Reference Citation Analysis: Find an Article, Find a Category, Find a Journal, Find a Scholar

For: Janjetovic K, Harhaji-Trajkovic L, Misirkic-Marjanovic M, Vucicevic L, Stevanovic D, Zogovic N, Sumarac-Dumanovic M, Micic D, Trajkovic V. In vitro and in vivo anti-melanoma action of metformin. Eur J Pharmacol 2011;668:373-82. [PMID: 21806981 DOI: 10.1016/j.ejphar.2011.07.004] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2011] [Revised: 05/20/2011] [Accepted: 07/07/2011] [Indexed: 02/07/2023]

For:	Janjetovic K, Harhaji-Trajkovic L, Misirkic-Marjanovic M, Vucicevic L, Stevanovic D, Zogovic N, Sumarac-Dumanovic M, Micic D, Trajkovic V. In vitro and in vivo anti-melanoma action of metformin. Eur J Pharmacol 2011;668:373-82. [PMID: 21806981 DOI: 10.1016/j.ejphar.2011.07.004] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2011] [Revised: 05/20/2011] [Accepted: 07/07/2011] [Indexed: 02/07/2023]

Number

Cited by Other Article(s)

Koltai T, Fliegel L. Exploring monocarboxylate transporter inhibition for cancer treatment. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024;5:135-169. [PMID: 38464385 PMCID: PMC10918235 DOI: 10.37349/etat.2024.00210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 12/01/2023] [Indexed: 03/12/2024] Open

Bashghareh A, Rastegar T, Modarresi P, Kazemzadeh S, Salem M, Hedayatpour A. Recovering Spermatogenesis By Protected Cryopreservation Using Metformin and Transplanting Spermatogonial Stem Cells Into Testis in an Azoospermia Mouse Model. Biopreserv Biobank 2024;22:68-81. [PMID: 37582284 DOI: 10.1089/bio.2022.0178] [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: 08/17/2023] Open

Abstract

Cryopreservation and transplantation of spermatogonial stem cells (SSCs) may serve as a new method to restore male fertility in patients undergoing chemotherapy or radiotherapy. However, SSCs may be damaged during cryopreservation due to the production of reactive oxygen species (ROS). Therefore, different antioxidants have been used as protective agents. Studies have shown that metformin (MET) has antioxidant activity. The aim of this study was to assess the antioxidant and antiapoptotic effects of MET in frozen-thawed SSCs. In addition, the effect of MET on the proliferation and differentiation of SSCs was evaluated. To this end, SSCs were isolated from mouse pups aged 3-6 days old, cultured, identified by flow cytometry (ID4, INTEGRIN β1+), and finally evaluated for survival and ROS rate. SSCs were transplanted after busulfan and cadmium treatment. Cryopreserved SSCs with and without MET were transplanted after 1 month of cryopreservation. Eight weeks after transplantation, the recipient testes were evaluated for the expression of apoptosis (BAX, BCL2), proliferation (PLZF), and differentiation (SCP3, TP1, TP2, PRM1) markers using immunohistochemistry, Western blot, and quantitative real-time polymerase chain reaction. The findings revealed that the survival rate of SSCs was higher in the 500 μm/mL MET group compared to the other groups (50 and 5000 μm/mL). MET significantly decreased the intracellular ROS production. Transplantation of SSCs increased the expression level of proliferation (PLZF) and differentiation (SCP3, TP1, TP2, PRM1) markers compared to azoospermia group, and their levels were significantly higher in the MET group compared to the cryopreservation group containing basic freezing medium (p < 0.05). MET increased the survival rate of SSCs, proliferation, and differentiation and decreased the ROS production and the apoptosis rate. Cryopreservation by MET seems to be effective in treating infertility.

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Boutaud M, Auger C, Verdier M, Christou N. Metformin Treatment Reduces CRC Aggressiveness in a Glucose-Independent Manner: An In Vitro and Ex Vivo Study. Cancers (Basel) 2023;15:3724. [PMID: 37509386 PMCID: PMC10378121 DOI: 10.3390/cancers15143724] [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: 03/29/2023] [Revised: 07/13/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open

Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther 2023;17:1907-1932. [PMID: 37397787 PMCID: PMC10312383 DOI: 10.2147/dddt.s409373] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/10/2023] [Indexed: 07/04/2023] Open

Hua Y, Zheng Y, Yao Y, Jia R, Ge S, Zhuang A. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J Transl Med 2023;21:403. [PMID: 37344841 DOI: 10.1186/s12967-023-04263-8] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 06/09/2023] [Indexed: 06/23/2023] Open

A novel cocrystal of metformin hydrochloride with citric acid: Systematic synthesis and computational simulation. Eur J Pharm Biopharm 2022;179:37-46. [PMID: 36041596 DOI: 10.1016/j.ejpb.2022.08.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 08/24/2022] [Indexed: 11/22/2022]

Feng SW, Chang PC, Chen HY, Hueng DY, Li YF, Huang SM. Exploring the Mechanism of Adjuvant Treatment of Glioblastoma Using Temozolomide and Metformin. Int J Mol Sci 2022;23:ijms23158171. [PMID: 35897747 PMCID: PMC9330793 DOI: 10.3390/ijms23158171] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/22/2022] [Accepted: 07/22/2022] [Indexed: 12/11/2022] Open

Abstract

Glioblastoma is the most frequent and lethal primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40–50% of all primary malignant brain tumors, with an annual incidence of 3–6 cases per 100,000 population. Despite maximum treatment, patients only have a median survival time of 15 months. Metformin is a biguanide drug utilized as the first-line medication in treating type 2 diabetes. Recently, researchers have noticed that metformin can contribute to antineoplastic activity. The objective of this study is to investigate the mechanism of metformin as a potential adjuvant treatment drug in glioblastoma. Glioblastoma cell lines U87MG, LNZ308, and LN229 were treated with metformin, and several cellular functions and metabolic states were evaluated. First, the proliferation capability was investigated using the MTS assay and BrdU assay, while cell apoptosis was evaluated using the annexin V assay. Next, a wound-healing assay and mesenchymal biomarkers (N-cadherin, vimentin, and Twist) were used to detect the cell migration ability and epithelial–mesenchymal transition (EMT) status of tumor cells. Gene set enrichment analysis (GSEA) was applied to the transcriptome of the metformin-treated glioblastoma cell line. Then, DCFH-DA and MitoSOX Red dyes were used to quantify reactive oxygen species (ROS) in the cytosol and mitochondria. JC-1 dye and Western blotting analysis were used to evaluate mitochondrial membrane potential and biogenesis. In addition, the combinatory effect of temozolomide (TMZ) with metformin treatment was assessed by combination index analysis. Metformin could decrease cell viability, proliferation, and migration, increase cell apoptosis, and disrupt EMT in all three glioblastoma cell lines. The GSEA study highlighted increased ROS and hypoxia in the metformin-treated glioblastoma cells. Metformin increased ROS production, impaired mitochondrial membrane potential, and reduced mitochondrial biogenesis. The combined treatment of metformin and TMZ had U87 as synergistic, LNZ308 as antagonistic, and LN229 as additive. Metformin alone or combined with TMZ could suppress mitochondrial transcription factor A, Twist, and O⁶-methylguanine-DNA methyltransferase (MGMT) proteins in TMZ-resistant LN229 cells. In conclusion, our study showed that metformin decreased metabolic activity, proliferation, migration, mitochondrial biogenesis, and mitochondrial membrane potential and increased apoptosis and ROS in some glioblastoma cells. The sensitivity of the TMZ-resistant glioblastoma cell line to metformin might be mediated via the suppression of mitochondrial biogenesis, EMT, and MGMT expression. Our work provides new insights into the choice of adjuvant agents in TMZ-resistant GBM therapy.

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Will We Unlock the Benefit of Metformin for Patients with Lung Cancer? Lessons from Current Evidence and New Hypotheses. Pharmaceuticals (Basel) 2022;15:ph15070786. [PMID: 35890085 PMCID: PMC9318003 DOI: 10.3390/ph15070786] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022] Open

Abstract Metformin has been under basic and clinical study as an oncological repurposing pharmacological agent for several years, stemming from observational studies which consistently evidenced that subjects who were treated with metformin had a reduced risk for development of cancer throughout their lives, as well as improved survival outcomes when diagnosed with neoplastic diseases. As a result, several basic science studies have attempted to dissect the relationship between metformin’s metabolic mechanism of action and antineoplastic cellular signaling pathways. Evidence in this regard was compelling enough that a myriad of randomized clinical trials was planned and conducted in order to establish the effect of metformin treatment for patients with diverse neoplasms, including lung cancer. As with most novel antineoplastic agents, early results from these studies have been mostly discouraging, though a recent analysis that incorporated body mass index may provide significant information regarding which patient subgroups might derive the most benefit from the addition of metformin to their anticancer treatment. Much in line with the current pipeline for anticancer agents, it appears that the benefit of metformin may be circumscribed to a specific patient subgroup. If so, addition of metformin to antineoplastic agents could prove one of the most cost-effective interventions proposed in the context of precision oncology. Currently published reviews mostly rely on a widely questioned mechanism of action by metformin, which fails to consider the differential effects of the drug in lean vs. obese subjects. In this review, we analyze the pre-clinical and clinical information available to date regarding the use of metformin in various subtypes of lung cancer and, further, we present evidence as to the differential metabolic effects of metformin in lean and obese subjects where, paradoxically, the obese subjects have reported more benefit with the addition of metformin treatment. The novel mechanisms of action described for this biguanide may explain the different results observed in clinical trials published in the last decade. Lastly, we present novel hypothesis regarding potential biomarkers to identify who might reap benefit from this intervention, including the role of prolyl hydroxylase domain 3 (PHD3) expression to modify metabolic phenotypes in malignant diseases. Collapse

Banella C, Catalano G, Travaglini S, Pelosi E, Ottone T, Zaza A, Guerrera G, Angelini DF, Niscola P, Divona M, Battistini L, Screnci M, Ammatuna E, Testa U, Nervi C, Voso MT, Noguera NI. Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment. Cancers (Basel) 2022;14:cancers14102565. [PMID: 35626170 PMCID: PMC9139619 DOI: 10.3390/cancers14102565] [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: 04/26/2022] [Revised: 05/17/2022] [Accepted: 05/20/2022] [Indexed: 02/01/2023] Open

Abstract

Simple Summary

Acute Myeloid Leukemias (AMLs) are rapidly progressive clonal neoplastic diseases. The overall 5-year survival rate is very poor: less than 5% in older patients aged over 65 years old. Elderly AML patients are often “unfit” for intensive chemotherapy, further highlighting the need of highly effective, well-tolerated new treatment options for AMLs. Growing evidence indicates that AML blasts feature a highly diverse and flexible metabolism consistent with the aggressiveness of the disease. Based on these evidences, we targeted the metabolic peculiarity and plasticity of AML cells with an association of ascorbate, which causes oxidative stress and interferes with hexokinase activity, and buformin, which completely shuts down mitochondrial contributions in ATP production. The ascorbate–buformin combination could be an innovative therapeutic option for elderly AML patients that are resistant to therapy.

Abstract

In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias’ (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate–buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options.

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Affiliation(s)

Cristina Banella Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (C.B.); (G.C.); (S.T.); (T.O.); (A.Z.) Department of Health Sciences, Meyer Children’s University Hospital, 50139 Florence, Italy
Gianfranco Catalano Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (C.B.); (G.C.); (S.T.); (T.O.); (A.Z.) Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Serena Travaglini Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (C.B.); (G.C.); (S.T.); (T.O.); (A.Z.) Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Elvira Pelosi Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (E.P.); (U.T.)
Tiziana Ottone Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (C.B.); (G.C.); (S.T.); (T.O.); (A.Z.) Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Alessandra Zaza Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (C.B.); (G.C.); (S.T.); (T.O.); (A.Z.) Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
Gisella Guerrera Neuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (G.G.); (D.F.A.); (L.B.)
Daniela Francesca Angelini Neuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (G.G.); (D.F.A.); (L.B.)
Pasquale Niscola Hematology Unit, Saint’ Eugenio Hospital, University of Rome Tor Vergata, 00144 Rome, Italy;
Mariadomenica Divona Policlinico Tor Vergata, University of Rome Tor Vergata, 00133 Rome, Italy;
Luca Battistini Neuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (G.G.); (D.F.A.); (L.B.)
Maria Screnci Banca Regionale Sangue Cordone Ombelicale UOC Immunoematologia e Medicina Trasfusionale, Policlinico Umberto I, 00161 Roma, Italy;
Emanuele Ammatuna Department of Hematology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
Ugo Testa Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (E.P.); (U.T.)
Clara Nervi Department of Medical and Surgical Sciences and Biotechnologies, University of Roma La Sapienza, 04100 Latina, Italy;
Maria Teresa Voso Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (C.B.); (G.C.); (S.T.); (T.O.); (A.Z.) Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Correspondence: (M.T.V.); (N.I.N.); Tel.: +39-06-501-703-225 (N.I.N.)
Nelida Ines Noguera Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy; (C.B.); (G.C.); (S.T.); (T.O.); (A.Z.) Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Correspondence: (M.T.V.); (N.I.N.); Tel.: +39-06-501-703-225 (N.I.N.)

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Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line. Int J Mol Sci 2022;23:ijms23042354. [PMID: 35216470 PMCID: PMC8876342 DOI: 10.3390/ijms23042354] [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: 01/26/2022] [Revised: 02/18/2022] [Accepted: 02/19/2022] [Indexed: 12/15/2022] Open

Catalani E, Giovarelli M, Zecchini S, Perrotta C, Cervia D. Oxidative Stress and Autophagy as Key Targets in Melanoma Cell Fate. Cancers (Basel) 2021;13:cancers13225791. [PMID: 34830947 PMCID: PMC8616245 DOI: 10.3390/cancers13225791] [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: 10/27/2021] [Revised: 11/10/2021] [Accepted: 11/17/2021] [Indexed: 01/18/2023] Open

Xu A, Lee J, Zhao Y, Wang Y, Li X, Xu P. Potential effect of EGCG on the anti-tumor efficacy of metformin in melanoma cells. J Zhejiang Univ Sci B 2021;22:548-562. [PMID: 34269008 DOI: 10.1631/jzus.b2000455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]

Yenmiş G, Beşli N, Yaprak Saraç E, Hocaoğlu Emre FS, Şenol K, Kanıgür G. Metformin promotes apoptosis in primary breast cancer cells by downregulation of cyclin D1 and upregulation of P53 through an AMPK-alpha independent mechanism. Turk J Med Sci 2021;51:826-834. [PMID: 33350292 PMCID: PMC8203121 DOI: 10.3906/sag-1908-112] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 12/17/2020] [Indexed: 12/25/2022] Open

Metformin mediated microRNA-7 upregulation inhibits growth, migration, and invasion of non-small cell lung cancer A549 cells. Anticancer Drugs 2021;31:345-352. [PMID: 31789625 PMCID: PMC7077962 DOI: 10.1097/cad.0000000000000875] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]

Vitali E, Boemi I, Tarantola G, Piccini S, Zerbi A, Veronesi G, Baldelli R, Mazziotti G, Smiroldo V, Lavezzi E, Spada A, Mantovani G, Lania AG. Metformin and Everolimus: A Promising Combination for Neuroendocrine Tumors Treatment. Cancers (Basel) 2020;12:2143. [PMID: 32748870 PMCID: PMC7464161 DOI: 10.3390/cancers12082143] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022] Open

Affiliation(s)

Eleonora Vitali Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center—IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 20089 Rozzano, Italy; (I.B.); (G.T.); (S.P.) Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
Ilena Boemi Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center—IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 20089 Rozzano, Italy; (I.B.); (G.T.); (S.P.)
Giulia Tarantola Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center—IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 20089 Rozzano, Italy; (I.B.); (G.T.); (S.P.) Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
Sara Piccini Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center—IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 20089 Rozzano, Italy; (I.B.); (G.T.); (S.P.) Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.)
Alessandro Zerbi Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.) Pancreas Surgery Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy
Giulia Veronesi School of Medicine, Vita-Salute San Raffaele University, 20100 Milan, Italy; Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, 20100 Milan, Italy
Roberto Baldelli Endocrinological Oncology, Service of Endocrinology, A.O. San Camillo-Forlanini, 13449 Rome, Italy;
Gherardo Mazziotti Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.) Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy;
Valeria Smiroldo Oncology Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy;
Elisabetta Lavezzi Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy;
Anna Spada Department of Clinical Sciences and Community Health, University of Milan, 20100 Milan, Italy; (A.S.); (G.M.)
Giovanna Mantovani Department of Clinical Sciences and Community Health, University of Milan, 20100 Milan, Italy; (A.S.); (G.M.) Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy
Andrea G. Lania Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy; (A.Z.); (G.M.); (A.G.L.) Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center—IRCCS, 20089 Rozzano, Italy;

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Daphnetin induces apoptosis in fibroblast-like synoviocytes from collagen-induced arthritic rats mainly via the mitochondrial pathway. Cytokine 2020;133:155146. [PMID: 32505094 DOI: 10.1016/j.cyto.2020.155146] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 05/22/2020] [Accepted: 05/23/2020] [Indexed: 01/27/2023]

Vitali E, Boemi I, Piccini S, Tarantola G, Smiroldo V, Lavezzi E, Brambilla T, Zerbi A, Carnaghi C, Mantovani G, Spada A, Lania AG. A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells. Mol Cell Endocrinol 2020;509:110803. [PMID: 32251713 DOI: 10.1016/j.mce.2020.110803] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 03/24/2020] [Accepted: 03/29/2020] [Indexed: 12/12/2022]

Mazurek M, Litak J, Kamieniak P, Kulesza B, Jonak K, Baj J, Grochowski C. Metformin as Potential Therapy for High-Grade Glioma. Cancers (Basel) 2020;12:E210. [PMID: 31952173 PMCID: PMC7016983 DOI: 10.3390/cancers12010210] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/09/2020] [Accepted: 01/13/2020] [Indexed: 12/15/2022] Open

Yu X, Zhou W, Wang H, Lu S, Jin Y, Fu J. Transdermal metformin hydrochloride-loaded cubic phases: in silico formulation optimization, preparation, properties, and application for local treatment of melanoma. Drug Deliv 2019;26:376-383. [PMID: 30905216 PMCID: PMC6442100 DOI: 10.1080/10717544.2019.1587046] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open

Yudhani RD, Astuti I, Mustofa M, Indarto D, Muthmainah M. Metformin Modulates Cyclin D1 and P53 Expression to Inhibit Cell Proliferation and to Induce Apoptosis in Cervical Cancer Cell Lines. Asian Pac J Cancer Prev 2019;20:1667-1673. [PMID: 31244286 PMCID: PMC7021606 DOI: 10.31557/apjcp.2019.20.6.1667] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Indexed: 12/11/2022] Open

Abstract

Background:

Cervical cancer is one of the most prevalent gynecological cancers worldwide and contributes in high mortality of Indonesian women. The efficacy of chemotherapy as a standart therapy for cervical cancer decreases because it frequenly rises adverse effects. Recent studies have found that metformin has a potential anticancer effect mostly through reduction of cyclin expression and activation of Activated Adenosine Monophosphate Kinase (AMPK). This study aimed to investigate the effect of metfomin on expression of cyclin D1 and p53 and apoptosis in HeLa cancer cell line.

Methods:

HeLa cells were treated with various doses of metformin and doxorubicin as a positive control. Cytotoxic effect of metformin was determined using the MTT assay. Immunocytochemistry was used to assess cyclin D1 and p53 expression and apoptosis levels of treated HeLa cells were analyzed using flowcytometry. Data of cyclin D1 expression was statistically analyzed using the Kruskal-Wallis test followed by the Tamhane test, whilst ANOVA and Tukey post Hoc tests were used to analyze data of p53 and apoptosis level. The significant value was p< 0.05.

Results:

Metformin was able to inhibit proliferation of HeLa cells with IC50 60 mM. HeLa cells treated with 60 and 120 mM metformin had lower cyclin D1 expression than HeLa cells treated without metformin and reached a significant difference (p= 0.001). Moreover, 30 mM or higher doses of metformin increase significantly p53 expression (p< 0.001). Induction of apoptosis was observed in HeLa cells treated with all doses of metformin and reached statistically difference (p= 0.04 and p < 0.001).

Conclusion:

Metformin can modulate cyclin D1 and p53 expression in HeLa cancer cell line, leading to inhibition of cell proliferation and induction of apoptosis. Other cyclin family members, CDK inhibitors and AMPK signaling should be further investigated in order to know mechanism of metformin action.

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Hoseini Shafa M, Jalal R, Kosari N, Rahmani F. Efficacy of metformin in mediating cellular uptake and inducing apoptosis activity of doxorubicin. Regul Toxicol Pharmacol 2018;99:200-212. [PMID: 30266241 DOI: 10.1016/j.yrtph.2018.09.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 08/11/2018] [Accepted: 09/23/2018] [Indexed: 01/08/2023]

Yu X, Jin Y, Du L, Sun M, Wang J, Li Q, Zhang X, Gao Z, Ding P. Transdermal Cubic Phases of Metformin Hydrochloride: In Silico and in Vitro Studies of Delivery Mechanisms. Mol Pharm 2018;15:3121-3132. [DOI: 10.1021/acs.molpharmaceut.8b00209] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]

de Souza Neto FP, Bernardes SS, Marinello PC, Melo GP, Luiz RC, Cecchini R, Cecchini AL. Metformin: oxidative and proliferative parameters in-vitro and in-vivo models of murine melanoma. Melanoma Res 2018;27:536-544. [PMID: 28877050 DOI: 10.1097/cmr.0000000000000391] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]

Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response. Oncotarget 2018;9:25808-25825. [PMID: 29899823 PMCID: PMC5995253 DOI: 10.18632/oncotarget.25380] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 04/24/2018] [Indexed: 12/22/2022] Open

Sena P, Mancini S, Benincasa M, Mariani F, Palumbo C, Roncucci L. Metformin Induces Apoptosis and Alters Cellular Responses to Oxidative Stress in Ht29 Colon Cancer Cells: Preliminary Findings. Int J Mol Sci 2018;19:1478. [PMID: 29772687 PMCID: PMC5983851 DOI: 10.3390/ijms19051478] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 04/25/2018] [Accepted: 05/10/2018] [Indexed: 12/25/2022] Open

Li K, Zhang TT, Wang F, Cui B, Zhao CX, Yu JJ, Lv XX, Zhang XW, Yang ZN, Huang B, Li X, Hua F, Hu ZW. Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression. Oncogene 2018. [PMID: 29520103 DOI: 10.1038/s41388-018-0172-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]

Abstract

Metformin has beneficial effects of preventing and treating cancers on type 2 diabetic patients. However, the role of metformin in non-diabetic cancer patients and the precise molecular mechanisms against cancer have not yet been sufficiently elucidated. We recently reported that the pseudokinase protein TRIB3 acts as a stress sensor linking metabolic stressors to cancer promotion by inhibiting autophagy and ubiquitin-proteasomal degradation systems; genetically abrogating of TRIB3 expression reduces tumourigenesis and cancer progression. Thus, TRIB3 is a potential therapeutic target for diverse cancers. In this study, we found that metformin attenuates melanoma growth and metastasis by reducing TRIB3 expression in non-diabetic C57BL/6 mice and diabetic KK-Ay mice; overexpression of TRIB3 protects metformin from the activation of autophagic flux, the clearance of accumulated tumour-promoting factors and the attenuation of tumour progression. We further elucidated that TRIB3 acts as an adaptor to recruit lysine acetyltransferase 5 (KAT5) to SMAD3 and induce a phosphorylation-dependent K333 acetylation of SMAD3, which sustains transcriptional activity of SMAD3 and subsequently enhances TRIB3 transcription. Metformin suppresses SMAD3 phosphorylation and decreases the KAT5/SMAD3 interaction, to attenuate the KAT5-mediated K333 acetylation of SMAD3, reduce the SMAD3 transcriptional activity and subsequent TRIB3 expression, thereby antagonizes melanoma progression. Together, our study not only defines a molecular mechanism by which metformin protects against melanoma progression by disturbing the KAT5/TRIB3/SMAD3 positive feedback loop in diabetes and non-diabetes mice, but also suggests a candidate diverse utility of metformin in tumour prevention and therapy because of suppressing stress protein TRIB3 expression.

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Affiliation(s)

Ke Li Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.,Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Ting-Ting Zhang Shandong University, Weihai, 264209, China
Feng Wang Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Bing Cui Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Chen-Xi Zhao Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Jiao-Jiao Yu Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Xiao-Xi Lv Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Xiao-Wei Zhang Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Zhao-Na Yang Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Bo Huang Institute of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China
Xia Li Shandong University, Weihai, 264209, China
Fang Hua Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Zhuo-Wei Hu Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.

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Yu X, Mao W, Zhai Y, Tong C, Liu M, Ma L, Yu X, Li S. Anti-tumor activity of metformin: from metabolic and epigenetic perspectives. Oncotarget 2018;8:5619-5628. [PMID: 27902459 PMCID: PMC5354934 DOI: 10.18632/oncotarget.13639] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 11/03/2016] [Indexed: 12/30/2022] Open

Guimarães TA, Farias LC, Santos ES, de Carvalho Fraga CA, Orsini LA, de Freitas Teles L, Feltenberger JD, de Jesus SF, de Souza MG, Santos SHS, de Paula AMB, Gomez RS, Guimarães ALS. Metformin increases PDH and suppresses HIF-1α under hypoxic conditions and induces cell death in oral squamous cell carcinoma. Oncotarget 2018;7:55057-55068. [PMID: 27474170 PMCID: PMC5342401 DOI: 10.18632/oncotarget.10842] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 07/09/2016] [Indexed: 01/18/2023] Open

Affiliation(s)

Talita Antunes Guimarães Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
Lucyana Conceição Farias Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
Eliane Sobrinho Santos Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.,Instituto Federal de Educação, Ciência e Tecnologia do Norte de Minas Gerais (IFNMG), Araçuaí, Minas Gerais, Brazil
Carlos Alberto de Carvalho Fraga Faculdades Integradas Pitágoras, Montes Claros, Minas Gerais, Brazil.,Faculdades Unidas do Norte de Minas, Montes Claros, Minas Gerais, Brazil
Lissur Azevedo Orsini Department of Clinical, Surgery and Oral Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Leandro de Freitas Teles Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
John David Feltenberger Texas Tech University Health Science Center, Lubbock, TX, USA
Sabrin Ferreira de Jesus Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
Marcela Gonçalves de Souza Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
Sérgio Henrique Sousa Santos Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil
Alfredo Maurício Batista de Paula Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
Ricardo Santiago Gomez Department of Clinical, Surgery and Oral Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
André Luiz Sena Guimarães Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil

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Effects of commonly used chronic medications on the outcomes of ipilimumab therapy in patients with metastatic melanoma. Melanoma Res 2018;26:609-615. [PMID: 27603551 DOI: 10.1097/cmr.0000000000000299] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]

Abstract

Ipilimumab can induce long-term survival in 20% of patients with metastatic melanoma. Concurrent chronic medications may impact the patient's immune system, possess antimelanoma properties, and potentially affect clinical outcomes. This retrospective study sought to describe the efficacy and toxicity effects of 12 classes of chronic medications in metastatic melanoma patients treated with ipilimumab. A total of 159 adults who received ipilimumab for metastatic melanoma at Mayo Clinic (Rochester, Minnesota, USA) from 1 March 2011 through 31 December 2014 were included. Classes of chronic medications included statins, metformin, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, calcium channel blockers, aspirin, non-steroidal anti-inflammatory drugs, H1 and H2 receptor antagonists, proton pump inhibitors (PPIs), antidepressants, and vitamin D supplements. Of the 12 medication classes, only PPIs were found to have an increased odds of experiencing a partial response or a complete response to ipilimumab [odds ratio: 3.73; confidence interval (CI): 1.26-11.04; P=0.02] on the basis of a case-control analysis. Although not significant, PPI use also trended toward improved overall survival and progression-free survival (hazard ratio: 0.44; CI: 0.17-1.15; P=0.09; and hazard ratio: 0.6; CI: 0.34-1.06; P=0.08, respectively) on the basis of Kaplan-Meier and Cox proportional hazard modeling. No medication class was associated with an increased risk of grades 3-5 immune-related adverse events with ipilimumab on the basis of case-control analysis. In summary, patients on PPIs may be more likely to experience a partial response/complete response following ipilimumab therapy. Because of the small sample size and the retrospective nature of this work, these findings are only descriptive and further study should be carried out. Other classes of chronic medications did not produce statistically significant effects for any of the measured outcomes.

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Zi F, Zi H, Li Y, He J, Shi Q, Cai Z. Metformin and cancer: An existing drug for cancer prevention and therapy. Oncol Lett 2018;15:683-690. [PMID: 29422962 PMCID: PMC5772929 DOI: 10.3892/ol.2017.7412] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 09/22/2017] [Indexed: 12/17/2022] Open

Fischer GM, Gopal YV, McQuade JL, Peng W, DeBerardinis RJ, Davies MA. Metabolic strategies of melanoma cells: Mechanisms, interactions with the tumor microenvironment, and therapeutic implications. Pigment Cell Melanoma Res 2018;31:11-30. [PMID: 29049843 PMCID: PMC5742019 DOI: 10.1111/pcmr.12661] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 10/09/2017] [Indexed: 12/15/2022]

Jaune E, Rocchi S. Metformin: Focus on Melanoma. Front Endocrinol (Lausanne) 2018;9:472. [PMID: 30186236 PMCID: PMC6110909 DOI: 10.3389/fendo.2018.00472] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 07/31/2018] [Indexed: 12/13/2022] Open

Dogan Turacli I, Candar T, Yuksel BE, Demirtas S. Role of metformin on base excision repair pathway in p53 wild-type H2009 and HepG2 cancer cells. Hum Exp Toxicol 2017;37:909-919. [DOI: 10.1177/0960327117737145] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]

Adeberg S, Bernhardt D, Harrabi SB, Nicolay NH, Hörner-Rieber J, König L, Repka M, Mohr A, Abdollahi A, Weber KJ, Debus J, Rieken S. Metformin Enhanced in Vitro Radiosensitivity Associates with G2/M Cell Cycle Arrest and Elevated Adenosine-5'-monophosphate-activated Protein Kinase Levels in Glioblastoma. Radiol Oncol 2017;51:431-437. [PMID: 29333122 PMCID: PMC5765320 DOI: 10.1515/raon-2017-0042] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 09/30/2017] [Indexed: 12/28/2022] Open

Affiliation(s)

Sebastian Adeberg University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Denise Bernhardt University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Semi B Harrabi University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Nils H Nicolay University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Juliane Hörner-Rieber University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Laila König University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Michael Repka Department of Radiation Medicine, Georgetown University Hospital, Washington DC, USA
Angela Mohr University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Amir Abdollahi University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany.,Tanslational Radiation Oncology, German Cancer Consortium (DKTK), National Center for Tumor Diseases German Cancer Research Center (DKFZ), Heidelberg, Germany
Klaus-Josef Weber University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Juergen Debus University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
Stefan Rieken University Hospital of Heidelberg, Department of Radiation Oncology, Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,Heidelberg Institute for Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany

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Pavlidou T, Rosina M, Fuoco C, Gerini G, Gargioli C, Castagnoli L, Cesareni G. Regulation of myoblast differentiation by metabolic perturbations induced by metformin. PLoS One 2017;12:e0182475. [PMID: 28859084 PMCID: PMC5578649 DOI: 10.1371/journal.pone.0182475] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 07/19/2017] [Indexed: 12/11/2022] Open

Preparation and characterization of metformin surface modified cellulose nanofiber gel and evaluation of its anti-metastatic potentials. Carbohydr Polym 2017;165:322-333. [DOI: 10.1016/j.carbpol.2017.02.067] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/19/2017] [Accepted: 02/16/2017] [Indexed: 11/17/2022]

Arbeláez-Quintero I, Palacios M. To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents. Stroke Res Treat 2017;2017:9756429. [PMID: 28634570 PMCID: PMC5467394 DOI: 10.1155/2017/9756429] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 10/22/2016] [Accepted: 10/26/2016] [Indexed: 12/11/2022] Open

Chen CH, Tsai HT, Chuang HC, Shiu LY, Su LJ, Chiu TJ, Luo SD, Fang FM, Huang CC, Chien CY. Metformin disrupts malignant behavior of oral squamous cell carcinoma via a novel signaling involving Late SV40 factor/Aurora-A. Sci Rep 2017;7:1358. [PMID: 28465536 PMCID: PMC5430965 DOI: 10.1038/s41598-017-01353-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 03/27/2017] [Indexed: 02/06/2023] Open

Chiyo T, Kato K, Iwama H, Fujihara S, Fujita K, Tadokoro T, Ohura K, Samukawa E, Yamana Y, Kobayashi N, Matsunaga T, Nishiyama N, Ayaki M, Yachida T, Morishita A, Kobara H, Mori H, Masaki T. Therapeutic potential of the antidiabetic drug metformin in small bowel adenocarcinoma. Int J Oncol 2017;50:2145-2153. [DOI: 10.3892/ijo.2017.3971] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 03/15/2017] [Indexed: 11/06/2022] Open

Tudor D, Nenu I, Filip GA, Olteanu D, Cenariu M, Tabaran F, Ion RM, Gligor L, Baldea I. Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy. PLoS One 2017;12:e0173241. [PMID: 28278159 PMCID: PMC5344368 DOI: 10.1371/journal.pone.0173241] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 02/18/2017] [Indexed: 12/16/2022] Open

Abstract

BACKGROUND

Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine-Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects.

METHODS

Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting.

RESULTS

GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT.

CONCLUSIONS

Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects.

GENERAL SIGNIFICANCE

Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy.

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Wokoun U, Hellriegel M, Emons G, Gründker C. Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors. Oncol Rep 2017;37:2418-2424. [PMID: 28350075 DOI: 10.3892/or.2017.5491] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 01/26/2017] [Indexed: 11/05/2022] Open

Drug Repurposing to Circumvent Chemotherapy Resistance in Brain Tumours. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/978-3-319-46505-0_6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]

Bhat M, Yanagiya A, Graber T, Razumilava N, Bronk S, Zammit D, Zhao Y, Zakaria C, Metrakos P, Pollak M, Sonenberg N, Gores G, Jaramillo M, Morita M, Alain T. Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells. Oncotarget 2016;8:50542-50556. [PMID: 28881582 PMCID: PMC5584165 DOI: 10.18632/oncotarget.10671] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 07/06/2016] [Indexed: 12/18/2022] Open

Affiliation(s)

Mamatha Bhat Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.,Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Canada, USA.,Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
Akiko Yanagiya Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada
Tyson Graber Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
Nataliya Razumilava Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.,Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
Steve Bronk Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
Domenick Zammit Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada
Yunhao Zhao Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada
Chadi Zakaria Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada
Peter Metrakos Department of Surgery, McGill University Health Centre, Montreal, Canada
Michael Pollak Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada
Nahum Sonenberg Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada
Gregory Gores Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
Maritza Jaramillo INRS Institut Armand-Frappier Research Centre, Laval, Quebec, Canada
Masahiro Morita Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada
Tommy Alain Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

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Zhang F, Li M, Wang J, Liang X, Su Y, Wang W. Finding New Tricks for Old Drugs: Tumoricidal Activity of Non-Traditional Antitumor Drugs. AAPS PharmSciTech 2016;17:539-52. [PMID: 27032934 DOI: 10.1208/s12249-016-0518-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/20/2016] [Indexed: 02/06/2023] Open

Guo Q, Liu Z, Jiang L, Liu M, Ma J, Yang C, Han L, Nan K, Liang X. Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase. Mol Med Rep 2016;13:2590-6. [PMID: 26847819 PMCID: PMC4768996 DOI: 10.3892/mmr.2016.4830] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Accepted: 01/11/2016] [Indexed: 11/16/2022] Open

Abstract

Metformin, the most widely administered oral anti-diabetic therapeutic agent, exerts its glucose-lowering effect predominantly via liver kinase B1 (LKB1)-dependent activation of adenosine monophosphate-activated protein kinase (AMPK). Accumulating evidence has demonstrated that metformin possesses potential antitumor effects. However, whether the antitumor effect of metformin is via the LKB1/AMPK signaling pathway remains to be determined. In the current study, the effects of metformin on proliferation, cell cycle progression, and apoptosis of human non-small cell lung cancer (NSCLC) H460 (LKB1-null) and H1299 (LKB1-positive) cells were assessed, and the role of LKB1/AMPK signaling in the anti-growth effects of metformin were investigated. Cell viability was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle distribution and apoptosis were assessed by flow cytometry, and protein expression levels were measured by western blotting. Metformin inhibited proliferation, induced significant cell cycle arrest at the G₀–G₁ phase and increased apoptosis in NSCLC cells in a time- and concentration-dependent manner, regardless of the level of LKB1 protein expression. Furthermore, knockdown of LKB1 with short hairpin RNA (shRNA) did not affect the antiproliferative effect of metformin in the H1299 cells. Metformin stimulated AMPK phosphorylation and subsequently suppressed the phosphorylation of mammalian target of rapamycin and its downstream effector, 70-kDa ribosomal protein S6 kinase in the two cell lines. These effects were abrogated by silencing AMPK with small interfering RNA (siRNA). In addition, knockdown of AMPK with siRNA inhibited the effect of metformin on cell proliferation in the two cell lines. These results provide evidence that the growth inhibition of metformin in NSCLC cells is mediated by LKB1-independent activation of AMPK, indicating that metformin may be a potential therapeutic agent for the treatment of human NSCLC.

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Donato AJ, Morgan RG, Walker AE, Lesniewski LA. Cellular and molecular biology of aging endothelial cells. J Mol Cell Cardiol 2015;89:122-35. [PMID: 25655936 PMCID: PMC4522407 DOI: 10.1016/j.yjmcc.2015.01.021] [Citation(s) in RCA: 355] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 01/05/2015] [Accepted: 01/27/2015] [Indexed: 12/29/2022]

Abstract

Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults. Greater endothelial oxidative stress with aging is a result of augmented production from the intracellular enzymes NADPH oxidase and uncoupled eNOS, as well as from mitochondrial respiration in the absence of appropriate increases in antioxidant defenses as regulated by relevant transcription factors, such as FOXO. Interestingly, it appears that NFkB, a critical inflammatory transcription factor, is sensitive to this age-related endothelial redox change and its activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus creating a vicious feed-forward cycle. This review will discuss the two macro-mechanistic processes, oxidative stress and inflammation, that contribute to endothelial dysfunction with advancing age as well as the cellular and molecular events that lead to the vicious cycle of inflammation and oxidative stress in the aged endothelium. Other potential mediators of this pro-inflammatory endothelial phenotype are increases in immune or senescent cells in the vasculature. Of note, genomic instability, telomere dysfunction or DNA damage has been shown to trigger cell senescence via the p53/p21 pathway and result in increased inflammatory signaling in arteries from older adults. This review will discuss the current state of knowledge regarding the emerging concepts of senescence and genomic instability as mechanisms underlying oxidative stress and inflammation in the aged endothelium. Lastly, energy sensitive/stress resistance pathways (SIRT-1, AMPK, mTOR) are altered in endothelial cells and/or arteries with aging and these pathways may modulate endothelial function via key oxidative stress and inflammation-related transcription factors. This review will also discuss what is known about the role of "energy sensing" longevity pathways in modulating endothelial function with advancing age. With the growing population of older adults, elucidating the cellular and molecular mechanisms of endothelial dysfunction with age is critical to establishing appropriate and measured strategies to utilize pharmacological and lifestyle interventions aimed at alleviating CVD risk. This article is part of a Special Issue entitled "SI: CV Aging".

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Vujic I, Sanlorenzo M, Posch C, Esteve-Puig R, Yen AJ, Kwong A, Tsumura A, Murphy R, Rappersberger K, Ortiz-Urda S. Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget 2015;6:969-78. [PMID: 25504439 PMCID: PMC4359268 DOI: 10.18632/oncotarget.2824] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 11/24/2014] [Indexed: 12/22/2022] Open

Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells. LEUKEMIA RESEARCH AND TREATMENT 2015;2015:516460. [PMID: 26688757 PMCID: PMC4673355 DOI: 10.1155/2015/516460] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 06/18/2015] [Accepted: 09/20/2015] [Indexed: 12/25/2022]

Kabel AM, Omar MS, Balaha MF, Borg HM. Effect of metformin and adriamycin on transplantable tumor model. Tissue Cell 2015;47:498-505. [PMID: 26276089 DOI: 10.1016/j.tice.2015.07.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/20/2015] [Accepted: 07/06/2015] [Indexed: 01/19/2023]

Palmieri G, Ombra M, Colombino M, Casula M, Sini M, Manca A, Paliogiannis P, Ascierto PA, Cossu A. Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets. Front Oncol 2015;5:183. [PMID: 26322273 PMCID: PMC4530319 DOI: 10.3389/fonc.2015.00183] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 07/26/2015] [Indexed: 12/12/2022] Open