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Rahman MA, Jalouli M, Bhajan SK, Al-Zharani M, Harrath AH. The Role of Hypoxia-Inducible Factor-1α (HIF-1α) in the Progression of Ovarian Cancer: Perspectives on Female Infertility. Cells 2025; 14:437. [PMID: 40136686 PMCID: PMC11941611 DOI: 10.3390/cells14060437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 03/27/2025] Open
Abstract
Hypoxia-Inducible Factor-1α (HIF-1α) is crucial in the progression of ovarian cancer, especially in influencing its tumor microenvironment and promoting pathogenic pathways that worsen female infertility. In hypoxic settings, HIF-1α is stabilized and activates the transcription of genes associated with angiogenesis, metabolic reprogramming, epithelial-to-mesenchymal transition, and therapeutic resistance. Angiogenesis and glycolytic reprogramming mediated by HIF-1 tumor proliferation, survival, and metastasis. Its dysfunction concurrently impairs ovarian homeostasis, undermining follicular growth, hormone synthesis, and the ovarian vascular network, consequently contributing to infertility. Moreover, HIF-1α induces persistent inflammation and oxidative stress, promoting an environment damaging to reproductive health. Due to its dual function in ovarian cancer growth and infertility, HIF-1α is a potential therapeutic target. Strategies including small molecule inhibitors and nanoparticle-mediated delivery of drugs possess the potential to reduce HIF-1α activity, hence reducing cancer progression while protecting fertility. This review seeks to clarify the molecular basis of HIF-1α in ovarian cancer and its effects on female infertility, providing insights into novel treatment approaches that target both controlling the disease and preserving fertility.
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Affiliation(s)
- Md Ataur Rahman
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA;
| | - Maroua Jalouli
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia; (M.J.); (M.A.-Z.)
| | - Sujay Kumar Bhajan
- Department of Biotechnology and Genetic Engineering, Faculty of Life Sciences, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh;
| | - Mohammed Al-Zharani
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia; (M.J.); (M.A.-Z.)
| | - Abdel Halim Harrath
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
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2
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Xia H, Tai XJ, Cheng W, Wu Y, He D, Wang LF, Liu H, Zhang SY, Sun YT, Liu HZ, Liu DD, Zhao HZ, Ji FY, Li XH. Metformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signalling. Sci Rep 2025; 15:6081. [PMID: 39971923 PMCID: PMC11839993 DOI: 10.1038/s41598-025-87537-z] [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: 05/29/2024] [Accepted: 01/20/2025] [Indexed: 02/21/2025] Open
Abstract
Small cell lung cancer (SCLC) is a therapeutically challenging disease. Metformin, an effective agent for the treatment of type 2 diabetes, has been shown to have antitumour effects on many cancers, including non-small cell lung cancer (NSCLC) and breast cancer. Currently, the antitumour effects of metformin on SCLC and the underlying molecular mechanisms remain unclear. CCK-8, EdU, colony formation, flow cytometry, immunofluorescence, molecular docking, western blotting, nude mouse transplanted tumour model, and immunohistochemistry experiments were conducted to analyse gene functions and the underlying mechanism involved. In vitro experiments demonstrated that metformin inhibited the growth of SCLC cells (H446, H526, H446/DDP and H526/DDP), which was confirmed in xenograft mouse models in vivo. Additionally, metformin induced cell cycle arrest, apoptosis, and autophagy in these SCLC cells. The molecular docking results indicated that metformin has a certain binding affinity for EGFR. The western blotting results revealed that metformin decreased the expression of EGFR, p-EGFR, AKT, and p-AKT, which could be reversed by EGF and SC79. Moreover, metformin activated AMPK and inactivated mTOR, and compound C and SC79 increased the levels of p-mTOR. Metformin can not only enhance the antitumour effect of cisplatin but also alleviate the toxic effects of cisplatin on the organs of xenograft model animals. In summary, the current study revealed that metformin inhibits the growth of SCLC by inducing autophagy and apoptosis via suppression of the EGFR/AKT/AMPK/mTOR pathway. Metformin might be a promising candidate drug for combination therapy of SCLC.
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Affiliation(s)
- Hong Xia
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Xue-Jiao Tai
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Wang Cheng
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Yi Wu
- Department of Oncology, Taihe Hospital, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Dan He
- School of Biomedical Engineering, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Li-Feng Wang
- School of Biomedical Engineering, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Hao Liu
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Shen-Yi Zhang
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Yu-Ting Sun
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Hang-Zhi Liu
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Dan-Dan Liu
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Hu-Zi Zhao
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China
| | - Fu-Yun Ji
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China.
- Yu-Yue Pathology Scientific Research Center, 313 Gaoteng Avenue, Jiulongpo District, Chongqing, 400039, China.
| | - Xi-Hua Li
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of Medicine, 30 Renmin Road, Shiyan, 442000, Hubei, China.
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Bie N, Li S, Liang Q, Zheng W, Xu S, Liu H, Zhang X, Wei Z, Yong T, Yang X, Gan L. Tumor-Repopulating Cell-Derived Microparticle-Based Therapeutics Amplify the Antitumor Effect through Synergistic Inhibition of Chemoresistance and Immune Evasion. Mol Pharm 2025; 22:733-746. [PMID: 39772575 DOI: 10.1021/acs.molpharmaceut.4c00709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Traditional chemotherapy often encounters failure attributed to drug resistance mediated by tumor-repopulating cells (TRCs) and chemotherapy-triggered immune suppression. The effective inhibition of TRCs and the mitigation of drug-induced immune suppression are pivotal for the successful chemotherapy. Here, TRC-derived microparticles (3D-MPs), characterized by excellent tumor-targeting and high TRC uptake properties, are utilized to deliver metformin and the chemotherapeutic drug doxorubicin ((DOX+Met)@3D-MPs). (DOX+Met)@3D-MPs efficiently enhance tumor accumulation and are highly internalized in tumor cells and TRCs. Additionally, (DOX+Met)@3D-MPs significantly decrease the chemotherapy-triggered upregulation in P-glycoprotein expression to enhance intracellular doxorubicin retention, resulting in increased chemotherapy sensitivity and immunogenic cell death in tumor cells and TRCs for improved antitumor immunity. Importantly, (DOX+Met)@3D-MPs also remarkably reduce chemotherapy-induced PD-L1 expression, efficiently alleviating immune suppression facilitated by the PD-L1/PD-1 axis to further enhance immunological response against malignancy. These results underscore the (DOX+Met)@3D-MPs' potential as a viable platform for augmenting the efficacy of antitumor therapies.
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Affiliation(s)
- Nana Bie
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Shiyu Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Qingle Liang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Wenxia Zheng
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Shiyi Xu
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Haojie Liu
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Xiaojuan Zhang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Zhaohan Wei
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Tuying Yong
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Lu Gan
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan 430074, China
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Li Q, Tong Y, Chen J, Xie T. Targeting programmed cell death via active ingredients from natural plants: a promising approach to cancer therapy. Front Pharmacol 2024; 15:1491802. [PMID: 39584140 PMCID: PMC11582395 DOI: 10.3389/fphar.2024.1491802] [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: 09/05/2024] [Accepted: 10/09/2024] [Indexed: 11/26/2024] Open
Abstract
Cancer is a serious public health problem in humans, and prevention and control strategies are still necessary. Therefore, the development of new therapeutic drugs is urgently needed. Targeting programmed cell death, particularly via the induction of cancer cell apoptosis, is one of the cancer treatment approaches employed. Recently, an increasing number of studies have shown that compounds from natural plants can target programmed cell death and kill cancer cells, laying the groundwork for use in future anticancer treatments. In this review, we focus on the latest research progress on the role and mechanism of natural plant active ingredients in different forms of programmed cell death, such as apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis, to provide a strong theoretical basis for the clinical development of antitumor drugs.
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Affiliation(s)
- Qian Li
- School of Pharmacy and Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yan Tong
- School of Pharmacy and Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jianxiang Chen
- School of Pharmacy and Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Tian Xie
- School of Pharmacy and Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
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Jemal M, Getinet M, Amare GA, Tegegne BA, Baylie T, Mengistu EF, Osman EE, Chura Waritu N, Adugna A. Non-metabolic enzyme function of pyruvate kinase M2 in breast cancer. Front Oncol 2024; 14:1450325. [PMID: 39411137 PMCID: PMC11473492 DOI: 10.3389/fonc.2024.1450325] [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: 06/17/2024] [Accepted: 09/12/2024] [Indexed: 10/19/2024] Open
Abstract
Breast cancer (BC) is a prevalent malignant tumor in women, and its incidence has been steadily increasing in recent years. Compared with other types of cancer, it has the highest mortality and morbidity rates in women. So, it is crucial to investigate the underlying mechanisms of BC development and identify specific therapeutic targets. Pyruvate kinase M2 (PKM2), an important metabolic enzyme in glycolysis, has been found to be highly expressed in BC. It can also move to the nucleus and interact with various transcription factors and proteins, including hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription 3 (STAT3), β-catenin, cellular-myelocytomatosis oncogene (c-Myc), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and mammalian sterile 20-like kinase 1 (MST1). This interaction leads to non-metabolic functions that control the cell cycle, proliferation, apoptosis, migration, invasion, angiogenesis, and tumor microenvironment in BC. This review provides an overview of the latest advancements in understanding the interactions between PKM2 and different transcription factors and proteins that influence the initiation and progression of BC. It also examined how natural drugs and noncoding RNAs affect various biological processes in BC cells through the regulation of the non-metabolic enzyme functions of PKM2. The findings provide valuable insights for improving the prognosis and developing targeted therapies for BC in the coming years.
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Affiliation(s)
- Mohammed Jemal
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Mamaru Getinet
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Gashaw Azanaw Amare
- Department of Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Bantayehu Addis Tegegne
- Department of Pharmacy, College of Medicine and Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Temesgen Baylie
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Enyew Fenta Mengistu
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Enatnesh Essa Osman
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Nuredin Chura Waritu
- Department of Biomedical Sciences, School of Medicine, Wolaita Sodo University, Wolaita Sodo, Ethiopia
| | - Adane Adugna
- Department of Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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Jinadasa AGRG, Akalanka HMK, Wageesha NDA, Ekanayake S. Metformin as a Potential In Vitro Anticancer Modulator of Adenosine Monophosphate Kinase: A Review. Int J Breast Cancer 2024; 2024:1094274. [PMID: 39246697 PMCID: PMC11380709 DOI: 10.1155/2024/1094274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/21/2024] [Accepted: 07/03/2024] [Indexed: 09/10/2024] Open
Abstract
Metformin (MET) is the commonly prescribed hypoglycemic agent used in the treatment of type 2 diabetes mellitus (DM). Pleiotropic effects of MET are emerging as a medication for other diseases including breast cancer (BC). Therefore, a literature review was conducted to investigate whether the anticancer effects of MET are mediated through adenosine monophosphate kinase (AMPK). This review assessed published data focusing on studies where BC cell lines were treated with MET to explore its potential anticancer effects via AMPK on BC cells. The published data reveals that activated AMPK induces anticancer effects primarily by suppressing cell proliferation, induction of apoptosis, and cell cycle arrest, inhibition of metastasis and invasion, alteration of tumor microenvironment, and downregulation of tumorigenesis. In addition, MET was observed to induce AMPK-mediated effects when combined with other drugs. Further studies on assessing the potential use of MET alone or in combination with other drugs would pave the way to design new treatment strategies for BC.
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Affiliation(s)
- A G R Greshamali Jinadasa
- Department of Basic Sciences Faculty of Allied Health Sciences University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| | - H M Kasuni Akalanka
- Rural Health Research Institute Charles Sturt University Orange, Orange, NSW 2800, Australia
| | - N D Amal Wageesha
- Department of Biochemistry Faculty of Medicine Sabaragamuwa University of Sri Lanka, PO Box 01, Hidellana, Ratnapura, Sri Lanka
| | - Sagarika Ekanayake
- Department of Biochemistry Faculty of Medical Science University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
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Sirtori CR, Castiglione S, Pavanello C. METFORMIN: FROM DIABETES TO CANCER TO PROLONGATION OF LIFE. Pharmacol Res 2024; 208:107367. [PMID: 39191336 DOI: 10.1016/j.phrs.2024.107367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/12/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024]
Abstract
The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.
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Affiliation(s)
- Cesare R Sirtori
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
| | - Sofia Castiglione
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Chiara Pavanello
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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De la Cruz-López KG, Alvarado-Ortiz E, Valencia-González HA, Beltrán-Anaya FO, Zamora-Fuentes JM, Hidalgo-Miranda A, Ortiz-Sánchez E, Espinal-Enríquez J, García-Carrancá A. Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines. BMC Cancer 2024; 24:853. [PMID: 39026155 PMCID: PMC11256429 DOI: 10.1186/s12885-024-12555-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 06/24/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Metformin, a widely prescribed antidiabetic drug, has shown several promising effects for cancer treatment. These effects have been shown to be mediated by dual modulation of the AMPK-mTORC1 axis, where AMPK acts upstream of mTORC1 to decrease its activity. Nevertheless, alternative pathways have been recently discovered suggesting that metformin can act through of different targets regulation. METHODS We performed a transcriptome screening analysis using HeLa xenograft tumors generated in NOD-SCID mice treated with or without metformin to examine genes regulated by metformin. Western Blot analysis, Immunohistochemical staining, and RT-qPCR were used to confirm alterations in gene expression. The TNMplot and GEPIA2 platform were used for in silico analysis of genes found up-regulated by metformin, in cervical cancer patients. We performed an AMPK knock-down using AMPK-targeted siRNAs and mTOR inhibition with rapamycin to investigate the molecular mechanisms underlying the effect of metformin in cervical cancer cell lines. RESULTS We shown that metformin decreases tumor growth and increased the expression of a group of antitumoral genes involved in DNA-binding transcription activator activity, hormonal response, and Dcp1-Dcp2 mRNA-decapping complex. We demonstrated that ZFP36 could act as a new molecular target increased by metformin. mTORC1 inhibition using rapamycin induces ZFP36 expression, which could suggest that metformin increases ZFP36 expression and requires mTORC1 inhibition for such effect. Surprisingly, in HeLa cells AMPK inhibition did not affect ZFP36 expression, suggesting that additional signal transducers related to suppressing mTORC1 activity, could be involved. CONCLUSIONS These results highlight the importance of ZFP36 activation in response to metformin treatment involving mTORC1 inhibition.
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Affiliation(s)
- Karen Griselda De la Cruz-López
- Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología., Av. San Fernando No. 22 Colonia Sección XVI, Tlalpan, Mexico City, 14080, Mexico
| | - Eduardo Alvarado-Ortiz
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Heriberto A Valencia-González
- Laboratorio de Células Troncales y Desarrollo Terapéutico Antineoplásico, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Fredy Omar Beltrán-Anaya
- Laboratorio de Diagnóstico e Investigación en Salud, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, Gro, Mexico
| | - José María Zamora-Fuentes
- Laboratorio de Oncología Teórica, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- Centro de Ciencias de La Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Alfredo Hidalgo-Miranda
- Laboratorio de Genómica de Cáncer, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Elizabeth Ortiz-Sánchez
- Laboratorio de Células Troncales y Desarrollo Terapéutico Antineoplásico, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Jesús Espinal-Enríquez
- Laboratorio de Oncología Teórica, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- Centro de Ciencias de La Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Alejandro García-Carrancá
- Laboratorio de Virus y Cáncer, Unidad de Investigación Biomédica en Cáncer. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México & Instituto Nacional de Cancerología., Av. San Fernando No. 22 Colonia Sección XVI, Tlalpan, Mexico City, 14080, Mexico.
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Dixon S, Tran A, Schrier MS, Dong J, Deth RC, Castejon A, Trivedi MS. Metformin-induced oxidative stress inhibits LNCaP prostate cancer cell survival. Mol Biol Rep 2024; 51:729. [PMID: 38862809 DOI: 10.1007/s11033-024-09662-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 05/21/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Preclinical and clinical studies over the past several decades have indicated the potential value of metformin, a widely utilized treatment for Type 2 diabetes, in prostate cancer therapy. Notably, these studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. In this study we investigated the role of metformin in regulating intracellular redox status and cell survival in LNCaP prostate cancer cells. METHODS AND RESULTS The cytotoxic effects of metformin with or without the presence of SBI0206965 (AMPK inhibitor) on LNCaP cells were determined using MTT and trypan blue exclusion assays. Seahorse XP extracellular analysis, Liquid Chromatography/ Mass Spectrophotometry (LC/MS), and 2,7- and Dichlorofluoresin diacetate (DCFDA) assay were used to assess the effects of metformin on cellular bioenergetics, redox status, and redox-related metabolites. mRNA expression and protein concentration of redox-related enzymes were measured using Real Time-qPCR and ELISA assay, respectively. Independently of AMP-activated protein kinase, metformin exhibited a dose- and time-dependent inhibition of LNCaP cell survival, a response mitigated by glutathione or N-acetylcysteine (ROS scavengers) treatment. Notably, these findings were concomitant with a decline in ATP levels and the inhibition of oxidative phosphorylation. The results further indicated metformin's induction of reactive oxygen species, which significantly decreased glutathione levels and the ratio of reduced to oxidized glutathione, as well as the transsulfuration metabolite, cystathionine. Consistent with an induction of oxidative stress condition, metformin increased mRNA levels of the master redox transcription factor Nrf-2 (nuclear factor erythroid-derived 2-like), as well as transsulfuration enzymes cystathionine beta-synthase and cystathionase and GSH synthesis enzymes γ-glutamylcysteine synthetase and glutathione synthetase. CONCLUSION Our findings highlight multiple mechanisms by which metformin-induced formation of reactive oxygen species may contribute to its efficacy in prostate cancer treatment, including promotion of oxidative stress, Nrf2 activation, and modulation of redox-related pathways, leading to its anti-survival action.
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Affiliation(s)
- Sashana Dixon
- Department of Pharmaceutical Sciences, Barry and Judy Silverman's College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA.
| | - Alice Tran
- Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Ft. Lauderdale, Florida, 33328, USA
| | - Matthew S Schrier
- Department of Pharmaceutical Sciences, Barry and Judy Silverman's College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA
| | - Jianan Dong
- Department of Pharmaceutical Sciences, Barry and Judy Silverman's College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA
| | - Richard C Deth
- Department of Pharmaceutical Sciences, Barry and Judy Silverman's College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA
| | - Ana Castejon
- Department of Pharmaceutical Sciences, Barry and Judy Silverman's College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA
| | - Malav S Trivedi
- Department of Pharmaceutical Sciences, Barry and Judy Silverman's College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA
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10
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Orang A, Marri S, McKinnon RA, Petersen J, Michael MZ. Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study. Cancers (Basel) 2024; 16:2055. [PMID: 38893174 PMCID: PMC11171104 DOI: 10.3390/cancers16112055] [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: 04/05/2024] [Revised: 05/13/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. METHODS The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA-target gene pairs. RESULTS Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA-target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression. CONCLUSIONS This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation.
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Affiliation(s)
- Ayla Orang
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Shashikanth Marri
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Ross A. McKinnon
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Janni Petersen
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Michael Z. Michael
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042, Australia
- Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, SA 5042, Australia
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11
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Shah S, Mansour HM, Aguilar TM, Lucke-Wold B. Advances in Anti-Cancer Drug Development: Metformin as Anti-Angiogenic Supplemental Treatment for Glioblastoma. Int J Mol Sci 2024; 25:5694. [PMID: 38891882 PMCID: PMC11171521 DOI: 10.3390/ijms25115694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
According to the WHO 2016 classification, glioblastoma is the most prevalent primary tumor in the adult central nervous system (CNS) and is categorized as grade IV. With an average lifespan of about 15 months from diagnosis, glioblastoma has a poor prognosis and presents a significant treatment challenge. Aberrant angiogenesis, which promotes tumor neovascularization and is a prospective target for molecular target treatment, is one of its unique and aggressive characteristics. Recently, the existence of glioma stem cells (GSCs) within the tumor, which are tolerant to chemotherapy and radiation, has been linked to the highly aggressive form of glioblastoma. Anti-angiogenic medications have not significantly improved overall survival (OS), despite various preclinical investigations and clinical trials demonstrating encouraging results. This suggests the need to discover new treatment options. Glioblastoma is one of the numerous cancers for which metformin, an anti-hyperglycemic medication belonging to the Biguanides family, is used as first-line therapy for type 2 diabetes mellitus (T2DM), and it has shown both in vitro and in vivo anti-tumoral activity. Based on these findings, the medication has been repurposed, which has shown the inhibition of many oncopromoter mechanisms and, as a result, identified the molecular pathways involved. Metformin inhibits cancer cell growth by blocking the LKB1/AMPK/mTOR/S6K1 pathway, leading to selective cell death in GSCs and inhibiting the proliferation of CD133+ cells. It has minimal impact on differentiated glioblastoma cells and normal human stem cells. The systematic retrieval of information was performed on PubMed. A total of 106 articles were found in a search on metformin for glioblastoma. Out of these six articles were Meta-analyses, Randomized Controlled Trials, clinical trials, and Systematic Reviews. The rest were Literature review articles. These articles were from the years 2011 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on metformin use in the treatment of glioblastoma were searched on clinicaltrials.gov. In this article, we examine and evaluate metformin's possible anti-tumoral effects on glioblastoma, determining whether or not it may appropriately function as an anti-angiogenic substance and be safely added to the treatment and management of glioblastoma patients.
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Affiliation(s)
- Siddharth Shah
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
| | - Hadeel M. Mansour
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
| | - Tania M. Aguilar
- College of Medicine at Chicago, University of Illinois, Chicago, IL 60612, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (S.S.)
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12
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Galal MA, Al-Rimawi M, Hajeer A, Dahman H, Alouch S, Aljada A. Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int J Mol Sci 2024; 25:4083. [PMID: 38612893 PMCID: PMC11012626 DOI: 10.3390/ijms25074083] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Mohammed Al-Rimawi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | | | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Samhar Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
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13
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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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14
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Papadakos SP, Argyrou A, Lekakis V, Arvanitakis K, Kalisperati P, Stergiou IE, Konstantinidis I, Schizas D, Koufakis T, Germanidis G, Theocharis S. Metformin in Esophageal Carcinoma: Exploring Molecular Mechanisms and Therapeutic Insights. Int J Mol Sci 2024; 25:2978. [PMID: 38474224 PMCID: PMC10932447 DOI: 10.3390/ijms25052978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 02/29/2024] [Accepted: 03/03/2024] [Indexed: 03/14/2024] Open
Abstract
Esophageal cancer (EC) remains a formidable malignancy with limited treatment options and high mortality rates, necessitating the exploration of innovative therapeutic avenues. Through a systematic analysis of a multitude of studies, we synthesize the diverse findings related to metformin's influence on EC. This review comprehensively elucidates the intricate metabolic pathways and molecular mechanisms through which metformin may exert its anti-cancer effects. Key focus areas include its impact on insulin signaling, AMP-activated protein kinase (AMPK) activation, and the mTOR pathway, which collectively contribute to its role in mitigating esophageal cancer progression. This review critically examines the body of clinical and preclinical evidence surrounding the potential role of metformin, a widely prescribed anti-diabetic medication, in EC management. Our examination extends to the modulation of inflammation, oxidative stress and angiogenesis, revealing metformin's potential as a metabolic intervention in esophageal cancer pathogenesis. By consolidating epidemiological and clinical data, we assess the evidence that supports metformin's candidacy as an adjuvant therapy for esophageal cancer. By summarizing clinical and preclinical findings, our review aims to enhance our understanding of metformin's role in EC management, potentially improving patient care and outcomes.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527 Athens, Greece;
| | - Alexandra Argyrou
- Academic Department of Gastroenterology, Laikon General Hospital, Athens University Medical School, 11527 Athens, Greece; (A.A.); (V.L.)
| | - Vasileios Lekakis
- Academic Department of Gastroenterology, Laikon General Hospital, Athens University Medical School, 11527 Athens, Greece; (A.A.); (V.L.)
| | - Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Polyxeni Kalisperati
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.); (I.E.S.)
| | - Ioanna E. Stergiou
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.); (I.E.S.)
| | | | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Theocharis Koufakis
- Second Propaedeutic Department of Internal Medicine, General Hospital “Hippokration”, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527 Athens, Greece;
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15
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Banisharif Dehkordi F, Ghatrehsamani M, Abdolvand M, Soltani A, Masoumi SH. Impact of Combination Therapy with Chemical Drugs and Megavoltage X-ray Exposure on Breast Cancer Stem Cells' Viability and Proliferation of MCF-7 and MDA-MB-231 Cell Lines. Curr Pharm Des 2024; 30:1341-1353. [PMID: 38676476 DOI: 10.2174/0113816128287325240329085055] [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: 12/05/2023] [Revised: 02/07/2024] [Accepted: 02/29/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Breast Cancer (BC) is a serious malignancy among women. However, chemotherapy is an important tool for cancer treatments, but the long-term use of chemotherapy drugs may lead to drug resistance and tumor recurrence. Since Breast Cancer Stem Cells (BCSCs) can be the main factor to induce BC treatment resistance and recurrence, investigation of BCSCs signaling pathways can be an effective modality to enhance cancer treatment efficiency. OBJECTIVE In this study, the effect of metformin, SB203580, and takinib alone or in combination with radiotherapy on MCF-7 and MDA-MB-231 breast cancer cell lines was evaluated. METHODS MCF-7 and MDA-MB-231 breast cancer cell lines were treated with metformin, SB203580, and takinib for 24 or 48 hours, followed by X-ray exposure. The MTT assay and flow cytometry analysis were performed to assess cell growth inhibition and cellular death, CXCr4 expression, and BCSCs, respectively. RESULTS The results showed the combination of takinib/SB203580 with radiotherapy to remarkably reduce the CXCR4 expression and BCSCs levels in the MCF-7 cell line. Also, the concurrent administration of takinib/metformin/radiotherapy significantly reduced BCSCs and CXCR4 metastatic markers in the MDA-MB- 231 cells. Since the MAPK signaling pathway has an important role in inducing drug resistance and cell proliferation, the use of SB203580 as an inhibitor of p38 MAPK can improve breast cancer treatment. Furthermore, metformin and ionizing radiation by suppression of the mTOR signaling pathway can control AMPK activation and cellular proliferation. CONCLUSION Anti-cancer and cytotoxic effects of metformin can be effective in this strategy. In conclusion, the combination of conventional chemotherapeutic drugs, including SB203580, metformin, and takinib with X-ray exposure can be a new approach to diminish the drug resistance of breast cancer.
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Affiliation(s)
- Fatemeh Banisharif Dehkordi
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahdi Ghatrehsamani
- Department of Microbiology and Immunology, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Maryam Abdolvand
- Department of Microbiology and Immunology, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Amin Soltani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Seyed Hossein Masoumi
- Medical Physics School of Allied Medical Sciences, Shahrekord University of Medical Sciences, Shahrekord, Iran
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16
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Li M, Feng Z, Han R, Hu B, Zhang R, Wang H. Paclitaxel promotes mTOR signaling-mediated apoptosis in esophageal cancer cells by targeting MUC20. Thorac Cancer 2023; 14:3089-3096. [PMID: 37772424 PMCID: PMC10626250 DOI: 10.1111/1759-7714.15091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND The aim of this study was to analyze the effect of paclitaxel on the apoptosis of esophageal cancer cells in relation to MUC20. METHODS RT-qPCR analysis, a CCK-8 assay, western blotting, and flow cytometry were used to analyze the anticancer effects of paclitaxel treatment or OE-MUC20 in vitro and in vivo. RESULTS The in vitro results showed that paclitaxel significantly induced MUC20 upregulation and that paclitaxel treatment or OE-MUC20 significantly decreased esophageal cancer cell viability and increased mTOR signaling activation and apoptosis. In addition, PKM2, a key downstream molecule of mTOR signaling, similarly showed significant upregulation after paclitaxel treatment in cells with OE-MUC20, and its expression was attenuated after treatment with mTOR inhibitors. In a nude mouse model, tumor growth was slow in the OE-MUC20 group and accelerated after inhibition of mTOR signaling. CONCLUSION These data suggest that MUC20 is an important target of paclitaxel in esophageal cancer and promotes apoptosis through activation of mTOR signaling.
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Affiliation(s)
- Meng Li
- Department of Thoracic SurgeryShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
- Department of Thoracic Surgery, Shandong Provincial HospitalShandong UniversityJinanChina
| | - Zhen Feng
- Department of Thoracic SurgeryShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
- Department of Thoracic Surgery, Shandong Provincial HospitalShandong UniversityJinanChina
| | - Rui Han
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Benchuang Hu
- Department of Thoracic SurgeryThe First People's Hospital of JiningJiningChina
| | - Renfeng Zhang
- Department of Laboratory MedicineShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
| | - Hui Wang
- Department of Thoracic SurgeryShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
- Department of Thoracic Surgery, Shandong Provincial HospitalShandong UniversityJinanChina
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17
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Sharma N, Dhingra R. Clinical potentials of metformin in cancer therapy. JOURNAL OF DIABETOLOGY 2023; 14:186-192. [DOI: 10.4103/jod.jod_84_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/28/2023] [Indexed: 01/05/2025] Open
Abstract
Abstract
Diabetes is a prevalent metabolic disorder that results in several comorbidities including cancer. Cancer becomes the most severe complication of diabetes patients. Growing evidence proved that impaired glucose homeostasis is an independent risk factor for the occurrence of various types of cancers including liver, pancreatic, gastric (stomach), colorectal, kidney, and breast cancers, and influences cancer prognosis. Diabetes mellitus and cancer have a bidirectional relationship, thus there is a need to look for drugs that can be beneficial in treating both diseases. Therefore, more research is focusing on evaluating the role of antihyperglycemic agents in the treatment of various types of cancers. Metformin, an FDA-approved first-line antihyperglycemic agent can be used as a monotherapy or as an adjuvant to chemotherapeutic agents in the treatment of various types of cancer. However, the exact mechanism of metformin as an anticancer agent is still unknown, the majority of the described putative mechanisms focus on promoting the activity of the AMP-activated protein kinase (AMPK) pathway. This review article thus gives insights into the prognosis of cancer in diabetes patients and aims to explore the possible mechanism of action of metformin in the prevention and treatment of cancer.
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Affiliation(s)
- Nidhi Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Sohna, Haryana, India
| | - Richa Dhingra
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Sohna, Haryana, India
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18
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Khajeh E, Aminizadeh E, Moghadam AD, Ramouz A, Klotz R, Golriz M, Merle U, Springfeld C, Chang D, Longerich T, Büchler MW, Mehrabi A. Association of perioperative use of statins, metformin, and aspirin with recurrence after curative liver resection in patients with hepatocellular carcinoma: A propensity score matching analysis. Cancer Med 2023; 12:19548-19559. [PMID: 37737550 PMCID: PMC10587989 DOI: 10.1002/cam4.6569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 08/22/2023] [Accepted: 09/11/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND Statins, metformin, and aspirin have been reported to reduce the incidence of hepatocellular carcinoma (HCC). However, the effect of their perioperative use on survival outcomes of HCC patients following curative liver resection still remains unclear. METHOD Three hundred and fifty three patients with a first diagnosis of HCC who underwent curative liver resection were included. Propensity score matching analysis with a users: nonusers ratio of 1:2 were performed for each of the medications (statins, metformin, and aspirin). Overall survival (OS) and recurrence-free survival (RFS) were evaluated and multivariable Cox proportional hazard analysis was performed. RESULTS Sixty two patients received statins, 48 patients used metformin, and 53 patients received aspirin for ≥90 days before surgery. None of the medications improved OS. RFS of statin users was significantly longer than that of nonusers (p = 0.021) in the matched cohort. Users of hydrophilic statins, but not lipophilic ones had a significantly longer RFS than nonusers. Multivariable analysis showed that statin use significantly improved RFS (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.17-0.97, p = 0.044). No difference was seen in RFS between metformin users and nonusers. Among patients with diabetes, RFS was nonsignificantly longer in metformin users than in non-metformin users (84.1% vs. 60.85%, p = 0.069) in the matched cohort. No difference in postoperative RFS was seen between aspirin users and nonusers. CONCLUSION Preoperative use of statins in patients with HCC can increase RFS after curative liver resection, but metformin and aspirin were not associated with improved survival. Randomized controlled trials are needed to confirm the findings of the present study.
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Affiliation(s)
- Elias Khajeh
- Department of General, Visceral, and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Ehsan Aminizadeh
- Department of General, Visceral, and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Arash Dooghaie Moghadam
- Department of General, Visceral, and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Ali Ramouz
- Department of General, Visceral, and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Rosa Klotz
- Department of General, Visceral, and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Mohammad Golriz
- Department of General, Visceral, and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
- Liver Cancer Center Heidelberg (LCCH)Heidelberg University HospitalHeidelbergGermany
| | - Uta Merle
- Liver Cancer Center Heidelberg (LCCH)Heidelberg University HospitalHeidelbergGermany
- Department of Internal Medicine IV, Gastroenterology & HepatologyHeidelberg University HospitalHeidelbergGermany
| | - Christoph Springfeld
- Liver Cancer Center Heidelberg (LCCH)Heidelberg University HospitalHeidelbergGermany
- Department of Medical OncologyNational Center for Tumor Diseases Heidelberg University HospitalHeidelbergGermany
| | - De‐Hua Chang
- Liver Cancer Center Heidelberg (LCCH)Heidelberg University HospitalHeidelbergGermany
- Department of Diagnostic and Interventional RadiologyHeidelberg University HospitalHeidelbergGermany
| | - Thomas Longerich
- Liver Cancer Center Heidelberg (LCCH)Heidelberg University HospitalHeidelbergGermany
- Institute of PathologyHeidelberg University HospitalHeidelbergGermany
| | - Markus W. Büchler
- Department of General, Visceral, and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Arianeb Mehrabi
- Department of General, Visceral, and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
- Liver Cancer Center Heidelberg (LCCH)Heidelberg University HospitalHeidelbergGermany
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Al-Zahrani NS, Zamzami MA, Baghdadi MA, El-Gowily AH, Ali EMM. Regulation of Protein-Induced Apoptosis and Autophagy in Human Hepatocytes Treated with Metformin and Paclitaxel In Silico and In Vitro. Biomedicines 2023; 11:2688. [PMID: 37893061 PMCID: PMC10604243 DOI: 10.3390/biomedicines11102688] [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: 07/06/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023] Open
Abstract
Metformin and paclitaxel therapy offer promising outcomes in the treatment of liver cancer. Combining paclitaxel with metformin enhances treatment effectiveness and mitigates the adverse effects associated with paclitaxel alone. This study explored the anticancer properties of metformin and paclitaxel in HepG2 liver cancer cells, MCF-7 breast cancer cells, and HCT116 colon cancer cells. The results demonstrated that the combination of these agents exhibited a lower IC50 in the tested cell lines compared to paclitaxel monotherapy. Notably, treating the HepG2 cell line with this combination led to a reduction in the G0/G1 phase and an increase in the S and G2/M phases, ultimately triggering early apoptosis. To further investigate the interaction between the cellular proteins with paclitaxel and metformin, an in silico study was conducted using proteins chosen from a protein data bank (PDB). Among the proteins studied, AMPK-α, EGFRK, and FKBP12-mTOR exhibited the highest binding free energy, with values of -11.01, -10.59, and -15.63 kcal/mol, respectively, indicating strong inhibitory or enhancing effects on these proteins. When HepG2 cells were exposed to both paclitaxel and metformin, there was an upregulation in the gene expression of AMPK-α, a key regulator of the energy balance in cancer growth, as well as apoptotic markers such as p53 and caspase-3, along with autophagic markers including beclin1 and ATG4A. This combination therapy of metformin and paclitaxel exhibited significant potential as a treatment option for HepG2 liver cancer. In summary, the combination of metformin and paclitaxel not only enhances treatment efficacy but also reduces side effects. It induces cell cycle alterations and apoptosis and modulates key cellular proteins involved in cancer growth, making it a promising therapy for HepG2 liver cancer.
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Affiliation(s)
- Norah Saeed Al-Zahrani
- Department of Clinical Biochemistry, Collage of Medicine, King Khalid University, Abha 61421, Saudi Arabia;
| | - Mazin Abdulaziz Zamzami
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohammed A. Baghdadi
- Research Center, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Saudi Arabia;
- Research Group “Cancer, Haemostasis and Angiogenesis”, INSERM U938, Saint-Antoine Research Center, University Institute of Cancerology, Faculty of Medicine, Sorbonne University, 75012 Paris, France
| | - Afnan H. El-Gowily
- Division of Biochemistry, Chemistry Department, Faculty of Science Tanta University, Tanta 31527, Egypt;
| | - Ehab M. M. Ali
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Division of Biochemistry, Chemistry Department, Faculty of Science Tanta University, Tanta 31527, Egypt;
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20
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Choi HK, Park SH, Lee J, Hwang JT. Review of Patents for Anticancer Agents Targeting Adenosine Monophosphate-Activated Protein Kinase. J Med Food 2023; 26:605-615. [PMID: 37590001 DOI: 10.1089/jmf.2023.k.0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023] Open
Abstract
Cancer, caused by abnormal and excessive cellular proliferation, can invade and destroy surrounding tissues and organs through the spreading of cancer cells. A general strategy for developing anticancer agents is to identify biomarkers that, if targeted, can produce a robust cytotoxic effect with minimal side effects. Cell-cycle regulators, checkpoint regulatory genes, and apoptosis-related genes are well-known biomarkers that inhibit cancer cell proliferation. Several compounds that target such biomarkers have been patented and more are being developed as novel therapies. Recent additions to this list include anticancer drugs that target signaling pathway proteins, such as 5' adenosine monophosphate-activated protein kinase (AMPK), which plays a vital role in cancer and normal cell metabolism. Herein, we have reviewed recent patents related to AMPK-targeting anticancer drugs and discussed the mechanisms of action of these drugs. We conclude that these recently published patents include several attractive compounds and methods for targeting AMPK. Further research and clinical trials are required to elucidate the comprehensive role of AMPK in cancer cell metabolism, identify its associated signal transduction systems, and develop novel activators that may find applications in cancer therapy. Clinical Trial Registration number: NCT01904123.
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Affiliation(s)
- Hyo-Kyoung Choi
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, Republic of Korea
| | - Soo-Hyun Park
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, Republic of Korea
| | - Jangho Lee
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, Republic of Korea
| | - Jin-Taek Hwang
- Food Functionality Research Division, Korea Food Research Institute, Jeollabuk-do, Republic of Korea
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21
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Lu MZ, Li DY, Wang XF. Effect of metformin use on the risk and prognosis of ovarian cancer: an updated systematic review and meta-analysis. Panminerva Med 2023; 65:351-361. [PMID: 31290300 DOI: 10.23736/s0031-0808.19.03640-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Emerging evidence suggests that metformin has a potential antitumor effect both in vitro and in vivo. Increasing epidemiological studies indicate that diabetic patients receiving metformin therapy have lower incidences of cancer and have better survival rates. However, there are limited and inconsistent studies available about the effect of metformin therapy on ovarian cancer (OC). Thus, we conducted this meta-analysis to study the effect of metformin therapy on OC. Meanwhile, we systematically reviewed relevant studies to provide a framework for future research. EVIDENCE ACQUISITION We conducted a systematic literature search on PubMed, Web of Science, Springerlink, CNKI, VIP, SinoMed, and Wanfang up to the period of October 2018. A random-effects meta-analysis model was used to derive pooled effect estimates. EVIDENCE SYNTHESIS A total of 13 studies were retrieved of which 5 studies explained the prevention and 8 studies explained the treatment for OC. Our pooled results showed that metformin has a potential preventive effect on OC in diabetic women (pooled odds ratio [OR] 0.62, 95% confidence interval [95% CI] 0.34, 1.11; P<0.001). In addition, metformin can also significantly prolong progression-free survival (PFS) (pooled hazard ratio [HR] 0.49, 95% CI 0.34, 0.70; P=0.002), and overall survival (OS) (HR 0.71, 95%CI 0.61, 0.82; P<0.001) in patients with OC, regardless of whether they had diabetes. CONCLUSIONS The use of metformin can potentially reduce the risk of OC among diabetics, and it also can significantly improve PFS and OS in patients with OC. A further large clinical investigation would be needed to adopt our finding in practice, however, our systematic review provides an insight for future study designs.
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Affiliation(s)
- Min-Zhen Lu
- Second Clinical Medical College of Southern Medical University, Guangzhou, China -
| | - De-Yu Li
- Department of Oncology, Fujian Provincial Hospital, Fujian, China
| | - Xue-Feng Wang
- Department of Obstetrics and Gynecology, Third Hospital of Southern Medical University, Guangzhou, China
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22
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Dong Y, Qi Y, Jiang H, Mi T, Zhang Y, Peng C, Li W, Zhang Y, Zhou Y, Zang Y, Li J. The development and benefits of metformin in various diseases. Front Med 2023; 17:388-431. [PMID: 37402952 DOI: 10.1007/s11684-023-0998-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/01/2023] [Indexed: 07/06/2023]
Abstract
Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
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Affiliation(s)
- Ying Dong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yingbei Qi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Haowen Jiang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Tian Mi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yunkai Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chang Peng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wanchen Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yongmei Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Yubo Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
| | - Yi Zang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Lingang Laboratory, Shanghai, 201203, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
| | - Jia Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
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23
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Ma Q, Sun J, Wang H, Zhou C, Li C, Wu Y, Wen Y, Zhang X, Ren X, Guo Z, Gong L, Zhang W. Far upstream element-binding protein 1 confers lobaplatin resistance by transcriptionally activating PTGES and facilitating the arachidonic acid metabolic pathway in osteosarcoma. MedComm (Beijing) 2023; 4:e257. [PMID: 37180822 PMCID: PMC10170244 DOI: 10.1002/mco2.257] [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: 10/18/2022] [Revised: 03/02/2023] [Accepted: 03/14/2023] [Indexed: 05/16/2023] Open
Abstract
Drug resistance is a major obstacle in cancer treatment and recurrence prevention and leads to poor outcomes in patients suffering from osteosarcoma. Clarification of the mechanism of drug resistance and exploration of effective strategies to overcome this obstacle could lead to clinical benefits for these patients. The expression of far upstream element-binding protein 1 (FUBP1) was found to be markedly elevated in osteosarcoma cell lines and clinical specimens compared with osteoblast cells and normal bone specimens. High expression of FUBP1 was correlated with a more aggressive phenotype and a poor prognosis in osteosarcoma patients. We found that overexpression of FUBP1 confers lobaplatin resistance, whereas the inhibition of FUBP1 sensitizes osteosarcoma cells to lobaplatin-induced cytotoxicity both in vivo and in vitro. Chromatin immunoprecipitation-seq and RNA-seq were performed to explore the potential mechanism. It was revealed that FUBP1 could regulate the transcription of prostaglandin E synthase (PTGES) and subsequently activate the arachidonic acid (AA) metabolic pathway, which leads to resistance to lobaplatin. Our investigation provides evidence that FUBP1 is a potential therapeutic target for osteosarcoma patients. Targeting FUBP1, its downstream target PTGES and the AA metabolic pathway may be promising strategies for sensitizing chemoresistant osteosarcoma cells to lobaplatin.
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Affiliation(s)
- Qiong Ma
- Department of PathologyTangdu HospitalAir Force Medical UniversityXi'anChina
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Jin Sun
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Huan Wang
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Chengpei Zhou
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Chenyu Li
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Yonghong Wu
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Yanhua Wen
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Xiaoyu Zhang
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Xingguang Ren
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Zheng Guo
- Orthopedic Oncology InstituteDepartment of Orthopedic SurgeryTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Li Gong
- Department of PathologyTangdu HospitalAir Force Medical UniversityXi'anChina
| | - Wei Zhang
- Department of PathologyTangdu HospitalAir Force Medical UniversityXi'anChina
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24
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Ghavami G, Kiasari RE, Pakzad F, Sardari S. Effect of metformin alone and in combination with etoposide and epirubicin on proliferation, apoptosis, necrosis, and migration of B-CPAP and SW cells as thyroid cancer cell lines. Res Pharm Sci 2023; 18:185-201. [PMID: 36873273 PMCID: PMC9976061 DOI: 10.4103/1735-5362.367797] [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: 04/03/2022] [Revised: 08/27/2022] [Accepted: 01/07/2023] [Indexed: 01/20/2023] Open
Abstract
Background and purpose There has not been a comprehensive study on the simultaneous effects of metformin, etoposide, and epirubicin on thyroid cancer cells. Hence, the current research proposed the in vitro study on the effect of metformin alone and in combination with etoposide and epirubicin on the rate of proliferation, apoptosis, necrosis, and migration against B-CPAP and SW-1736 cells as thyroid cancer cell lines. Experimental approach MTT-based proliferation assay, combination index method, flow cytometry, and scratch wound healing assays were used to evaluate the simultaneous effects of the three approved drugs against thyroid cancer cells. Findings/Results This study showed that the toxic concentration of metformin on normal Hu02 cells was more than 10 folds higher than B-CPAP and SW cancerous cells. Metformin in combination with epirubicin and etoposide could increase percentages of B-CPAP and SW cells in early and late apoptosis and necrosis phases in comparison with their single concentrations, significantly. Metformin in combination with epirubicin and etoposide could arrest the S phase in B-CPAP and SW cells, significantly. Metformin in combination with epirubicin and etoposide could reduce ~100% migration rate, whereas single concentrations of epirubicin and etoposide could reduce ~50% migration rate. Conclusion and implication Combined treatment of metformin with anticancer drugs epirubicin and etoposide can increase the mortality in thyroid cancer cell lines and reduce the toxicity of these drugs on the normal cell line, which could be the starting point for proposing a new combination strategy in the therapy of thyroid cancer to induce more potency and reduce acute toxicity.
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Affiliation(s)
- Ghazaleh Ghavami
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, I.R. Iran
| | - Ramin Ebrahimi Kiasari
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, I.R. Iran
| | - Faezeh Pakzad
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, I.R. Iran
| | - Soroush Sardari
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, I.R. Iran
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25
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Novel Anti-Cancer Products Targeting AMPK: Natural Herbal Medicine against Breast Cancer. MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28020740. [PMID: 36677797 PMCID: PMC9863744 DOI: 10.3390/molecules28020740] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/01/2023] [Accepted: 01/04/2023] [Indexed: 01/15/2023]
Abstract
Breast cancer is a common cancer in women worldwide. The existing clinical treatment strategies have been able to limit the progression of breast cancer and cancer metastasis, but abnormal metabolism, immunosuppression, and multidrug resistance involving multiple regulators remain the major challenges for the treatment of breast cancer. Adenosine 5'-monophosphate (AMP)-Activated Protein Kinase (AMPK) can regulate metabolic reprogramming and reverse the "Warburg effect" via multiple metabolic signaling pathways in breast cancer. Previous studies suggest that the activation of AMPK suppresses the growth and metastasis of breast cancer cells, as well as stimulating the responses of immune cells. However, some other reports claim that the development and poor prognosis of breast cancer are related to the overexpression and aberrant activation of AMPK. Thus, the role of AMPK in the progression of breast cancer is still controversial. In this review, we summarize the current understanding of AMPK, particularly the comprehensive bidirectional functions of AMPK in cancer progression; discuss the pharmacological activators of AMPK and some specific molecules, including the natural products (including berberine, curcumin, (-)-epigallocatechin-3-gallate, ginsenosides, and paclitaxel) that influence the efficacy of these activators in cancer therapy; and elaborate the role of AMPK as a potential therapeutic target for the treatment of breast cancer.
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26
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Du Y, Zhu YJ, Zhou YX, Ding J, Liu JY. Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study. MOLECULAR BIOMEDICINE 2022; 3:41. [PMID: 36484892 PMCID: PMC9733765 DOI: 10.1186/s43556-022-00108-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/18/2022] [Indexed: 12/13/2022] Open
Abstract
Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20-30 μM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.
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Affiliation(s)
- Yang Du
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ya-Juan Zhu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yi-Xin Zhou
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Jing Ding
- grid.54549.390000 0004 0369 4060Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan China
| | - Ji-Yan Liu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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27
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Sakamoto K, Okabayashi K, Matsui S, Seishima R, Shigeta K, Kitagawa Y. Association of Tumor Pathological Response with the Use of Metformin During Neoadjuvant Chemoradiotherapy in Rectal and Esophageal/Gastroesophageal Cancer Patients: a Systematic Review and Meta-analysis. J Gastrointest Surg 2022; 26:2227-2236. [PMID: 35829868 DOI: 10.1007/s11605-022-05354-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/30/2022] [Indexed: 01/31/2023]
Abstract
PURPOSE Metformin has been reported to be associated with improved cancer prognosis when used in combination with chemotherapy and/or radiotherapy. In this study, we present a systematic review and meta-analyses of studies evaluating the association of tumor pathological response with the use of metformin during neoadjuvant chemoradiotherapy (NACRT) in rectal and esophageal/gastroesophageal cancer patients. METHODS We systematically searched databases for articles that compared concurrent metformin use with no metformin use in cancer patients treated with NACRT following the PRISMA 2020. The design and quality of the collected studies were reviewed, and meta-analyses were performed on the pathologic complete response (pCR) rate, tumor regression grade (TRG), T factor downstaging, and N factor downstaging. RESULTS Three databases were searched, and 220 papers were screened. Five retrospective cohort study papers were eligible for the meta-analysis, with a total of 2041 patients. The included papers contained only rectal and esophageal/gastroesophageal cancers. In the metformin group, the pCR rate was 26% [20-32%], and metformin was associated with the pCR rate (odds ratio [OR] = 0.51 [0.34-0.76], p < 0.01). Meta-regression analysis of the pCR rate showed a positive correlation with adenocarcinoma (coefficient = 0.13 [0.02-0.25], p = 0.03) and fluoropyrimidine anticancer drug use (coefficient = 0.01 [0.001-0.02], p = 0.03). CONCLUSIONS The results suggest that metformin is associated with pCR rate when used in combination with NACRT. The association of metformin and pCR rate in combination with fluoropyrimidine anticancer drugs was observed mostly for adenocarcinoma patients.
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Affiliation(s)
- Kyoko Sakamoto
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Koji Okabayashi
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Shimpei Matsui
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Ryo Seishima
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Kohei Shigeta
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 1608582, Japan
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Cheung YMM, Hughes M, Harrod J, Files J, Kirkner G, Buckley L, Lin NU, Tolaney SM, McDonnell ME, Min L. The Effects of Diabetes and Glycemic Control on Cancer Outcomes in Individuals With Metastatic Breast Cancer. J Clin Endocrinol Metab 2022; 107:2511-2521. [PMID: 35766387 PMCID: PMC9761575 DOI: 10.1210/clinem/dgac375] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Indexed: 01/08/2023]
Abstract
BACKGROUND It is unclear whether diabetes and glycemic control affects the outcomes of breast cancer, especially among those with metastatic disease. This study aims to determine the impact of diabetes and hyperglycemia on cancer progression and mortality in individuals with metastatic breast cancer (MBC). METHODS Patients with a diagnosis of MBC between 2010 and 2021 were identified using the MBC database at 2 academic institutions. We evaluated the effects of diabetes and glycemic control on overall survival (OS) and time to next treatment (TTNT). RESULTS We compared 244 patients with diabetes (median age 57.6 years) to 244 patients without diabetes (matched for age, sex, ethnicity, and receptor subtype). OS at 5 years [diabetes: 54% (95% CI 47-62%) vs controls: 56% (95% CI 49-63%), P = 0.65] and TTNT at 1 year [diabetes: 43% (95% CI 36-50%) vs controls: 44% (95% CI 36-51%), P = 0.33] were similar between groups. A subgroup analysis comparing those with good glycemic control and those with poor glycemic control among patients with specific receptor subtype profiles showed no differences in OS at 5 years or TTNT at 1 year. In an 8-year landmark subgroup analysis, there was worse OS among individuals with diabetes compared to controls, and OS was found to be better among those with good glycemic control compared to those with poor control. CONCLUSIONS Diabetes was not associated with increased mortality in individuals with MBC at 5 years. However, diabetes and hyperglycemia were associated with worse OS among a cohort of longer-term survivors. These findings suggest that individualized diabetes and glycemic goals should be considered in patients with MBC.
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Affiliation(s)
- Yee-Ming M Cheung
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA
- Department of Medicine, Endocrine Unit, Austin Hospital, University of Melbourne, Victoria, Australia
| | - Melissa Hughes
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
| | - Julia Harrod
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA
| | - Janet Files
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
| | - Greg Kirkner
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
| | - Lauren Buckley
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
| | - Nancy U Lin
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
| | - Marie E McDonnell
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA
| | - Le Min
- Correspondence: Le Min, MD, PhD, Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA 02115, USA.
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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: 16] [Impact Index Per Article: 5.3] [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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El Zarif T, Yibirin M, De Oliveira-Gomes D, Machaalani M, Nawfal R, Bittar G, Bahmad HF, Bitar N. Overcoming Therapy Resistance in Colon Cancer by Drug Repurposing. Cancers (Basel) 2022; 14:cancers14092105. [PMID: 35565237 PMCID: PMC9099737 DOI: 10.3390/cancers14092105] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Despite improvements in standardized screening methods and the development of promising therapies for colorectal cancer (CRC), survival rates are still low. Drug repurposing offers an affordable solution to achieve new indications for previously approved drugs that could play a protagonist or adjuvant role in the treatment of CRC. In this review, we summarize the current data supporting drug repurposing as a feasible option for patients with CRC. Abstract Colorectal cancer (CRC) is the third most common cancer in the world. Despite improvement in standardized screening methods and the development of promising therapies, the 5-year survival rates are as low as 10% in the metastatic setting. The increasing life expectancy of the general population, higher rates of obesity, poor diet, and comorbidities contribute to the increasing trends in incidence. Drug repurposing offers an affordable solution to achieve new indications for previously approved drugs that could play a protagonist or adjuvant role in the treatment of CRC with the advantage of treating underlying comorbidities and decreasing chemotherapy toxicity. This review elaborates on the current data that supports drug repurposing as a feasible option for patients with CRC with a focus on the evidence and mechanism of action promising repurposed candidates that are widely used, including but not limited to anti-malarial, anti-helminthic, anti-inflammatory, anti-hypertensive, anti-hyperlipidemic, and anti-diabetic agents.
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Affiliation(s)
- Talal El Zarif
- Faculty of Medicine, Lebanese University, Beirut 1003, Lebanon; (T.E.Z.); (M.M.); (R.N.)
| | - Marcel Yibirin
- Internal Medicine Residency Program, Department of Medicine, Boston University Medical Center, Boston, MA 02218, USA;
| | - Diana De Oliveira-Gomes
- Department of Research, Foundation for Clinic, Public Health, and Epidemiological Research of Venezuela (FISPEVEN), Caracas 1050, Venezuela;
| | - Marc Machaalani
- Faculty of Medicine, Lebanese University, Beirut 1003, Lebanon; (T.E.Z.); (M.M.); (R.N.)
| | - Rashad Nawfal
- Faculty of Medicine, Lebanese University, Beirut 1003, Lebanon; (T.E.Z.); (M.M.); (R.N.)
| | | | - Hisham F. Bahmad
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Correspondence: ; Tel.: +1-786-961-0216
| | - Nizar Bitar
- Head of Hematology-Oncology Division, Sahel General Hospital, Beirut 1002, Lebanon;
- President of the Lebanese Society of Medical Oncology (LSMO), Beirut 1003, Lebanon
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Mascaraque-Checa M, Gallego-Rentero M, Nicolás-Morala J, Portillo-Esnaola M, Cuezva JM, González S, Gilaberte Y, Juarranz Á. Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy. Mol Metab 2022; 60:101496. [PMID: 35405370 PMCID: PMC9048115 DOI: 10.1016/j.molmet.2022.101496] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 11/25/2022] Open
Abstract
Objective Cancer metabolic reprogramming promotes resistance to therapies. In this study, we addressed the role of the Warburg effect in the resistance to photodynamic therapy (PDT) in skin squamous cell carcinoma (sSCC). Furthermore, we assessed the effect of metformin treatment, an antidiabetic type II drug that modulates metabolism, as adjuvant to PDT. Methods For that, we have used two human SCC cell lines: SCC13 and A431, called parental (P) and from these cell lines we have generated the corresponding PDT resistant cells (10GT). Results Here, we show that 10GT cells induced metabolic reprogramming to an enhanced aerobic glycolysis and reduced activity of oxidative phosphorylation, which could influence the response to PDT. This result was also confirmed in P and 10GT SCC13 tumors developed in mice. The treatment with metformin caused a reduction in aerobic glycolysis and an increase in oxidative phosphorylation in 10GT sSCC cells. Finally, the combination of metformin with PDT improved the cytotoxic effects on P and 10GT cells. The combined treatment induced an increase in the protoporphyrin IX production, in the reactive oxygen species generation and in the AMPK expression and produced the inhibition of AKT/mTOR pathway. The greater efficacy of combined treatments was also seen in vivo, in xenografts of P and 10GT SCC13 cells. Conclusions Altogether, our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC.
Cell resistant to Photodynamic therapy (PDT) is due to the metabolic reprogramming. Metformin modulates energetic metabolism in PDT-resistant cells, sensitizing to PDT. Metformin increases protoporphyrin IX and reactive oxygen species generation. Metformin+PDT is proposed as potential therapy against skin squamous cell carcinoma.
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Increased LZTS1 expression is associated with a good response to paclitaxel-based chemotherapy in breast cancer. Pathol Res Pract 2022; 234:153915. [PMID: 35500500 DOI: 10.1016/j.prp.2022.153915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/09/2022] [Accepted: 04/22/2022] [Indexed: 11/21/2022]
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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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Jiang S, Luo Y, Zhan Z, Tang Z, Zou J, Ying Y, Lin H, Huang D, Luo L. AMP-activated protein kinase re-sensitizes A549 to paclitaxel via up-regulating solute carrier organic anion transporter family member 1B3 expression. Cell Signal 2022; 91:110215. [PMID: 34920124 DOI: 10.1016/j.cellsig.2021.110215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 11/03/2022]
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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: 52] [Impact Index Per Article: 17.3] [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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Tawfik SM, Abdollah MRA, Elmazar MM, El-Fawal HAN, Abdelnaser A. Effects of Metformin Combined With Antifolates on HepG2 Cell Metabolism and Cellular Proliferation. Front Oncol 2022; 12:828988. [PMID: 35186762 PMCID: PMC8851913 DOI: 10.3389/fonc.2022.828988] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 01/11/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most prevalent types of cancers worldwide, continues to maintain high levels of resistance to standard therapy. As clinical data revealed poor response rates, the need for developing new methods has increased to improve the overall wellbeing of patients with HCC. Furthermore, a growing body of evidence shows that cancer metabolic changes are a key feature of many types of human malignancies. Metabolic reprogramming refers to cancer cells’ ability to change their metabolism in order to meet the increased energy demand caused by continuous growth, rapid proliferation, and other neoplastic cell characteristics. For these reasons, metabolic pathways may become new therapeutic and chemopreventive targets. The aim of this study was to investigate the metabolic alterations associated with metformin (MET), an anti-diabetic agent when combined with two antifolate drugs: trimethoprim (TMP) or methotrexate (MTX), and how metabolic changes within the cancer cell may be used to increase cellular death. In this study, single drugs and combinations were investigated using in vitro assays including cytotoxicity assay (MTT), RT-qPCR, annexin V/PI apoptosis assay, scratch wound assay and Seahorse XF analysis, on a human HCC cell line, HepG2. The cytotoxicity assay showed that the IC50 of MET as single therapy was 44.08 mM that was reduced to 22.73 mM and 29.29 mM when combined with TMP and MTX, respectively. The co-treatment of both drugs increased p53 and Bax apoptotic markers, while decreased the anti-apoptotic marker; Bcl-2. Both combinations increased the percentage of apoptotic cells and halted cancer cell migration when compared to MET alone. Furthermore, both combinations decreased the MET-induced increase in glycolysis, while also inducing mitochondrial damage, altering cancer cell bioenergetics. These findings provide an exciting insight into the anti-proliferative and apoptotic effects of MET and anti-folates on HepG2 cells, and how in combination, may potentially combat the aggressiveness of HCC.
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Affiliation(s)
- Sherouk M Tawfik
- Department of Chemistry, School of Sciences and Engineering, The American University in Cairo, Cairo, Egypt.,Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt.,The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Maha R A Abdollah
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt.,The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Mohey M Elmazar
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Hassan A N El-Fawal
- Institute of Global Public Health, School of Sciences and Engineering, The American University in Cairo, Cairo, Egypt
| | - Anwar Abdelnaser
- Institute of Global Public Health, School of Sciences and Engineering, The American University in Cairo, Cairo, Egypt
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Cho AR, Park WY, Lee HJ, Sim DY, Im E, Park JE, Ahn CH, Shim BS, Kim SH. Antitumor Effect of Morusin via G1 Arrest and Antiglycolysis by AMPK Activation in Hepatocellular Cancer. Int J Mol Sci 2021; 22:10619. [PMID: 34638959 PMCID: PMC8508967 DOI: 10.3390/ijms221910619] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/27/2021] [Accepted: 09/27/2021] [Indexed: 12/29/2022] Open
Abstract
Though Morusin isolated from the root of Morus alba was known to have antioxidant, anti-inflammatory, antiangiogenic, antimigratory, and apoptotic effects, the underlying antitumor effect of Morusin is not fully understood on the glycolysis of liver cancers. Hence, in the current study, the antitumor mechanism of Morusin was explored in Hep3B and Huh7 hepatocellular carcninomas (HCC) in association with glycolysis and G1 arrest. Herein, Morusin significantly reduced the viability and the number of colonies in Hep3B and Huh7 cells. Moreover, Morusin significantly increased G1 arrest, attenuated the expression of cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) and upregulated p21 and p27 in Hep3B and Huh7 cells. Interestingly, Morusin significantly activated phosphorylation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) but attenuated the expression of the p-mammalian target of protein kinase B (AKT), rapamycin (mTOR), c-Myc, hexokinase 2(HK2), pyruvate kinases type M2 (PKM2), and lactate dehydrogenase (LDH) in Hep3B and Huh7 cells. Consistently, Morusin suppressed lactate, glucose, and adenosine triphosphate (ATP) in Hep3B and Huh7 cells. Conversely, the AMPK inhibitor compound C reduced the ability of Morusin to activate AMPK and attenuate the expression of p-mTOR, HK2, PKM2, and LDH-A and suppressed G1 arrest induced by Morusin in Hep3B cells. Overall, these findings suggest that Morusin exerts an antitumor effect in HCCs via AMPK mediated G1 arrest and antiglycolysis as a potent dietary anticancer candidate.
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Affiliation(s)
| | | | | | | | | | | | | | - Bum-Sang Shim
- Molecular Cancer Target Herbal Research Laboratory, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (A.-R.C.); (W.-Y.P.); (H.-J.L.); (D.-Y.S.); (E.I.); (J.-E.P.); (C.-H.A.)
| | - Sung-Hoon Kim
- Molecular Cancer Target Herbal Research Laboratory, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; (A.-R.C.); (W.-Y.P.); (H.-J.L.); (D.-Y.S.); (E.I.); (J.-E.P.); (C.-H.A.)
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Deguchi T, Hosoya K, Kim S, Murase Y, Yamamoto K, Bo T, Yasui H, Inanami O, Okumura M. Metformin preferentially enhances the radio-sensitivity of cancer stem-like cells with highly mitochondrial respiration ability in HMPOS. MOLECULAR THERAPY-ONCOLYTICS 2021; 22:143-151. [PMID: 34514095 PMCID: PMC8413836 DOI: 10.1016/j.omto.2021.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 08/12/2021] [Indexed: 01/06/2023]
Abstract
Metformin has many anti-cancer effects, alone or in combination with radiation. However, the mechanism underlying its radio-sensitized effect is still unclear, especially for cancer stem-like cells (CSCs). Here, the radio-sensitized effect of metformin was investigated, and its mechanism was revealed in CSCs derived from canine osteosarcoma cell line (HMPOS), a canine osteosarcoma cell line. Spheroid cells (SCs) were used as CSCs-rich cells derived from sphere formation, and SCs were compared with normal adherent culture cells (ACs). The radio-sensitizing effect of metformin using clonogenic assay and tumor growth in mice xenograft model were evaluated, and the mechanism of its radio-sensitization focusing on mitochondrial function was revealed. Metformin significantly enhanced radio-sensitivity of SCs through its inhibition of the mitochondrial function, as shown by decreased oxygen consumption, decreased mitochondrial membrane potential, and decreased ATP production. Additionally, SCs had a higher ability of mitochondrial respiration than ACs, which may have caused difference of their sensitivity of metformin and irradiation. In conclusion, mitochondrial function might play an important role in the sensitivity of metformin and irradiation, and drugs that target mitochondrial respiration, such as metformin, are promising radio-sensitizers to target CSCs.
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Affiliation(s)
- Tatsuya Deguchi
- Laboratory of Veterinary Surgery, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
| | - Kenji Hosoya
- Laboratory of Veterinary Surgery, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
| | - Shango Kim
- Laboratory of Veterinary Surgery, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
| | - Yusuke Murase
- Laboratory of Veterinary Surgery, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
| | - Kumiko Yamamoto
- Laboratory of Radiation Biology, Department of Applied Veterinary Science, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
| | - Tomoki Bo
- Laboratory of Radiation Biology, Department of Applied Veterinary Science, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
| | - Hironobu Yasui
- Laboratory of Radiation Biology, Department of Applied Veterinary Science, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
| | - Osamu Inanami
- Laboratory of Radiation Biology, Department of Applied Veterinary Science, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
| | - Mahiro Okumura
- Laboratory of Veterinary Surgery, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9 Sapporo, Hokkaido 060-0818, Japan
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Tsakiridis EE, Broadfield L, Marcinko K, Biziotis OD, Ali A, Mekhaeil B, Ahmadi E, Singh K, Mesci A, Zacharidis PG, Anagnostopoulos AE, Berg T, Muti P, Steinberg GR, Tsakiridis T. Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses. Transl Oncol 2021; 14:101209. [PMID: 34479029 PMCID: PMC8411238 DOI: 10.1016/j.tranon.2021.101209] [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: 06/14/2021] [Revised: 08/03/2021] [Accepted: 08/18/2021] [Indexed: 11/05/2022] Open
Abstract
Combined metformin + salicylate treatment has improved anti-tumor efficacy in prostate cancer. At clinically achievable doses, it induces increased metabolic stress and sensitizes tumors to radiation. Metformin + salicylate blocks pathways of de novo lipogenesis and protein synthesis. In combination with radiation suppresses HIF1a and DNA replication. This work supports clinical investigation of metformin + salicylate in combination with radiotherapy. Background There is need for well-tolerated therapies for prostate cancer (PrCa) secondary prevention and to improve response to radiotherapy (RT). The anti-diabetic agent metformin (MET) and the aspirin metabolite salicylate (SAL) are shown to activate AMP-activated protein kinase (AMPK), suppress de novo lipogenesis (DNL), the mammalian target of rapamycin (mTOR) pathway and reduce PrCa proliferation in-vitro. The purpose of this study was to examine whether combined MET+SAL treatment could provide enhanced PrCa tumor suppression and improve response to RT. Methods Androgen-sensitive (22RV1) and resistant (PC3, DU-145) PrCa cells and PC3 xenografts were used to examine whether combined treatment with MET+SAL can provide improved anti-tumor activity compared to each agent alone in non-irradiated and irradiated PrCa cells and tumors. Mechanisms of action were investigated with analysis of signaling events, mitochondria respiration and DNL activity assays. Results We observed that PrCa cells are resistant to clinically relevant doses of MET. Combined MET + SAL treatment provides synergistic anti-proliferative activity at clinically relevant doses and enhances the anti-proliferative effects of RT. This was associated with suppression of oxygen consumption rate (OCR), activation of AMPK, suppression of acetyl-CoA carboxylase (ACC)-DNL and mTOR-p70s6k/4EBP1 and HIF1α pathways. MET + SAL reduced tumor growth in non-irradiated tumors and enhanced the effects of RT. Conclusion MET+SAL treatment suppresses PrCa cell proliferation and tumor growth and enhances responses to RT at clinically relevant doses. Since MET and SAL are safe, widely-used and inexpensive agents, these data support the investigation of MET+SAL in PrCa clinical trials alone and in combination with RT.
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Affiliation(s)
- Evangelia E Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Lindsay Broadfield
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Katarina Marcinko
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Olga-Demetra Biziotis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Amr Ali
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Bassem Mekhaeil
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Elham Ahmadi
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Kanwaldeep Singh
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Aruz Mesci
- Department of Radiation Oncology, Juravinski Cancer Center, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada
| | - Panayiotis G Zacharidis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Alexander E Anagnostopoulos
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Tobias Berg
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Paola Muti
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Gregory R Steinberg
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Theodoros Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Radiation Oncology, Juravinski Cancer Center, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada.
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Qin S, Ingle JN, Kim W, Gao H, Weinshilboum RM, Wang L. ZNF423 modulates the AMP-activated protein kinase pathway and metformin response in a single nucleotide polymorphisms, estrogen and selective estrogen receptor modulator dependent fashion. Pharmacogenet Genomics 2021; 31:155-164. [PMID: 34001842 PMCID: PMC8340948 DOI: 10.1097/fpc.0000000000000435] [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: 01/12/2021] [Accepted: 03/24/2021] [Indexed: 11/26/2022]
Abstract
OBJECTIVES We previously discovered that the single nucleotide polymorphisms (SNP) rs9940645 in the ZNF423 gene regulate ZNF423 expression and serve as a potential biomarker for response to selective estrogen receptor modulators (SERMs). Here we explored pathways involved in ZNF423-mediated SERMs response and drugs that potentially sensitize SERMs. METHODS RNA sequencing and label-free quantitative proteomics were performed to identify genes and pathways that are regulated by ZNF423 and the ZNF423 SNP. Both cultured cells and mouse xenograft models with different ZNF423 SNP genotypes were used to study the cellular responses to metformin. RESULTS We identified ribosome and AMP-activated protein kinase (AMPK) signaling as potential pathways regulated by ZNF423 or ZNF423 rs9940645 SNP. Moreover, using clustered regularly interspaced short palindromic repeats/Cas9-engineered ZR75-1 breast cancer cells with different ZNF423 SNP genotypes, striking differences in cellular responses to metformin, either alone or in the combination of tamoxifen, were observed in both cell culture and the mouse xenograft model. CONCLUSIONS We found that AMPK signaling is modulated by the ZNF423 rs9940645 SNP in estrogen and SERM-dependent fashion. The ZNF423 rs9940645 SNP affects metformin response in breast cancer and could be a potential biomarker for tailoring the metformin treatment.
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Affiliation(s)
- Sisi Qin
- Department of Molecular Pharmacology and Experimental Therapeutics
| | - James N. Ingle
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Wootae Kim
- Department of Molecular Pharmacology and Experimental Therapeutics
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Huanyao Gao
- Department of Molecular Pharmacology and Experimental Therapeutics
| | | | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics
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Zhu Z, Jiang T, Suo H, Xu S, Zhang C, Ying G, Yan Z. Metformin Potentiates the Effects of Anlotinib in NSCLC via AMPK/mTOR and ROS-Mediated Signaling Pathways. Front Pharmacol 2021; 12:712181. [PMID: 34421608 PMCID: PMC8373262 DOI: 10.3389/fphar.2021.712181] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 07/21/2021] [Indexed: 12/24/2022] Open
Abstract
Anlotinib is a novel multi-targeted tyrosine kinase inhibitor with activity against soft tissue sarcoma, small cell lung cancer, and non-small cell lung cancer (NSCLC). Potentiating the anticancer effect of anlotinib in combination strategies remains a clinical challenge. Metformin is an oral agent that is used as a first-line therapy for type 2 diabetes. Interesting, metformin also exerts broad anticancer effects through the activation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR). Here, we evaluated the possible synergistic effect of anlotinib and metformin in NSCLC cells. The results showed that metformin enhanced the antiproliferative effect of anlotinib. Moreover, anlotinib combined with metformin induced apoptosis and oxidative stress, which was associated with the activation of AMPK and inhibition of mTOR. Reactive oxygen species (ROS)- mediated p38/JNK MAPK and ERK signaling may be involved in the anticancer effects of this combination treatment. Our results show that metformin potentiates the efficacy of anlotinib in vivo by increasing the sensitivity of NSCLC cells to the drug. These data provide a potential rationale for the combination of anlotinib and metformin for the treatment of patients with NSCLC or other cancers.
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Affiliation(s)
- Zhongling Zhu
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Teng Jiang
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Huirong Suo
- Department of Pharmacy, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Shan Xu
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Cai Zhang
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Guoguang Ying
- Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zhao Yan
- Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Continuing Education and Science and Technology Service, China Anti-cancer Association, Tianjin, China
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Tsakiridis T, Pond GR, Wright J, Ellis PM, Ahmed N, Abdulkarim B, Roa W, Robinson A, Swaminath A, Okawara G, Wierzbicki M, Valdes M, Levine M. Metformin in Combination With Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: The OCOG-ALMERA Randomized Clinical Trial. JAMA Oncol 2021; 7:1333-1341. [PMID: 34323924 DOI: 10.1001/jamaoncol.2021.2328] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Importance Unresected locally advanced non-small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied. Objective To examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC. Design, Setting, and Participants The Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019. Interventions Patients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months. Main Outcomes and Measures The primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis. Results The trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival rate was 34.8% (95% CI, 16.6%-53.7%) in the metformin arm and 63.0% (95% CI, 42.1%-78.1%) in the control arm (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 47.4% (95% CI, 26.3%-65.9%) in the metformin arm and 85.2% (95% CI, 65.2%-94.2%) in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event. Conclusions and Relevance In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT02115464.
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Affiliation(s)
- Theodoros Tsakiridis
- Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada.,Department of Oncology, McMaster University, Hamilton, Ontario, Canada.,Walker Family Cancer Center, St Catharines, Ontario, Canada
| | - Gregory R Pond
- Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada.,Department of Oncology, McMaster University, Hamilton, Ontario, Canada.,Ontario Clinical Oncology Group, Hamilton, Ontario, Canada
| | - Jim Wright
- Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada.,Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Peter M Ellis
- Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada.,Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Naseer Ahmed
- Cancer Care Manitoba, Winnipeg, Manitoba, Canada
| | | | - Wilson Roa
- Cross Cancer Institute, Edmonton, Alberta, Canada
| | | | - Anand Swaminath
- Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada.,Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Gordon Okawara
- Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada.,Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Marcin Wierzbicki
- Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada.,Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Mario Valdes
- Grand River Cancer Center, Kitchener, Ontario, Canada
| | - Mark Levine
- Juravinski Cancer Center, Hamilton Health Science, Hamilton, Ontario, Canada.,Department of Oncology, McMaster University, Hamilton, Ontario, Canada.,Ontario Clinical Oncology Group, Hamilton, Ontario, Canada
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Biguanides drugs: Past success stories and promising future for drug discovery. Eur J Med Chem 2021; 224:113726. [PMID: 34364161 DOI: 10.1016/j.ejmech.2021.113726] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 07/27/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022]
Abstract
Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment.
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Veeramachaneni R, Yu W, Newton JM, Kemnade JO, Skinner HD, Sikora AG, Sandulache VC. Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects. J Immunother Cancer 2021; 9:jitc-2021-002773. [PMID: 34230113 PMCID: PMC8261884 DOI: 10.1136/jitc-2021-002773] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Metformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can also generate immunomodulatory effects in solid tumors and is currently being investigated as an adjunct to immune checkpoint inhibitors (ICIs). We hypothesized that metformin would generate a shift in immunity unfavorable to tumor growth and tested this hypothesis in a preclinical model of head and neck cancer. METHODS Using a syngeneic mouse model of human papillomavirus-associated head and neck cancer (mEER/MTEC), we tested the impact of metformin on systemic and local immunity and tumor growth velocity. We compared the effects of acute and chronic treatment regimens on immunocyte presence and activation using a combination of flow cytometry and targeted transcriptomic analysis. RESULTS Acute metformin exposure generated measurable shifts in systemic myeloid and T-cell populations in non-tumor-bearing mice and decreased myeloid derived suppressor cell (MDSC) levels in tumor draining lymph nodes of tumor-bearing mice. Although metformin decreased regulatory T-cell (T-reg) and MDSC levels and increased CD8+ levels in murine tumors when combined with ICIs, acute metformin exposure was insufficient to generate substantial antitumor activity. Conversely, long-term metformin treatment significantly reduced tumor growth velocity, increased the CD8+/T-reg ratio, increased tumor infiltrating lymphocyte levels and upregulated component genes of the previously validated T-cell inflamed expression profile. CONCLUSIONS Metformin generates complex systemic and local immune effects which vary as a function of treatment duration. Combinatorial strategies with ICIs must take into account both the complexity and variability of these effects in order to generate maximal antitumor activity in future clinical trials.
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Affiliation(s)
- Ratna Veeramachaneni
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Wangjie Yu
- Bobby R. Alford Department of Otolaryngology- Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Jared M Newton
- Bobby R. Alford Department of Otolaryngology- Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.,Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Jan O Kemnade
- Hematology/Oncology Section; Medical Care Line, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.,Hematology/Oncology Section, Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Heath D Skinner
- Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Andrew G Sikora
- Department of Head and Neck Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Vlad C Sandulache
- Bobby R. Alford Department of Otolaryngology- Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA .,ENT Section; Operative Care Line, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.,Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, 77030, Texas, USA
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Korsakova L, Krasko JA, Stankevicius E. Metabolic-targeted Combination Therapy With Dichloroacetate and Metformin Suppresses Glioblastoma Cell Line Growth In Vitro and In Vivo. In Vivo 2021; 35:341-348. [PMID: 33402483 DOI: 10.21873/invivo.12265] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIM We investigated the hypothesis that dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and metformin (MET), an antidiabetic agent and complex I inhibitor, have synergistic cytotoxic effects in glioblastoma cells in vitro and in vivo. MATERIALS AND METHODS We performed dose response experiments and combination index calculation. Apoptotic and necrotic cells were estimated by flow cytometry. Cell metabolism was evaluated by Seahorse analysis and lactate export. Overall survival and tumor volume growth experiments were performed in C57BL/6 mice GL-261 allograft model. RESULTS DCA and MET showed dose-dependent cytotoxicity and synergistic effects. DCA alleviated the increase in lactate production induced by MET. Seahorse analysis showed that DCA treatment results in increased oxygen consumption rate, which is decreased by MET. DCA and MET significantly inhibited tumor growth and increased overall survival in mice. CONCLUSION Compounds targeting tumor cell metabolism could become potential treatment options for glioblastoma multiforme.
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Affiliation(s)
- Laura Korsakova
- Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania;
| | | | - Edgaras Stankevicius
- Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania;
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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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Luo X, Chen X, Wang L, Yang B, Cai S. Metformin Adjunct With Antineoplastic Agents for the Treatment of Lung Cancer: A Meta-Analysis of Randomized Controlled Trials and Observational Cohort Studies. Front Pharmacol 2021; 12:639016. [PMID: 34149406 PMCID: PMC8209491 DOI: 10.3389/fphar.2021.639016] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 05/20/2021] [Indexed: 12/20/2022] Open
Abstract
Objective: Resistance to anticancer agents ensures a poor prognosis in patients with lung cancer. Metformin could enhance the anticancer effects of standard antineoplastic agents [traditional chemotherapy drugs, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), or immune checkpoint inhibitors (ICIs)]; however, it is unclear whether metformin can be combined with antineoplastic agents in the treatment of lung cancer. To explore the efficacy of combinational strategies, we performed a systematic review and meta-analysis for diabetic and non-diabetic patients with lung cancer. Method: An electronic literature search was performed to obtain relevant randomized controlled trials (RCTs) and observational cohort studies. Hazard ratios (HR) with 95% confidence intervals (CI) of overall survival (OS) and progression-free survival (PFS) outcomes were extracted. Subgroup analysis by antineoplastic agents, study type, histology and clinical stage were investigated. Results: 14 studies (three RCTs and eleven observational cohort studies) consisting 3,856 patients were included in the meta-analysis. Compared to standard antineoplastic agents alone (traditional chemotherapy drugs, EGFR-TKIs or ICIs), the antineoplastic agents combined with metformin significantly improved OS (HR 0.73, 95% CI 0.66–0.81, p < 0.00001) and PFS (HR 0.72, 95% CI 0.59–0.88, p = 0.001); a similar association was found in observational evidence. Limited data from RCTs showed no differences in OS or PFS. Conclusion: Metformin plus antineoplastic agents may improve survival outcomes of patients with lung cancer. Further investigation is needed.
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Affiliation(s)
- Xiaofeng Luo
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, China.,School of Pharmacy, China Medical University, Shenyang, China
| | - Xi Chen
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, China.,School of Pharmacy, China Medical University, Shenyang, China
| | - Lin Wang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, China.,School of Pharmacy, China Medical University, Shenyang, China
| | - Bowen Yang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
| | - Shuang Cai
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, China.,School of Pharmacy, China Medical University, Shenyang, China
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Molecular and Cellular Mechanisms of Metformin in Cervical Cancer. Cancers (Basel) 2021; 13:cancers13112545. [PMID: 34067321 PMCID: PMC8196882 DOI: 10.3390/cancers13112545] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. Metformin exerts anticancer effects, alone or in combination with other agents, on cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Abstract Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.
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Cunha Júnior AD, Bragagnoli AC, Costa FO, Carvalheira JBC. Repurposing metformin for the treatment of gastrointestinal cancer. World J Gastroenterol 2021; 27:1883-1904. [PMID: 34007128 PMCID: PMC8108031 DOI: 10.3748/wjg.v27.i17.1883] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/13/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus type 2 and cancer share many risk factors. The pleiotropic insulin-dependent and insulin-independent effects of metformin might inhibit pathways that are frequently amplified in neoplastic tissue. Particularly, modulation of inflammation, metabolism, and cell cycle arrest are potential therapeutic cancer targets utilized by metformin to boost the anti-cancer effects of chemotherapy. Studies in vitro and in vivo models have demonstrated the potential of metformin as a chemo- and radiosensitizer, besides its chemopreventive and direct therapeutic activity in digestive system (DS) tumors. Hence, these aspects have been considered in many cancer clinical trials. Case-control and cohort studies and associated meta-analyses have evaluated DS cancer risk and metformin usage, especially in colorectal cancer, pancreatic cancer, and hepatocellular carcinoma. Most clinical studies have demonstrated the protective role of metformin in the risk for DS cancers and survival rates. On the other hand, the ability of metformin to enhance the actions of chemotherapy for gastric and biliary cancers is yet to be investigated. This article reviews the current findings on the anti-cancer mechanisms of metformin and its apparatus from pre-clinical and ongoing studies in DS malignancies.
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Affiliation(s)
- Ademar Dantas Cunha Júnior
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | | | - Felipe Osório Costa
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
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Alimoradi N, Firouzabadi N, Fatehi R. Metformin and insulin-resistant related diseases: Emphasis on the role of microRNAs. Biomed Pharmacother 2021; 139:111662. [PMID: 34243629 DOI: 10.1016/j.biopha.2021.111662] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/16/2021] [Accepted: 04/22/2021] [Indexed: 12/14/2022] Open
Abstract
Metformin is one of the most prescribed drugs in type II diabetes (T2DM) which has recently found new applications in the prevention and treatment of various illnesses, from metabolic disorders to cardiovascular and age-related diseases. Metformin improves insulin resistance (IR) by modulating metabolic mechanisms and mitochondrial biogenesis. Alternation of microRNAs (miRs) in the treatment of IR-related illnesses has been observed by metformin therapy. MiRs are small non-coding RNAs that play important roles in RNA silencing, targeting the 3'untranslated region (3'UTR) of most mRNAs and inhibiting the translation of related proteins. As a result, their dysregulation is associated with many diseases. Metformin may alter miRs levels in the treatment of various diseases by AMPK-dependent or AMPK-independent mechanisms. Here, we summarized the therapeutic role of metformin by modifying the aberrant expression of miRs as potential biomarkers or therapeutic targets in diseases in which IR plays a key role.
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Affiliation(s)
- Nahid Alimoradi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Reihaneh Fatehi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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