micha JP, Rettenmaier MA, Bohart RD, Goldstein BH. A phase II, open-label, non-randomized, prospective study assessing paclitaxel, carboplatin and metformin in the treatment of advanced stage ovarian carcinoma. J Gynecol Oncol 2023; 34:e15. [PMID: 36509462 PMCID: PMC9995875 DOI: 10.3802/jgo.2023.34.e15] [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: 03/11/2022] [Revised: 08/02/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE The purpose of this study was to assess the efficacy and tolerability of a paclitaxel, carboplatin and metformin regimen in the first-line treatment of advanced-stage ovarian, fallopian tube, and primary peritoneal carcinoma. METHODS Eligible subjects underwent surgery and 6 cycles of neoadjuvant or adjuvant dose-dense intravenous paclitaxel (80 mg/m²), carboplatin (area under the curve 5 or 6 on Day 1), and oral metformin (850 mg daily). Study participants who completed their primary therapy and attained a clinically defined complete or partial response (PR) were treated with a planned 12 cycles of paclitaxel (135 mg/m² every 21 days) and metformin (850 mg twice daily) maintenance therapy. RESULTS Thirty subjects received a median of 6 cycles (range, 5-6) of primary induction chemotherapy and were eligible for response evaluation; twenty-three patients exhibited a complete response, while 3 study patients obtained a PR (an overall response rate of 86.7%). Grade 3-4 hematological toxicity included neutropenia (43.3%), thrombocytopenia (10%) and anemia (36.7%). There was no incidence of grade 3-4 neuropathy although 15 patients (50%) developed grade ≤2 neurotoxicity. Additionally, we observed grade ≤2 diarrhea in 20 (66.7%) subjects. The median progression-free survival was 21 months (range, 3-52) and overall median survival was 35 months (range, 15-61). The subjects also received an aggregate 103 cycles (median, 12; range, 6-12) of maintenance chemotherapy. CONCLUSION The study results suggest that the combination of paclitaxel, carboplatin and metformin is associated with moderate efficacy and a reasonable toxicity profile.
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Affiliation(s)
- John P Micha
- Women's Cancer Research Foundation, Laguna Beach, CA, USA
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19
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Van J, Hahn Y, Silverstein B, Li C, Cai F, Wei J, Katiki L, Mehta P, Livatova K, DelPozzo J, Kobayashi T, Huang Y, Kobayashi S, Liang Q. Metformin Inhibits Autophagy, Mitophagy and Antagonizes Doxorubicin-Induced Cardiomyocyte Death. INTERNATIONAL JOURNAL OF DRUG DISCOVERY AND PHARMACOLOGY 2023; 2:37-51. [PMID: 38487671 PMCID: PMC10939033 DOI: 10.53941/ijddp.0201004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/17/2024]
Abstract
The antidiabetic drug metformin has been shown to reduce cardiac injury under various pathological conditions, including anticancer drug doxorubicin (DOX)-induced cardiotoxicity, which makes metformin a prime candidate for repurposing. However, the mechanisms that mediate the cardioprotective effects of metformin remain highly controversial. In this study, we tested a prevailing hypothesis that metformin activates autophagy/mitophagy to reduce DOX cardiotoxicity. FVB/N mice and H9C2 cardiac myoblasts were treated with metformin, respectively. Autophagy/mitophagy was determined by Western blot analysis of microtubule-associated protein light chain 3, form-II (LC3-II), a well-established marker of autophagic vesicles. Although metformin had minimal effects on basal LC3-II levels, it significantly inhibited the accumulation of LC3-II levels by the lysosomal protease inhibitors pepstatin A and E64d in both total cell lysates and mitochondrial fractions. Also, dual fluorescent autophagy/mitophagy reporters demonstrated that metformin slowed the degradation rate of autophagic cargos or mitochondrial fragments in the lysosomes. These surprising results suggest that metformin inhibits rather than stimulates autophagy/mitophagy, sharply contrasting the popular belief. In addition, metformin diminished DOX-induced autophagy/mitophagy as well as cardiomyocyte death. Together, these results suggest that the cardioprotective effects of metformin against DOX cardiotoxicity may be mediated by its ability to inhibit autophagy and mitophagy, although the underlying molecular mechanisms remain to be determined.
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Affiliation(s)
- Jennifer Van
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Younghee Hahn
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Brett Silverstein
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Cairong Li
- Clinical Medical College, Hubei University of Science and Technology, Xianning 332306, China
| | - Fei Cai
- Clinical Medical College, Hubei University of Science and Technology, Xianning 332306, China
| | - Jia Wei
- Department of Cardiology, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710000, China
| | - Lokesh Katiki
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Puja Mehta
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Katherine Livatova
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Jaclyn DelPozzo
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Tamayo Kobayashi
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Yuan Huang
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Satoru Kobayashi
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
| | - Qiangrong Liang
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York 10001, United States
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20
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Postlewait LM. Assessment of Novel Therapeutics for Individualized Breast Cancer Care in the Modern Era: The Role of Metformin in Breast Cancer Therapy. Ann Surg Oncol 2023; 30:1-3. [PMID: 36224510 DOI: 10.1245/s10434-022-12627-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/19/2022] [Indexed: 12/13/2022]
Affiliation(s)
- Lauren M Postlewait
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
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21
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DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N, Mantzoros C. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism 2022; 137:155332. [PMID: 36240884 DOI: 10.1016/j.metabol.2022.155332] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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Affiliation(s)
- Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Niyoti Reddy
- Department of Medicine, School of Medicine, Boston University, Boston, USA
| | - Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Filippaios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Elliot Sternthal
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Sindos, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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22
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Taurelli Salimbeni B, Corvaja C, Valenza C, Zagami P, Curigliano G. The triple negative breast cancer drugs graveyard: a review of failed clinical trials 2017-2022. Expert Opin Investig Drugs 2022; 31:1203-1226. [PMID: 36413823 DOI: 10.1080/13543784.2022.2151433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers (BC) and has the worst prognosis. It is characterized by the absence of both hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). TNBC has more limited therapeutic options compared to other subtypes, meaning that there is still a long way to go to discover target treatments. AREAS COVERED Our review aims to summarize phase II/III clinical trials enrolling patients with TNBC that have been published between 2017 and 2022 but failed to reach their primary endpoint. We here try to emphasize the limitations and weaknesses noted in negative studies and to point out unexpected results which might be useful to enhance the therapeutic approach to TNBC disease. EXPERT OPINION A deeper understanding of the mechanisms behind TNBC heterogeneity allowed to enhance the knowledge of new prognostic and predictive biomarkers of response. However, it is also through several failed clinical trials that we were able to define new therapeutic approaches which improved TNBC patients' clinical outcomes. Nowadays, we still need to overcome several difficulties to fully recognize different intracellular and extracellular pathways that crosstalk in TNBC and the mechanisms of resistance to identify novel tailored-patients' therapies.
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Affiliation(s)
- Beatrice Taurelli Salimbeni
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Irccs, Milan, Italy.,Department of Clinical and Molecular Medicine, Oncology Unit, "la Sapienza" University of Rome, Azienda Ospedaliera Sant'Andrea, Rome, Italy
| | - Carla Corvaja
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Irccs, Milan, Italy.,Department of Medicine, University of Udine, Udine, Italy
| | - Carmine Valenza
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Irccs, Milan, Italy.,Department of Oncology and Haematology, University of Milan, Milan, Italy
| | - Paola Zagami
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Irccs, Milan, Italy.,Department of Oncology and Haematology, University of Milan, Milan, Italy.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, Irccs, Milan, Italy.,Department of Oncology and Haematology, University of Milan, Milan, Italy
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Wen J, Yi Z, Chen Y, Huang J, Mao X, Zhang L, Zeng Y, Cheng Q, Ye W, Liu Z, Liu F, Liu J. Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials. BMC Med 2022; 20:402. [PMID: 36280839 PMCID: PMC9594974 DOI: 10.1186/s12916-022-02599-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/10/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND To investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18). METHODS Databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries ( ClinicalTrials.gov ; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models. RESULTS Of the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82-1.15, I2 = 50%) and OS (HR 0.98, 95% CI 0.86-1.13, I2 = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74-1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03-2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies. CONCLUSION Metformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number CRD42022324672.
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Affiliation(s)
- Jie Wen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuyao Chen
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jing Huang
- National Clinical Research Center for Mental Disorders and Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xueyi Mao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liyang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu Zeng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wenrui Ye
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fangkun Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Jingfang Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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24
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Essa NM, Salem HF, Elgendy MO, Gabr A, Omran MM, Hassan NA, Tashkandi HM, Harakeh S, Boshra MS. Efficacy of Metformin as Adjuvant Therapy in Metastatic Breast Cancer Treatment. J Clin Med 2022; 11:jcm11195505. [PMID: 36233373 PMCID: PMC9572354 DOI: 10.3390/jcm11195505] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/08/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Metformin has been reported to have an anti-tumorigenic impact against metastatic breast cancer (MBC) cells through several mechanisms. Its effect can be evaluated by using many variables such as the response rate (RR) as well as the progression-free survival (PFS). Materials and methods: A prospective study was conducted to investigate and estimate the metformin effect on MBC. About 107 subjects were included in the study and were divided into two groups: Group A included non-diabetic MBC patients treated with metformin in conjunction with chemotherapy and group B included those treated with chemotherapy alone. Both PFS and RR were used as a criteria to evaluate the treatment outcome. Associated adverse effects of metformin were also assessed. Results: The average age of the participants in group A and group B was 50 vs. 47.5, respectively. No significant differences were detected between both cohorts concerning RR levels (regression disease (RD) 27.8% vs. 12.5%, stationary disease (SD) 44.4% vs. 41.7%, progression disease (PD) 27.8% vs. 45.8%, respectively, p = 0.074). Moreover, PFS showed no significant difference between both groups (p = 0.753). There was no significant correlation between metformin concentration and their adverse effects on the study participants. Conclusion: Metformin as an adjuvant therapy to MBC undergoing chemotherapy showed no significant survival benefit as determined by RR and PFS.
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Affiliation(s)
- Nourhan M. Essa
- Clinical Pharmacy Department, Faculty of Pharmacy, New Valley University, El-Kharja 72511, Egypt
| | - Heba F. Salem
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62521, Egypt
| | - Marwa O. Elgendy
- Department of Clinical Pharmacy, Teaching Hospital of Faculty of Medicine, Faculty of Medicine, Beni-Suef University, Beni-Suef 62521, Egypt
- Department of Clinical Pharmacy, Faculty of Pharmacy, Nahda University (NUB), Beni-Suef 62764, Egypt
| | - A. Gabr
- Medical Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut 71111, Egypt
| | - Mervat M. Omran
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Giza 11796, Egypt
| | - Nivin A. Hassan
- Pharmacology and Experimental Oncology Unit, Cancer Biology Department, South Egypt Cancer Institute, Assuit University, Assiut 71515, Egypt
| | - Hanaa M. Tashkandi
- Department of General Surgery, School of Medicine, King Abdulaziz University, P.O. Box 80218, Jeddah 21589, Saudi Arabia
| | - Steve Harakeh
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 22254, Saudi Arabia
- Yousef Abdul Latif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah 22254, Saudi Arabia
- Correspondence: (S.H.); (M.S.B.); Tel.: +966-00966559392266 (S.H.); +20-1280571448 (M.S.B.); Fax: +966-126952076 (S.H.); +20-822317953 (M.S.B.)
| | - Marian S. Boshra
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62521, Egypt
- Correspondence: (S.H.); (M.S.B.); Tel.: +966-00966559392266 (S.H.); +20-1280571448 (M.S.B.); Fax: +966-126952076 (S.H.); +20-822317953 (M.S.B.)
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Ohno M, Kitanaka C, Miyakita Y, Tanaka S, Sonoda Y, Mishima K, Ishikawa E, Takahashi M, Yanagisawa S, Ohashi K, Nagane M, Narita Y. Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies. Cancers (Basel) 2022; 14:cancers14174222. [PMID: 36077758 PMCID: PMC9454846 DOI: 10.3390/cancers14174222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.
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Affiliation(s)
- Makoto Ohno
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Chifumi Kitanaka
- Department of Molecular Cancer Science, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan
| | - Yasuji Miyakita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Shota Tanaka
- Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yukihiko Sonoda
- Department of Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan
| | - Kazuhiko Mishima
- Department of Neuro-Oncology/Neurosurgery, International Medical Center, Saitama Medical University, Hidaka 350-1298, Japan
| | - Eiichi Ishikawa
- Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba 350-8576, Japan
| | - Masamichi Takahashi
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Shunsuke Yanagisawa
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Ken Ohashi
- Department of General Internal Medicine, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Motoo Nagane
- Department of Neurosurgery, Kyorin University Faculty of Medicine, Mitaka 181-8611, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
- Correspondence: ; Tel.: +81-3-3542-2511
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Gupta U, Saren BN, Khaparkhuntikar K, Madan J, Singh PK. Applications of lipid-engineered nanoplatforms in the delivery of various cancer therapeutics to surmount breast cancer. J Control Release 2022; 348:1089-1115. [PMID: 35640765 DOI: 10.1016/j.jconrel.2022.05.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/18/2022] [Accepted: 05/21/2022] [Indexed: 11/30/2022]
Abstract
Breast cancer (BC) is the most extensively accounted malignancy among the women across the globe and is treatable in 70-80% of patients with early-stage, non-metastatic cancer. The current available therapies have been found to be less effective to treat distant organ metastases and advanced breast cancers. The clinical efficacy hugely suffers from chemoresistance, non-specific toxicity, relapse and other associated adverse effects. Furthermore, lack of controlled delivery and effective temporospatial presence of chemotherapeutics has resulted in suboptimal therapeutic response. Nanotechnology based approaches have been widely used over the period as they are nanometric, offer controlled and site-specific drug release along with reduced toxicity, improved half-life, and stability. Lipid-based nanoplatforms have grabbed a tremendous attention for delivering cancer therapeutics as they are cost-effective, scalable and provide better entrapment efficiency. In this review, all the promising applications of lipid-engineered nanotechnological tools for breast cancer will be summarized and discussed. Subsequently, BC therapy achieved with the aid of chemotherapeutics, phytomedicine, genes, peptides, photosensitizers, diagnostic and immunogenic agents etc. will be reviewed and discussed. This review gives tabular information on all the results obtained pertaining to the physicochemical properties of the lipidic nanocarrier, in vitro studies conferring to mechanistic drug release profile, cell viability, cellular apoptosis and in vivo studies referring to cellular internalisation, reduction of tumor volume, PK-PD profile, bioavailability achieved and anti-tumor activity in detail. It also gives complete information on the most relevant clinical trials done on lipidic nanoplatforms over two decades in tabular form. The review highlights the current status and future prospects of lipidic nanoplatforms with streamlined focus on cancer nanotherapeutics.
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Affiliation(s)
- Ujala Gupta
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Brojendra Nath Saren
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Kedar Khaparkhuntikar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Jitender Madan
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Pankaj Kumar Singh
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
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Liang M, Li JW, Luo H, Lulu S, Calbay O, Shenoy A, Tan M, Law BK, Huang S, Xiao TS, Chen H, Wu L, Chang J, Lu J. Epithelial-Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress. Cells 2022; 11:cells11142208. [PMID: 35883651 PMCID: PMC9322750 DOI: 10.3390/cells11142208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/01/2022] [Accepted: 07/13/2022] [Indexed: 12/25/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelial genes but also a myriad of additional genomic targets that may carry out significant biological functions. Therefore, we reasoned that EMT inherently causes various concomitant phenotypes, some of which may create targetable vulnerabilities for cancer treatment. In the present study, we found that Snail transcription factors bind to the promoters of multiple genes encoding subunits of the AMP-activated protein kinase (AMPK) complex, and expression of AMPK genes was markedly downregulated by EMT. Accordingly, high AMPK expression in tumors correlated with epithelial cell markers and low AMPK expression in tumors was strongly associated with adverse prognosis. AMPK is the principal sensor of cellular energy status. In response to energy stress, AMPK is activated and critically reprograms cellular metabolism to restore energy homeostasis and maintain cell survival. We showed that activation of AMPK by energy stress was severely impaired by EMT. Consequently, EMT cancer cells became hypersensitive to a variety of energy stress conditions and primarily underwent pyroptosis, a regulated form of necrotic cell death. Collectively, the study suggests that EMT impedes the activation of AMPK signaling induced by energy stress and sensitizes cancer cells to pyroptotic cell death under energy stress conditions. Therefore, while EMT promotes malignant progression, it concurrently induces collateral vulnerabilities that may be therapeutically exploited.
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Affiliation(s)
- Mingwei Liang
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.L.); (J.W.L.); (H.L.); (S.L.); (A.S.)
| | - Jennifer W. Li
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.L.); (J.W.L.); (H.L.); (S.L.); (A.S.)
| | - Huacheng Luo
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.L.); (J.W.L.); (H.L.); (S.L.); (A.S.)
| | - Sarah Lulu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.L.); (J.W.L.); (H.L.); (S.L.); (A.S.)
| | - Ozlem Calbay
- Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (O.C.); (S.H.)
| | - Anitha Shenoy
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.L.); (J.W.L.); (H.L.); (S.L.); (A.S.)
| | - Ming Tan
- Graduate Institute of Biomedical Sciences and Research Center for Cancer Biology, China Medical University, Taichung 406040, Taiwan;
| | - Brian K. Law
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Shuang Huang
- Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (O.C.); (S.H.)
| | - Tsan Sam Xiao
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA;
| | - Hao Chen
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China;
| | - Lizi Wu
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Jia Chang
- Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA;
| | - Jianrong Lu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.L.); (J.W.L.); (H.L.); (S.L.); (A.S.)
- Correspondence:
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Halada S, Casado-Medrano V, Baran JA, Lee J, Chinmay P, Bauer AJ, Franco AT. Hormonal Crosstalk Between Thyroid and Breast Cancer. Endocrinology 2022; 163:6588704. [PMID: 35587175 PMCID: PMC9653009 DOI: 10.1210/endocr/bqac075] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Indexed: 12/09/2022]
Abstract
Differentiated thyroid cancer and breast cancer account for a significant portion of endocrine-related malignancies and predominately affect women. As hormonally responsive tissues, the breast and thyroid share endocrine signaling. Breast cells are responsive to thyroid hormone signaling and are affected by altered thyroid hormone levels. Thyroid cells are responsive to sex hormones, particularly estrogen, and undergo protumorigenic processes upon estrogen stimulation. Thyroid and sex hormones also display significant transcriptional crosstalk that influences oncogenesis and treatment sensitivity. Obesity-related adipocyte alterations-adipocyte estrogen production, inflammation, feeding hormone dysregulation, and metabolic syndromes-promote hormonal alterations in breast and thyroid tissues. Environmental toxicants disrupt endocrine systems, including breast and thyroid homeostasis, and influence pathologic processes in both organs through hormone mimetic action. In this brief review, we discuss the hormonal connections between the breast and thyroid and perspectives on hormonal therapies for breast and thyroid cancer. Future research efforts should acknowledge and further explore the hormonal crosstalk of these tissues in an effort to further understand the prevalence of thyroid and breast cancer in women and to identify potential therapeutic options.
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Affiliation(s)
- Stephen Halada
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Victoria Casado-Medrano
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Julia A Baran
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Joshua Lee
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Poojita Chinmay
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Andrew J Bauer
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Aime T Franco
- Correspondence: Aime T. Franco, Ph.D., Pediatric Thyroid Center Translational Laboratory, The University of Pennsylvania and Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA.
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Joharatnam-Hogan N, Morganstein DL. Diabetes and Cancer - optimising glycaemic control. J Hum Nutr Diet 2022; 36:504-513. [PMID: 35748508 DOI: 10.1111/jhn.13051] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/31/2022] [Indexed: 01/08/2023]
Abstract
Diabetes and cancer are both common and increasingly prevalent conditions, but emerging epidemiological evidence confirms that the risk of developing a number of common cancers is increased in those with type 2 diabetes. The risk of cancer in type 1 diabetes is less clearly defined, and therefore this review will focus on type 2 diabetes. Emerging evidence also supports an influence of diabetes on outcomes of cancer treatment. However, this relationship is bi-directional, with cancer and its treatment impacting on glucose control, whilst there is also emerging evidence that diabetes care can deteriorate after a cancer diagnosis (summarised in Figure 1). Despite these clear links there is a lack of evidence to guide clinicians in how to manage patients with diabetes during their cancer treatment. Although recent UK guidelines have started to address this, with the development of guidance for the management of hyperglycaemia in cancer, there is a clear need for wider guidance on the management of multi-morbidity during cancer, including diabetes and obesity, to incorporate nutritional management We have therefore undertaken a narrative review of the evidence of links between type 2 diabetes and cancer incidence and outcomes, and discuss the challenges to diabetes care during cancer treatment. This article is protected by copyright. All rights reserved.
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Affiliation(s)
| | - Daniel L Morganstein
- Royal Marsden Hospital, Fulham Roal, London, SW3 6JJ, UK.,Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK
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30
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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: 125] [Impact Index Per Article: 41.7] [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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Akingbesote ND, Norman A, Zhu W, Halberstam AA, Zhang X, Foldi J, Lustberg MB, Perry RJ. A precision medicine approach to metabolic therapy for breast cancer in mice. Commun Biol 2022; 5:478. [PMID: 35595952 PMCID: PMC9122928 DOI: 10.1038/s42003-022-03422-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/26/2022] [Indexed: 02/03/2023] Open
Abstract
Increasing evidence highlights approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic drugs. To our knowledge, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach for this devastating disease. Here, we treat lean breast tumor-bearing mice with the SGLT2 inhibitor dapagliflozin as monotherapy and in combination with paclitaxel chemotherapy. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival. Further, the ability of dapagliflozin to enhance the efficacy of chemotherapy correlates with its effect to reduce circulating insulin in some but not all breast tumors. Our data suggest a genetic signature for breast tumors more likely to respond to dapagliflozin in combination with paclitaxel. In the current study, tumors driven by mutations upstream of canonical insulin signaling pathways responded to this combined treatment, whereas tumors driven by mutations downstream of canonical insulin signaling did not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach.
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Affiliation(s)
- Ngozi D Akingbesote
- Department of Celullar and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
| | - Aaron Norman
- Department of Celullar and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
| | - Wanling Zhu
- Department of Celullar and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
| | - Alexandra A Halberstam
- Department of Celullar and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
| | - Xinyi Zhang
- Department of Celullar and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
| | - Julia Foldi
- Department of Internal Medicine (Hematology/Oncology), Yale University School of Medicine, New Haven, CT, USA
| | - Maryam B Lustberg
- Department of Internal Medicine (Hematology/Oncology), Yale University School of Medicine, New Haven, CT, USA
| | - Rachel J Perry
- Department of Celullar and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
- Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA.
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Metformin and Cancer, an Ambiguanidous Relationship. Pharmaceuticals (Basel) 2022; 15:ph15050626. [PMID: 35631452 PMCID: PMC9144507 DOI: 10.3390/ph15050626] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 01/27/2023] Open
Abstract
The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 diabetics and inhibit cell growth in various cancers, including pancreatic, colon, prostate, ovarian, and breast cancer. While metformin is a known adenosine monophosphate-activated protein kinase (AMPK) agonist and an inhibitor of the electron transport chain complex I, its mechanism of action in cancer cells as well as its effect on cancer metabolism is not clearly established. In this review, we will give an update on the role of metformin as an antitumoral agent and detail relevant evidence on the potential use and mechanisms of action of metformin in cancer. Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology.
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Barakat HE, Hussein RRS, Elberry AA, Zaki MA, Ramadan ME. The impact of metformin use on the outcomes of locally advanced breast cancer patients receiving neoadjuvant chemotherapy: an open-labelled randomized controlled trial. Sci Rep 2022; 12:7656. [PMID: 35538143 PMCID: PMC9091204 DOI: 10.1038/s41598-022-11138-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 04/19/2022] [Indexed: 12/20/2022] Open
Abstract
Recently, several clinical trials have attempted to find evidence that supports the anticancer use of metformin in breast cancer (BC) patients. The current study evaluates the anticancer activity of metformin in addition to neoadjuvant chemotherapy (NACT) in locally advanced BC patients. Additionally, we assess the safety and tolerability of this combination and its effect on the quality of life (QoL) of BC patients. Eighty non-diabetic female patients with proven locally advanced BC were randomized into two arms. The first arm received anthracycline/taxane-based NACT plus metformin. The second arm received anthracycline/taxane-based NACT only. Overall response rate (ORR), clinical complete response (cCr), pathological complete response (pCR), and breast conservative rate (BCR) were evaluated between both groups, and correlated with serum metformin concentration. ORR, cCr, pCR, and BCR increased non-significantly in the metformin group compared to the control group; 80.6% vs 68.4%, 27.8% vs 10.5%, 22.2% vs 10.5%, and 19.4% vs 13.2%, respectively. A trend towards cCR and pCR was associated with higher serum metformin concentrations. Metformin decreased the incidence of peripheral neuropathy, bone pain, and arthralgia, although worsened the gastrointestinal adverse events. Metformin combination with NACT has no effect on the QoL of BC patients. Metformin combination with NACT is safe, tolerable, and improves non-significantly the clinical and pathological tumor response of BC patients.
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Affiliation(s)
- Hadeer Ehab Barakat
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
| | - Raghda R S Hussein
- Department of Clinical Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
- Department of Clinical Pharmacy, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Ahmed Abdullah Elberry
- Department of Pharmacy Practice, Batterjee Medical College, Pharmacy Program, Jeddah, Saudi Arabia
- Department of Clinical Pharmacology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
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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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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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Metformin and Breast Cancer: Where Are We Now? Int J Mol Sci 2022; 23:ijms23052705. [PMID: 35269852 PMCID: PMC8910543 DOI: 10.3390/ijms23052705] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/25/2022] [Accepted: 02/27/2022] [Indexed: 12/16/2022] Open
Abstract
Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes–associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist’s armamentarium for the prevention and treatment of breast cancer.
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Singh M, Nicol AT, DelPozzo J, Wei J, Singh M, Nguyen T, Kobayashi S, Liang Q. Demystifying the Relationship Between Metformin, AMPK, and Doxorubicin Cardiotoxicity. Front Cardiovasc Med 2022; 9:839644. [PMID: 35141304 PMCID: PMC8818847 DOI: 10.3389/fcvm.2022.839644] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but its long-term use can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity and concurrently enhance its antitumor efficacy would be of great clinical value. In this respect, the classical antidiabetic drug metformin (MET) has stood out, appearing to have both antitumor and cardioprotective properties. MET is proposed to achieve these beneficial effects through the activation of AMP-activated protein kinase (AMPK), an essential regulator of mitochondrial homeostasis and energy metabolism. AMPK itself has been shown to protect the heart and modulate tumor growth under certain conditions. However, the role and mechanism of the hypothesized MET-AMPK axis in DOX cardiotoxicity and antitumor efficacy remain to be firmly established by in vivo studies using tumor-bearing animal models and large-scale prospective clinical trials. This review summarizes currently available literature for or against a role of AMPK in MET-mediated protection against DOX cardiotoxicity. It also highlights the emerging evidence suggesting distinct roles of the AMPK subunit isoforms in mediating the functions of unique AMPK holoenzymes composed of different combinations of isoforms. Moreover, the review provides a perspective regarding future studies that may help fully elucidate the relationship between MET, AMPK and DOX cardiotoxicity.
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Affiliation(s)
- Manrose Singh
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Akito T. Nicol
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Jaclyn DelPozzo
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Jia Wei
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xian, China
| | - Mandeep Singh
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Tony Nguyen
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Satoru Kobayashi
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
| | - Qiangrong Liang
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, United States
- *Correspondence: Qiangrong Liang
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Barczyński B, Frąszczak K, Kotarski J. Perspectives of metformin use in endometrial cancer and other gynaecological malignancies. J Drug Target 2021; 30:359-367. [PMID: 34753372 DOI: 10.1080/1061186x.2021.2005072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Insulin resistance and hyperinsulinemia play a key role in type 1 endometrial cancer pathogenesis. Most of these cancers develop on a background of overweight or type 2 diabetes mellitus (T2DM). One of the medications widely used in the treatment of T2DM is biguanide derivative, metformin, which exerts promising anticancer properties principally through activation of adenosine monophosphate kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) pathways. Many epidemiological studies on diabetic patients show potential preventative role of metformin in endometrial cancer patients, but data regarding its therapeutic role is still limited. So far, most of attention has been paid to the concept of metformin use in fertility sparing treatment of early-stage cancer. Another investigated alternative is its application in patients with primary advanced or recurrent disease. In this review we present the latest data on clinical use of metformin in endometrial cancer patients and potential underlying mechanisms of its activity. Finally, we present some most important clinical information regarding metformin efficacy in other gynaecological malignancies, mainly breast and ovarian cancer.
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Affiliation(s)
- Bartłomiej Barczyński
- Ist Department of Oncological Gynaecology and Gynaecology, Medical University of Lublin, Lublin, Poland
| | - Karolina Frąszczak
- Ist Department of Oncological Gynaecology and Gynaecology, Medical University of Lublin, Lublin, Poland
| | - Jan Kotarski
- Ist Department of Oncological Gynaecology and Gynaecology, Medical University of Lublin, Lublin, Poland
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Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo. Cancers (Basel) 2021; 13:cancers13184612. [PMID: 34572837 PMCID: PMC8468269 DOI: 10.3390/cancers13184612] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 01/14/2023] Open
Abstract
Simple Summary Recent studies have shown that metformin combined with clinical chemotherapeutic drugs could cause decreased cell toxicity and attenuate tumor resistance in various types of cancer. The aim of the present study was to elucidate whether combined treatment with metformin and everolimus has a synergistic anticancer effect in human cervical cancer in vitro and in vivo. The results showed that this combined treatment synergistically inhibited the growth of human cervical cancer cell lines and xenografts in nude mice, and induced caspase-dependent apoptosis, promoting sub-G1- and G0/G1-phase arrest and enhancing mtROS production. Combined treatment also synergistically inactivated PI3K/AKT signaling and activated MAPKs signaling in cervical cancer. Our data suggested that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combined treatment provides a novel therapeutic strategy for patients with cervical cancer. Abstract Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.
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Lusica PMM, Eugenio KPY, Sacdalan DBL, Jimeno CA. A systematic review and meta-analysis on the efficacy and safety of metformin as adjunctive therapy among women with metastatic breast cancer. Cancer Treat Res Commun 2021; 29:100457. [PMID: 34543887 DOI: 10.1016/j.ctarc.2021.100457] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Breast cancer is the most common cancer among women worldwide and is one of the leading causes of cancer-related mortalities. Metformin has been found to have direct and indirect antitumor mechanisms, and because of its availability and good safety profile, it has been investigated to be useful in various malignancies including breast cancer. OBJECTIVE This study aims to determine the efficacy and safety of metformin administration as adjunctive therapy on mortality among females with breast cancer. METHODS This is a systematic review and meta-analysis of randomized clinical trials (RCTs) on the use of metformin as adjunctive therapy when combined with standard chemotherapy on the outcomes of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and clinical benefit rate (CBR). RESULTS After a comprehensive literature search, only three phase 2 RCTs on the use of metformin as adjunctive therapy for locally advanced and metastatic breast cancer were included. Clinical trials on early breast cancer are still ongoing and none were included in the present review. This study, based on the systematic review, revealed that metformin added to standard chemotherapy does not improve the PFS and OS among women with metastatic breast cancer, and likewise, has no impact on the ORR with a relative risk of 1.42 95% CI 0.45-4.55 and CBR with an RR of 0.87, 95% CI 0.55-1.37. It appears to be safe and may even be protective for the development of neutropenia based on at least one study. CONCLUSION This study clarifies that there is insufficient evidence on the benefits of metformin on survival among women with metastatic breast cancer.
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Affiliation(s)
- Patricia Marie M Lusica
- University of the Philippines - Philippine General Hospital, Department of Medicine, Philippines.
| | - Kyle Patrick Y Eugenio
- University of the Philippines - Philippine General Hospital, Department of Medicine, Philippines
| | - Danielle Benedict L Sacdalan
- University of the Philippines - Philippine General Hospital, Department of Medicine, Philippines; University of the Philippines College of Medicine, Department of Pharmacology and Toxicology, Philippines
| | - Cecilia A Jimeno
- University of the Philippines - Philippine General Hospital, Department of Medicine, Philippines; University of the Philippines College of Medicine, Department of Pharmacology and Toxicology, Philippines
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Schettini F, Giuliano M, Lambertini M, Bartsch R, Pinato DJ, Onesti CE, Harbeck N, Lüftner D, Rottey S, van Dam PA, Zaman K, Mustacchi G, Gligorov J, Awada A, Campone M, Wildiers H, Gennari A, Tjan-Heijnen VCG, Cortes J, Locci M, Paris I, Del Mastro L, De Placido S, Martín M, Jerusalem G, Venturini S, Curigliano G, Generali D. Anthracyclines Strike Back: Rediscovering Non-Pegylated Liposomal Doxorubicin in Current Therapeutic Scenarios of Breast Cancer. Cancers (Basel) 2021; 13:4421. [PMID: 34503231 PMCID: PMC8430783 DOI: 10.3390/cancers13174421] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non-pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450-480 mg/m2. Following three pivotal first-line phase III trials in HER2-negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2-negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms.
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Affiliation(s)
- Francesco Schettini
- Translational Genomics and Targeted Therapies in Solid Tumors Research Group, 08036 Barcelona, Spain;
- Department of Medical Oncology, Hospital Clinic of Barcelona, 08036 Barcelona, Spain
| | - Mario Giuliano
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (M.G.); (S.D.P.)
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, 16132 Genova, Italy; (M.L.); (L.D.M.)
- Department of Medical Oncology, U.O.C Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Rupert Bartsch
- Division of Oncology, Department of Medicine 1, Medical University of Vienna, 1090 Vienna, Austria;
| | - David James Pinato
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK;
- Department of Translational Medicine, Università del Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy;
| | - Concetta Elisa Onesti
- Clinical and Oncological Research Department, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Nadia Harbeck
- Breast Center, Department OB&GYN and CCCLMU, LMU University Hospital, 81377 Munich, Germany;
| | - Diana Lüftner
- Department of Hematology, Oncology and Tumor Immunology, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Sylvie Rottey
- Department of Medical Oncology, UZ Gent, 9000 Gent, Belgium;
| | - Peter A. van Dam
- Oncology Department, University Hospital Antwerp (UZA), 2650 Edegem, Belgium;
| | - Khalil Zaman
- Oncology Department, Lausanne University Hospital CHUV, 1011 Lausanne, Switzerland;
| | - Giorgio Mustacchi
- Division of Medical Oncology, University of Trieste, 34127 Trieste, Italy;
| | - Joseph Gligorov
- Department of Medical Oncology, Tenon Hospital, Institut Universitaire de Cancérologie AP-HP, Sorbonne University, 75004 Paris, France;
| | - Ahmad Awada
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Bruxelles, Belgium;
| | - Mario Campone
- Division of Medical Oncology, Institut de Cancérologie de l’Ouest-Pays de la Loire, 44800 Saint-Herblain, France;
| | - Hans Wildiers
- Department of General Medical Oncology, University Hospital Leuven, 3000 Leuven, Belgium;
| | - Alessandra Gennari
- Department of Translational Medicine, Università del Piemonte Orientale “A. Avogadro”, 28100 Novara, Italy;
| | - Vivianne C. G. Tjan-Heijnen
- Division of Medical Oncology, Maastricht University Medical Center (MUMC), 6229 Maastricht, The Netherlands;
| | - Javier Cortes
- Oncology Department, IOB Institute of Oncology, Quiron Group, 08023 Madrid, Spain;
- Vall d’Hebron Institute of Oncology (VHIO), Centro Cellex, 08035 Carrer de Natzaret, Spain
| | - Mariavittoria Locci
- Department of Neuroscience, Reproductive Medicine, Odontostomatology, University of Naples Federico II, 80131 Naples, Italy;
| | - Ida Paris
- Department of Woman and Child Health and Public Health, Woman Health Area, Fondazione Policlinico Universitario A, Gemelli IRCCS, 00168 Rome, Italy;
| | - Lucia Del Mastro
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, 16132 Genova, Italy; (M.L.); (L.D.M.)
- Department of Medical Oncology, U.O.C Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Sabino De Placido
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (M.G.); (S.D.P.)
| | - Miguel Martín
- Departamento de Medicina, Instituto de Investigación Sanitaria Gregorio Marañón Universidad Complutense, 28007 Madrid, Spain;
| | - Guy Jerusalem
- Division of Medical Oncology, CHU Sart Tilman Liège and University of Liège, 4000 Liège, Belgium;
| | - Sergio Venturini
- Management Department, University of Turin, 10124 Torino, Italy;
| | - Giuseppe Curigliano
- Istituto Europeo di Oncologia, IRCCS ed Università di Milano, 20141 Milano, Italy;
| | - Daniele Generali
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy
- Multidisciplinary Unit of Breast Pathology and Translational Research, Cremona Hospital, Viale Concordia 1, 26100 Cremona, Italy
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Wang Q, Ma X, Long J, Du X, Pan B, Mao H. Metformin and survival of women with breast cancer: A meta-analysis of randomized controlled trials. J Clin Pharm Ther 2021; 47:263-269. [PMID: 34397110 DOI: 10.1111/jcpt.13500] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 07/16/2021] [Accepted: 07/23/2021] [Indexed: 12/24/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Metformin has been suggested to confer anticancer efficacy. However, it remains uncertain whether additional use of metformin could improve survival of women with breast cancer. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the influence of metformin on survival outcome in women with breast cancer. METHODS Relevant RCTs were obtained by search of PubMed, Embase and Cochrane's Library databases from inception to 15 May 2021. A random-effects model incorporating the potential publication bias was used to pool the results. RESULTS AND DISCUSSION Five phase II RCTs including 396 non-diabetic women with breast cancer were included in the meta-analysis. Pooled results showed that additional use of metformin was not associated with improved progression-free survival (PFS, hazard ratio [HR]: 1.00, 95% confidence interval [CI]: 0.70 to 1.43, p = 0.98; I2 = 32%) or overall survival (OS, HR: 1.00, 95% CI: 0.71 to 1.39, p = 0.98; I2 = 0%). Sensitivity analysis by excluding one study at a time showed consistent results (HR for PFS: 0.91 to 1.14, p all >0.05; HR for OS: 0.88 to 1.21, P all >0.05). WHAT IS NEW AND CONCLUSION Current evidence from phase II clinical trials does not support that additional use of metformin could improve the survival outcome in women with breast cancer.
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Affiliation(s)
- Qiandan Wang
- The First Department of Breast Surgery, Gansu Provincial Maternity and Child-care Hospital, Gansu, China
| | - Xiufen Ma
- The First Department of Breast Surgery, Gansu Provincial Maternity and Child-care Hospital, Gansu, China
| | - Jianping Long
- The First Department of Breast Surgery, Gansu Provincial Maternity and Child-care Hospital, Gansu, China
| | - Xiaoyan Du
- The First Department of Breast Surgery, Gansu Provincial Maternity and Child-care Hospital, Gansu, China
| | - Bin Pan
- The First Department of Breast Surgery, Gansu Provincial Maternity and Child-care Hospital, Gansu, China
| | - Hongyan Mao
- The First Department of Breast Surgery, Gansu Provincial Maternity and Child-care Hospital, Gansu, China
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Potential intrinsic subtype dependence on the association between metformin use and survival in surgically resected breast cancer: a Korean national population-based study. Int J Clin Oncol 2021; 26:2004-2016. [PMID: 34374879 DOI: 10.1007/s10147-021-02005-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 07/26/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Numerous studies have suggested that metformin treatment can increase breast cancer survival; however, it is unclear whether its effects interact with intrinsic subtype or diabetic status. Therefore, we conducted a large nationwide study to assess this in women with surgically resected invasive breast cancer. METHODS Patients with newly diagnosed breast cancer between 2007 and 2016 were identified using the national health insurance claims database of South Korea. Metformin or other drug exposures was defined as medication for ≥ 90 days. Breast cancer subtypes were classified into four groups based on hormonal therapy and anti-HER2 treatments. RESULTS A total of 117,333 patients were included (median follow-up duration, 90 months). Type 2 diabetes mellitus (T2DM) affected significantly overall survival (OS, 7 years, 89.7% vs. 92.4%, p < 0.001). A significant interaction was found between the use of metformin and insulin in patients with T2DM (p = 0.018). Thus, the subsequent analysis was limited to these patients and propensity score matching was performed. We found significantly increased OS in patients treated with metformin (7-year OS, 88.3% vs. 85.6%, p < 0.001). Interestingly, a significant effect was observed in the hormonal therapy (HT)+/HER2-targeted therapy (Tx)- group (p < 0.001), whereas no specific association was observed in the HT-/HER2 Tx- group (p = 0.220). CONCLUSIONS Metformin administration may be associated with reduced mortality in patients with surgically resected breast cancer, particularly in the HT+/HER2 Tx- group. Clinical trials investigating metformin as a combination agent in breast cancer should stratify patients by curative resection, intrinsic subtype, the presence of T2DM, and the use of insulin.
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Yang J, Zhou Y, Xie S, Wang J, Li Z, Chen L, Mao M, Chen C, Huang A, Chen Y, Zhang X, Khan NUH, Wang L, Zhou J. Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J Exp Clin Cancer Res 2021; 40:206. [PMID: 34162423 PMCID: PMC8223374 DOI: 10.1186/s13046-021-02012-7] [Citation(s) in RCA: 226] [Impact Index Per Article: 56.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/10/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. METHODS The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. RESULTS Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc- inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. CONCLUSIONS This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.
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Affiliation(s)
- Jingjing Yang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Yulu Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Shuduo Xie
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Ji Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Zhaoqing Li
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Lini Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Misha Mao
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Cong Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Aihua Huang
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
| | - Yongxia Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | - Xun Zhang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China
| | | | - Linbo Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China.
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China.
| | - Jichun Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000, Zhejiang, China.
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, 310000, Zhejiang, China.
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Morio K, Kurata Y, Kawaguchi-Sakita N, Shiroshita A, Kataoka Y. Efficacy of Metformin in Patients With Breast Cancer Receiving Chemotherapy or Endocrine Therapy: Systematic Review and Meta-analysis. Ann Pharmacother 2021; 56:245-255. [PMID: 34137294 DOI: 10.1177/10600280211025792] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Previous studies have suggested that metformin might improve survival outcomes in patients with breast cancer. However, findings on the efficacy of metformin with chemotherapy or endocrine therapy are inconsistent. OBJECTIVE To clarify the efficacy of metformin with chemotherapy or endocrine therapy in breast cancer patients according to the treatment setting, including neoadjuvant, adjuvant, and metastasis/recurrence. METHODS We systematically searched for randomized controlled trials (RCTs) in MEDLINE, CENTRAL, and EMBASE from inception through July 2020. Overall survival (OS), progression-free survival (PFS), and hypoglycemia rate were the primary outcomes. Secondary outcomes included severe adverse events (SAEs) and relapse-free survival. We used the Grading of Recommendations Assessment, Development, and Evaluation approach and performed a meta-analysis to evaluate the efficacy and safety of metformin with chemotherapy and endocrine therapy in patients with breast cancer. RESULTS Our systematic review included 412 participants from 5 trials. Metformin showed little to no difference in OS (hazard ratio [HR] = 1.13; 95% CI = 0.71-1.81; certainty of evidence [COE], moderate) and PFS (HR = 1.14; 95% CI = 0.86-1.50; COE, moderate) in patients with metastasis/recurrence. The evidence was very uncertain about the effect of metformin on survival outcomes in patients who received metformin with neoadjuvant or adjuvant treatment. Metformin showed little to no difference in hypoglycemia and SAEs. CONCLUSION AND RELEVANCE Metformin should be discouraged routinely in nondiabetic patients with metastatic/recurrent breast cancer. Further RCTs are needed to verify whether metformin with chemotherapy or endocrine therapy results in significant clinical benefits in the neoadjuvant or adjuvant setting.
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Affiliation(s)
- Kayoko Morio
- Kobe University Hospital, Japan.,Systematic Review Workshop Peer Support Group (SRWS-PSG), Japan
| | - Yasuko Kurata
- Systematic Review Workshop Peer Support Group (SRWS-PSG), Japan.,Okayama University Hospital, Japan
| | | | - Akihiro Shiroshita
- Systematic Review Workshop Peer Support Group (SRWS-PSG), Japan.,Ichinomiya-nishi Hospital, Aichi, Japan
| | - Yuki Kataoka
- Systematic Review Workshop Peer Support Group (SRWS-PSG), Japan.,Kyoto Min-Iren Asukai Hospital, Japan
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Mahoutforoush A, Solouk A, Hamishehkar H, Haghbin Nazarpak M, Abbaspour-Ravasjani S. Novel decorated nanostructured lipid carrier for simultaneous active targeting of three anti-cancer agents. Life Sci 2021; 279:119576. [PMID: 33965376 DOI: 10.1016/j.lfs.2021.119576] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/18/2021] [Accepted: 04/26/2021] [Indexed: 12/18/2022]
Abstract
Cancer-targeted co-delivery of therapeutic agents has been recognized as an effective strategy for increasing efficacy and reducing side effects of therapeutic agents. In this study, we used methotrexate (MTX) alone as a targeting moiety and chemotherapeutic agent and in combination with docetaxel (DTX) and doxorubicin (DOX) as chemotherapeutic agents to stop cancer cell proliferation with the aid of newly designed nanostructured lipid carriers (NLCs). The physicochemical properties of our designed nanocomplexes were evaluated by DLS, FT-IR spectroscopy, SEM, and TEM. Moreover, the targeting efficiency of the designed and synthesized nanoplatforms was evaluated on the folate receptor (FR) positive human breast cancer cell line (MCF-7) and FR negative human alveolar basal epithelial cells (A549). The NLCs/DTX/DOX/CS and NLCs/DTX/DOX/CS-MTX complexes significantly increased the cell cytotoxicity and the cell apoptosis rate. However, the complexes significantly reduced the capability of colony formation and cell migration. Our results revealed that NLCs/DTX/DOX/CS-MTX had synergistic cytotoxicity, reactive oxygen spaces, autophagy, and the apoptosis induction ability with an enhanced cellular internalization rate in FR-positive cancer cells, thorough MTX recognition capability. We conclude that the NLCs/DTX/DOX/CS-MTX complex is a new promising paradigm for breast cancer-targeted co-delivery.
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Affiliation(s)
- Amin Mahoutforoush
- Department of Biomedical Engineering, Central Tehran Branch, Islamic Azad University, Tehran 13185/768, Iran
| | - Atefeh Solouk
- Biomedical Engineering Department, Amirkabir University of Technology (Tehran Polytechnic), Tehran 1591634311, Iran
| | - Hamed Hamishehkar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Masoumeh Haghbin Nazarpak
- New Technologies Research Center (NTRC), Amirkabir University of Technology, Tehran 1591634653, Iran
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Kawakita E, Koya D, Kanasaki K. CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology. Cancers (Basel) 2021; 13:cancers13092191. [PMID: 34063285 PMCID: PMC8124456 DOI: 10.3390/cancers13092191] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Dipeptidyl peptidase (DPP)-4 inhibitor is widely used for type 2 diabetes. Although DPP-4/CD26 has been recognized as both a suppressor and inducer in tumor biology due to its various functions, how DPP-4 inhibitor affects cancer progression in diabetic patients is still unknown. The aim of this review is to summarize one unfavorable aspect of DPP-4 inhibitor in cancer-bearing diabetic patients. Abstract DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field.
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Affiliation(s)
- Emi Kawakita
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan;
| | - Daisuke Koya
- Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Japan;
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
| | - Keizo Kanasaki
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan;
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan
- Correspondence: ; Tel.: +81-853-20-2183
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Doruk Analan P, Kaya E. Is There a Relationship Between Insulin Resistance and Breast Cancer-Related Lymphedema? A Preliminary Study. Lymphat Res Biol 2021; 20:76-81. [PMID: 33761281 DOI: 10.1089/lrb.2019.0072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: High blood insulin levels, insulin resistance (IR), and obesity are components of metabolic syndrome (MetS). The literature has indicated a high risk of breast cancer in patients with MetS. However, no studies have been conducted evaluating the relationship between breast cancer-related lymphedema (BCRL), one of the most frequently encountered postbreast cancer treatment conditions, and IR. Therefore, the aim of this study was to evaluate whether there is a relationship between BCRL and IR. Methods and Results: A total of 28 patients diagnosed with breast carcinoma were included in this preliminary study. Patients were divided into BCRL (n = 15; mean age: 55.2 ± 11.2 years) and non-BCRL (control) groups (n = 13; mean age: 55.17 ± 6.57 years). Body mass index (BMI), waist and hip circumference, and fasting blood glucose and blood insulin levels of all patients were recorded. The Homeostasis Model Assessment (HOMA) test was used for the calculation of IR measurement with a value of 2.5 taken as an indicator of IR. Parameters were compared between groups. BMI, waist circumference measurements, blood insulin, and HOMA-IR levels were statistically significantly higher in the BCRL group than the control group (p < 0.05). HOMA-IR values >2.5 were found in 14 patients in the BCRL group. In the control group, only three patients had IR based on HOMA-IR criteria (p = 0.000). Hip circumference measurements and fasting blood glucose levels were similar between the groups (p > 0.05). Conclusions: BCRL appears to be associated with waist circumference, fasting blood insulin level, and HOMA-IR levels. In routine clinical practice, evaluation of IR may be important in the follow-up of this patient population.
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Affiliation(s)
- Pınar Doruk Analan
- Department of Physical Medicine & Rehabilitation, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Emine Kaya
- Department of Physical Medicine & Rehabilitation, Adana City Training and Research Hospital, Adana, Turkey
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Abstract
PURPOSE OF REVIEW Mitochondria have a major impact on virtually all processes linked to oncogenesis. Thus, mitochondrial metabolism inhibition has emerged as a promising anticancer strategy. In this review, we discuss the anticancer potential of mitochondrial inhibitors, with particular focus on metformin, in the context of more effective, targeted therapeutic modalities, and diagnostic strategies for cancer patients. RECENT FINDINGS Metformin has gained interest as an antitumor agent. However, promising results have not been translated into remarkable advances in the clinical practice. Recent findings emphasize the need of providing a metabolic context in which mitochondrial inhibitors may elicit its anticancerous effects. In addition, mitochondria are critical regulators in orchestrating immune responses. Thus, the immunomodulatory effect of mitochondrial inhibitors should also be taken into account to optimize its clinical use. Targeting mitochondrial metabolic network represents a promising therapeutic strategy in cancer. However, there is a need to define the metabolic context in which mitochondrial inhibitors are more effective, as well as how the cross-talk between many immunological functions and mitochondrial functionality may be exploited for a therapeutic benefit in cancer patients.
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Mouron S, Bueno MJ, Muñoz M, Quintela-Fandino M. Monitoring vascular normalization: new opportunities for mitochondrial inhibitors in breast cancer. Oncoscience 2021; 8:1-13. [PMID: 33869665 PMCID: PMC8018703 DOI: 10.18632/oncoscience.523] [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: 07/29/2020] [Accepted: 02/08/2021] [Indexed: 11/25/2022] Open
Abstract
Preclinical evidence indicates the potential of targeting mitochondrial respiration as a therapeutic strategy. We previously demonstrated that mitochondrial inhibitors’ efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Using molecular imaging, we showed how the same antiangiogenic agent may display different normalizing properties in patients with the same tumor type. This is of key importance, since patients experiencing normalization seem to get more benefit from standard chemotherapy combinations, and also could be eligible for combination with antimitochondrial agents. This scenario emphasizes the need for monitoring vascular normalization in order to optimize the use of antiangiogenics. We have also proposed a method to evaluate anti-mitochondrial agents’ pharmacodynamics; despite promising accuracy in animal studies the clinical results were inconclusive, highlighting the need for research in this field. Regarding patients that respond to antiangiogenics increasing vessel abnormality, in this case an immunosuppressive tumor microenvironment is generated. Whether anti-mitochondrial agents can positively modulate the activity of T effector cell subpopulations remains an area of active research. Our research sheds light on the importance of refining the use of antiangiogenics, highlighting the relevance of tracing vascular normalization as a potential biomarker for antiangiogenics to assist patient-tailored medicine and exploring the role of mitochondrial inhibitors in the context of vascular normalization and correction of hypoxia.
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Affiliation(s)
- Silvana Mouron
- Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain
| | - Maria J Bueno
- Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain
| | - Manuel Muñoz
- Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain
| | - Miguel Quintela-Fandino
- Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain.,Medical Oncology, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain.,Medical Oncology, Hospital Universitario Quiron, Pozuelo de Alarcon, Madrid, Spain.,Department of Medicine, Universidad Autonóma de Madrid, Madrid, Spain
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