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1
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He J, Luo Y, Ding Y, Zhu L. Metformin Inhibits the Progression of Pancreatic Cancer Through Regulating miR-378a-3p/VEGFA/RGC-32 Axis. Cancer Med 2024; 13:e70446. [PMID: 39606802 PMCID: PMC11602749 DOI: 10.1002/cam4.70446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/02/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a major contributor to global cancer-related mortality. While the inhibitory effect of metformin (Met) on PC has been reported, the underlying mechanism remains elusive. METHODS We established BxPC-3 cell models with miR-378a-3p and VEGFA knockdown. The expression of miR-378a-3p, VEGFA, and RGC-32 in PC and normal tissues was analyzed using GEPIA, TCGA databases. Cell proliferation, invasion, migration, and apoptosis were assessed through CCK8, Transwell, wound healing, and flow cytometry. RESULTS Significantly lower expression of miR-378a-3p was observed in PC tissues and cells. Knockdown of miR-378a-3p reversed the impact of Met on cell viability in PANC-1 and BxPC3. VEGFA emerged as a potential regulator in PC and a downstream target of miR-378a-3p. The interaction between VEGFA and RGC-32 played a crucial role in PC regulation. Knockdown of VEGFA substantially reversed the impact of miR-378a-3p inhibitor on tumor growth and the epithelial-mesenchymal transition (EMT) process. Moreover, knockdown of VEGFA effectively countered the influence of miR-378a-3p inhibitor on cell viability and the EMT process in BxPC3 cells. CONCLUSIONS Met exerted inhibitory effects on PC through the miR-378a-3p/VEGFA/RGC-32 pathway. Strategies targeting the miR-378a-3p/VEGFA/RGC-32 axis represent a novel avenue for the prevention and treatment of PC.
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Affiliation(s)
- Jinli He
- Department of GastroenterologyThe First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangChina
| | - Yixing Luo
- Department of GastroenterologyThe First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangChina
| | - Ying Ding
- Department of Medical CosmetologyThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangChina
| | - Liang Zhu
- Department of GastroenterologyThe First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangChina
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2
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Elmahboub Y, Albash R, Magdy William M, Rayan AH, Hamed NO, Ousman MS, Raslan NA, Mosallam S. Metformin Loaded Zein Polymeric Nanoparticles to Augment Antitumor Activity against Ehrlich Carcinoma via Activation of AMPK Pathway: D-Optimal Design Optimization, In Vitro Characterization, and In Vivo Study. Molecules 2024; 29:1614. [PMID: 38611893 PMCID: PMC11013883 DOI: 10.3390/molecules29071614] [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: 03/13/2024] [Revised: 03/24/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Metformin (MET), an antidiabetic drug, is emerging as a promising anticancer agent. This study was initiated to investigate the antitumor effects and potential molecular targets of MET in mice bearing solid Ehrlich carcinoma (SEC) as a model of breast cancer (BC) and to explore the potential of zein nanoparticles (ZNs) as a carrier for improving the anticancer effect of MET. ZNs were fabricated through ethanol injection followed by probe sonication method. The optimum ZN formulation (ZN8) was spherical and contained 5 mg zein and 30 mg sodium deoxycholate with a small particle size and high entrapment efficiency percentage and zeta potential. A stability study showed that ZN8 was stable for up to three months. In vitro release profiles proved the sustained effect of ZN8 compared to the MET solution. Treatment of SEC-bearing mice with ZN8 produced a more pronounced anticancer effect which was mediated by upregulation of P53 and miRNA-543 as well as downregulation of NF-κB and miRNA-191-5p gene expression. Furthermore, ZN8 produced a marked elevation in pAMPK and caspase-3 levels as well as a significant decrease in cyclin D1, COX-2, and PGE2 levels. The acquired findings verified the potency of MET-loaded ZNs as a treatment approach for BC.
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Affiliation(s)
- Yasmina Elmahboub
- Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza 12585, Egypt;
| | - Rofida Albash
- Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza 12585, Egypt;
| | - Mira Magdy William
- Department of Biochemistry, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt
| | - Amal H. Rayan
- Department of Medical Education, College of Medicine, AlMaarefa University, Diriyah, Riyadh 13713, Saudi Arabia
| | - Najat O. Hamed
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, AlMaarefa University, Diriyah, Riyadh 13713, Saudi Arabia;
| | - Mona S. Ousman
- Emergency Medical Services, College of Applied Sciences, AlMaarefa University, Diriyah, Riyadh 13713, Saudi Arabia;
| | - Nahed A Raslan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt;
- Clinical Pharmacy Program, College of Health Sciences and Nursing, Al-Rayan Colleges, Medina 42541, Saudi Arabia
| | - Shaimaa Mosallam
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt;
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3
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Mencucci MV, Abba MC, Maiztegui B. Decoding the role of microRNA dysregulation in the interplay of pancreatic cancer and type 2 diabetes. Mol Cell Endocrinol 2024; 583:112144. [PMID: 38161049 DOI: 10.1016/j.mce.2023.112144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/22/2023] [Accepted: 12/23/2023] [Indexed: 01/03/2024]
Abstract
This study examines the complex relationship between pancreatic cancer (PC) and type 2 diabetes (T2D) by focusing on the role of microRNAs (miRNAs). miRNAs are small non-coding RNAs that regulate gene expression and have been implicated in many diseases, including T2D and cancer. To begin, we conducted a literature review to identify miRNAs associated with the PC-T2D link. However, we found limited research on this specific association, with most studies focusing on the antitumor effects of metformin. Furthermore, we performed a bioinformatics analysis to identify new potential miRNAs that might be relevant in the context of PC-T2D. First, we identified miRNAs and gene expression alterations common to both diseases using publicly available datasets. Subsequently, we performed an integrative analysis between the identified miRNAs and genes alterations. As a result, we identified nine miRNAs that could potentially play an important role in the interplay between PC and T2D. These miRNAs have the potential to influence nearby cells and distant tissues, affecting critical processes like extracellular matrix remodeling and cell adhesion, ultimately contributing to the development of T2D or PC. Taken together, these analyses underscore the importance of further exploring the role of miRNAs in the complex interplay of PC and T2D.
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Affiliation(s)
- María Victoria Mencucci
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET-CeAs CICPBA), Facultad de Ciencias Médicas UNLP, 60 y 120 (s/n), 1900 La Plata, Argentina.
| | - Martín Carlos Abba
- CINIBA, Centro de Investigaciones Inmunológicas Básicas y Aplicadas (UNLP-CICPBA), Facultad de Ciencias Médicas UNLP, La Plata, Argentina.
| | - Bárbara Maiztegui
- CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET-CeAs CICPBA), Facultad de Ciencias Médicas UNLP, 60 y 120 (s/n), 1900 La Plata, Argentina.
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4
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Perazza F, Leoni L, Colosimo S, Musio A, Bocedi G, D’Avino M, Agnelli G, Nicastri A, Rossetti C, Sacilotto F, Marchesini G, Petroni ML, Ravaioli F. Metformin and the Liver: Unlocking the Full Therapeutic Potential. Metabolites 2024; 14:186. [PMID: 38668314 PMCID: PMC11052067 DOI: 10.3390/metabo14040186] [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: 03/06/2024] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Metformin is a highly effective medication for managing type 2 diabetes mellitus. Recent studies have shown that it has significant therapeutic benefits in various organ systems, particularly the liver. Although the effects of metformin on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are still being debated, it has positive effects on cirrhosis and anti-tumoral properties, which can help prevent the development of hepatocellular carcinoma. Furthermore, it has been proven to improve insulin resistance and dyslipidaemia, commonly associated with liver diseases. While more studies are needed to fully determine the safety and effectiveness of metformin use in liver diseases, the results are highly promising. Indeed, metformin has a terrific potential for extending its full therapeutic properties beyond its traditional use in managing diabetes.
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Affiliation(s)
- Federica Perazza
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Laura Leoni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Santo Colosimo
- Doctorate School of Nutrition Science, University of Milan, 20122 Milan, Italy;
| | | | - Giulia Bocedi
- U.O. Diabetologia, Ospedale C. Magati, Scandiano, 42019 Reggio Emilia, Italy;
| | - Michela D’Avino
- S.C. Endocrinologia Arcispedale Santa Maria Nuova, 42123 Reggio Emilia, Italy;
| | - Giulio Agnelli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Alba Nicastri
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Chiara Rossetti
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Federica Sacilotto
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Giulio Marchesini
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Maria Letizia Petroni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
- Division of Hepatobiliary and Immunoallergic Diseases, Department of Internal Medicine, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy
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5
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Zhang W, Zhao T, Gao X, Ma S, Gong T, Yang Y, Li M, Cao G, Guo X, Li B. miR-10a-5p Regulates the Proliferation and Differentiation of Porcine Preadipocytes Targeting the KLF11 Gene. Animals (Basel) 2024; 14:337. [PMID: 38275797 PMCID: PMC10812476 DOI: 10.3390/ani14020337] [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: 12/11/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/27/2024] Open
Abstract
In the swine industry, meat quality, color, and texture are influenced by the excessive differentiation of fat cells. miRNAs have emerged as integral regulators of adipose development. This study delves into the influence of miR-10a-5b on the proliferation and differentiation of pig preadipocytes. Our findings reveal that miR-10a-5b is prevalent across various tissues. It hinders preadipocyte proliferation, amplifies the expression of adipogenic genes, promotes lipid accumulation, and, as a result, advances preadipocyte differentiation. We predict that KLF11 is the target gene of miRNA. A dual-fluorescence reporter assay was conducted to validate the binding sites of miR-10a-5b on the 3'UTR of the KLF11 mRNA. Results showed that miR-10a-5b targeted KLF11 3'UTR and reduced the fluorescence activity of the dual-fluorescent reporter vector. Our research also indicates that miR-10a-5b targets and downregulates the expression of both mRNA and the protein levels of KLF11. During the differentiation of the preadipocytes, KLF11 inhibited adipose differentiation and was able to suppress the promotion of adipose differentiation by miR-10a-5b. This underscores miR-10a-5b's potential as a significant regulator of preadipocyte behavior by modulating KLF11 expression, offering insights into the role of functional miRNAs in fat deposition.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xiaohong Guo
- College of Animal Science, Shanxi Agricultural University, Jinzhong 030801, China; (W.Z.); (T.Z.); (X.G.); (S.M.); (T.G.); (Y.Y.); (M.L.); (G.C.)
| | - Bugao Li
- College of Animal Science, Shanxi Agricultural University, Jinzhong 030801, China; (W.Z.); (T.Z.); (X.G.); (S.M.); (T.G.); (Y.Y.); (M.L.); (G.C.)
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6
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Zhang Y, Zhou F, Guan J, Zhou L, Chen B. Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review. Biomolecules 2023; 13:250. [PMID: 36830619 PMCID: PMC9953052 DOI: 10.3390/biom13020250] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 02/03/2023] Open
Abstract
Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.
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Affiliation(s)
| | | | | | | | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
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7
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Dehghanian F, Azhir Z, Khalilian S, Grüning B. Non-coding RNAs underlying the pathophysiological links between type 2 diabetes and pancreatic cancer: A systematic review. J Diabetes Investig 2022; 13:405-428. [PMID: 34859606 PMCID: PMC8902405 DOI: 10.1111/jdi.13727] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/11/2021] [Accepted: 11/30/2021] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes is known as a risk factor for pancreatic cancer (PC). Various genetic and environmental factors cause both these global chronic diseases. The mechanisms that define their relationships are complex and poorly understood. Recent studies have implicated that metabolic abnormalities, including hyperglycemia and hyperinsulinemia, could lead to cell damage responses, cell transformation, and increased cancer risk. Hence, these kinds of abnormalities following molecular events could be essential to develop our understanding of this complicated link. Among different molecular events, focusing on shared signaling pathways including metabolic (PI3K/Akt/mTOR) and mitogenic (MAPK) pathways in addition to regulatory mechanisms of gene expression such as those involved in non-coding RNAs (miRNAs, circRNAs, and lncRNAs) could be considered as powerful tools to describe this association. A better understanding of the molecular mechanisms involved in the development of type 2 diabetes and pancreatic cancer would help us to find a new research area for developing therapeutic and preventive strategies. For this purpose, in this review, we focused on the shared molecular events resulting in type 2 diabetes and pancreatic cancer. First, a comprehensive literature review was performed to determine similar molecular pathways and non-coding RNAs; then, the final results were discussed in more detail.
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Affiliation(s)
- Fariba Dehghanian
- Department of Cell and Molecular Biology and MicrobiologyFaculty of Biological Science and TechnologyUniversity of IsfahanIsfahanIran
| | - Zahra Azhir
- Department of Cell and Molecular Biology and MicrobiologyFaculty of Biological Science and TechnologyUniversity of IsfahanIsfahanIran
| | - Sheyda Khalilian
- Department of Cell and Molecular Biology and MicrobiologyFaculty of Biological Science and TechnologyUniversity of IsfahanIsfahanIran
| | - Björn Grüning
- Department of Computer ScienceBioinformatics GroupUniversity of FreiburgFreiburgGermany
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8
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Tseng HH, Chen YZ, Chou NH, Chen YC, Wu CC, Liu LF, Yang YF, Yeh CY, Kung ML, Tu YT, Tsai KW. Metformin inhibits gastric cancer cell proliferation by regulation of a novel Loc100506691-CHAC1 axis. MOLECULAR THERAPY-ONCOLYTICS 2021; 22:180-194. [PMID: 34514098 PMCID: PMC8416970 DOI: 10.1016/j.omto.2021.08.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 08/13/2021] [Indexed: 12/30/2022]
Abstract
Long noncoding RNAs (lncRNAs) are a group of nonprotein coding transcripts that play a critical role in cancer progression. However, the role of lncRNA in metformin-induced inhibition of cell growth and its biological function in gastric cancer remain largely unknown. In this study, we identified an oncogenic lncRNA, Loc100506691, the expression of which was decreased in gastric cancer cells with metformin treatment. Moreover, Loc100506691 was significantly overexpressed in gastric cancer compared with adjacent normal tissues (p < 0.001), and high Loc100506691 expression was significantly correlated with poor survival of patients with gastric cancer. Additionally, Loc100506691 knockdown could significantly suppress gastric cancer cell growth in vitro, and ectopic Loc100506691 expression accelerated tumor growth in an in vivo mouse model. Analysis of the cell cycle revealed that Loc100506691 knockdown induced cell cycle arrest at the G2/M phase by impairing cell entry from the G2/M to G1 phase. Loc100506691 negatively regulated CHAC1 expression by modulating miR-26a-5p/miR-330-5p expression, and CHAC1 knockdown markedly attenuated Loc100506691 knockdown-induced gastric cancer cell growth and motility suppression. We concluded that anti-proliferative effects of metformin in gastric cancer may be partially caused by suppression of the Loc100506691-miR-26a-5p/miR-330-5p-CHAC1 axis.
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Affiliation(s)
- Hui-Hwa Tseng
- Division of Anatomic Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
| | - You-Zuo Chen
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.,Department of Biological Science and Technology, I-Shou University, Kaohsiung 82445, Taiwan
| | - Nan-Hua Chou
- Department of Surgery Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Yen-Chih Chen
- Division of Gastrointestinal Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical of Foundation, New Taipei City 23124, Taiwan
| | - Chao-Chuan Wu
- Division of Gastrointestinal Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical of Foundation, New Taipei City 23124, Taiwan
| | - Li-Feng Liu
- Department of Biological Science and Technology, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yi-Fang Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Chung-Yu Yeh
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Ya-Ting Tu
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
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9
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Xu Q, Wang Y, Li X, Du Y, Li Y, Zhu J, Lin Y. miR-10a-5p Inhibits the Differentiation of Goat Intramuscular Preadipocytes by Targeting KLF8 in Goats. Front Mol Biosci 2021; 8:700078. [PMID: 34490349 PMCID: PMC8418121 DOI: 10.3389/fmolb.2021.700078] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 07/13/2021] [Indexed: 11/13/2022] Open
Abstract
Intramuscular fat contributes to the improvement of meat quality of goats. MicroRNAs (miRNAs) have been reported to regulate adipocyte differentiation and maturation. The aim of our study was to clarify whether miR-10a-5p regulates goat intramuscular preadipocyte (GIPC) differentiation and its direct downstream signaling pathway. GIPCs were isolated from longissimus dorsi, whose miR-10a-5p level was measured at different time point of differentiation induction. Adipogenic differentiation of the GIPCs was evaluated by Oil Red O and BODIPY staining, and the expression changes of adipogenic genes like ACC, ATGL, CEBPβ, PPARγ, etc. Related mechanisms were verified by qPCR, a bioinformatic analysis, a dual-luciferase reporter assay, overexpression, and siRNA transfection. Oil Red O and BODIPY staining both with adipogenic gene detection showed that miR-10a-5p suppressed the accumulation of lipid droplets in GIPCs and inhibited its differentiation. The dual-luciferase reporter assay experiment revealed that miR-10a-5p regulates GIPC differentiation by directly binding to KLF8 3’UTR to regulate its expression. Thus, the results indicated that miR-10a-5p inhibits GIPC differentiation by targeting KLF8 and supply a new target for fat deposition and meat quality improvement.
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Affiliation(s)
- Qing Xu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
| | - Yong Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
| | - Xin Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
| | - Yu Du
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Yanyan Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Sichuan Province, Southwest Minzu University, Chengdu, China.,College of Animal Science and Veterinary, Southwest Minzu University, Chengdu, China
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10
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Kalayarasan R. Diabetes and pancreatic cancer: Exploring the two-way traffic. World J Gastroenterol 2021; 27:4939-4962. [PMID: 34497428 PMCID: PMC8384733 DOI: 10.3748/wjg.v27.i30.4939] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is often associated with a poor prognosis. Long-standing diabetes mellitus is considered as an important risk factor for its development. This risk can be modified by the use of certain antidiabetic medications. On the other hand, new-onset diabetes can signal towards an underlying PC in the elderly population. Recently, several attempts have been made to develop an effective clinical tool for PC screening using a combination of history of new-onset diabetes and several other clinical and biochemical markers. On the contrary, diabetes affects the survival after treatment for PC. We describe this intimate and complex two-way relationship of diabetes and PC in this review by exploring the underlying pathogenesis.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur 342005, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Raja Kalayarasan
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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Metformin and Gastrointestinal Cancer Development in Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea. Clin Transl Gastroenterol 2021; 11:e00254. [PMID: 33105165 PMCID: PMC7587422 DOI: 10.14309/ctg.0000000000000254] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Clinical studies have produced conflicting results on the effects of metformin on gastrointestinal cancer development. We aimed to investigate the association between metformin use and stomach, colon, liver, and pancreatic cancer development among patients with newly diagnosed, drug-naïve type 2 diabetes. METHODS This retrospective study evaluated propensity score-matched patients with newly diagnosed type 2 diabetes from the Korean National Health Insurance Service database. Metformin users were categorized into tertiles according to the cumulative dose or duration of metformin treatment, and the risks of gastrointestinal cancers were compared. RESULTS Metformin users had reduced risks of developing stomach cancer (hazard ratio [HR]: 0.841, 95% confidence interval [CI]: 0.797-0.887), colon cancer (HR: 0.865, 95% CI: 0.822-0.91), and liver cancer (HR: 0.709, 95% CI: 0.675-0.746; P < 0.001). However, metformin users did not have a reduced overall risk of pancreatic cancer (HR: 1.335, 95% CI: 1.209-1.475; P < 0.001). The risks tended to decrease at higher cumulative doses and durations of metformin use, with significantly reduced risks of all 4 cancers at the highest cumulative dose (≥1,200,000 mg) and the longest duration (≥2,000 days) of metformin use. DISCUSSION This population-based data suggest that metformin could be associated with reductions in the risks of stomach, colon, and liver cancers, as well a reduced risk of pancreatic cancer in some subgroups. Metformin has benefit as a first-line treatment for type 2 diabetes mellitus. A further role in cancer risk reduction could be studied in controlled trials.
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12
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Eibl G, Rozengurt E. Metformin: review of epidemiology and mechanisms of action in pancreatic cancer. Cancer Metastasis Rev 2021; 40:865-878. [PMID: 34142285 DOI: 10.1007/s10555-021-09977-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 05/27/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma continues to be a lethal disease, for which efficient treatment options are very limited. Increasing efforts have been taken to understand how to prevent or intercept this disease at an early stage. There is convincing evidence from epidemiologic and preclinical studies that the antidiabetic drug metformin possesses beneficial effects in pancreatic cancer, including reducing the risk of developing the disease and improving survival in patients with early-stage disease. This review will summarize the current literature about the epidemiological data on metformin and pancreatic cancer as well as describe the preclinical evidence illustrating the anticancer effects of metformin in pancreatic cancer. Underlying mechanisms and targets of metformin will also be discussed. These include direct effects on transformed pancreatic epithelial cells and indirect, systemic effects on extra-pancreatic tissues.
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Affiliation(s)
- Guido Eibl
- Department of Surgery, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA.
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA
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13
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Alimoradi N, Firouzabadi N, Fatehi R. How metformin affects various malignancies by means of microRNAs: a brief review. Cancer Cell Int 2021; 21:207. [PMID: 33849540 PMCID: PMC8045276 DOI: 10.1186/s12935-021-01921-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/07/2021] [Indexed: 12/15/2022] Open
Abstract
Metformin known as the first-line orally prescribed drug for lowering blood glucose in type II diabetes (T2DM) has recently found various therapeutic applications including in cancer. Metformin has been studied for its influences in prevention and treatment of cancer through multiple mechanisms such as microRNA (miR) regulation. Alteration in the expression of miRs by metformin may play an important role in the treatment of various cancers. MiRs are single-stranded RNAs that are involved in gene regulation. By binding to the 3'UTR of target mRNAs, miRs influence protein levels. Irregularities in the expression of miRs that control the expression of oncogenes and tumor suppressor genes are associated with the onset and progression of cancer. Metformin may possess an effect on tumor prevention and progression by modifying miR expression and downstream pathways. Here, we summarize the effect of metformin on different types of cancer by regulating the expression of various miRs and the associated downstream molecules.
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Affiliation(s)
- Nahid Alimoradi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Firouzabadi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Reihaneh Fatehi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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14
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Wan X, Guo D, Zhu Q, Qu R. microRNA-382 suppresses the progression of pancreatic cancer through the PI3K/Akt signaling pathway by inhibition of Anxa3. Am J Physiol Gastrointest Liver Physiol 2020; 319:G309-G322. [PMID: 32463333 DOI: 10.1152/ajpgi.00322.2019] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Pancreatic cancer (PC) is a lethal cancer in the digestive system. microRNAs (miRNAs) have been demonstrated to participate in PC progression. In this context, we, thus, aimed to explore the mechanism of miR-382 in epithelial mesenchymal transition (EMT) and lymph node metastasis in PC in relation to Anxa3 and the PI3K/Akt signaling pathway. Gene expression data sets GSE16515, GSE71989, and GSE32676 were screened out, with the findings showing the significance of miR-382 and annexin A3 (Anxa3) in PC. A total of 115 PC patients were selected for determination of miR-382 and Anxa3 expression with lowly expressed miR-382 and highly expressed Anxa3 found via RT-quantitative PCR and Western blot analysis. Additionally, negative correlation was found between miR-382 and Anxa3 in PC. Dual-luciferase reporter gene assay and in situ hybridization results confirmed that miR-382 negatively regulated Anxa3. miR-382 targeted Anxa3 and suppressed PC progression by blocking the PI3K/Akt signaling pathway. After a series of gain- and loss-of function approaches, upregulation of miR-382 or silencing of Anxa3 inhibited the EMT and lymph node metastasis, as evidenced by increased level of E-cadherin and decreased level of N-cadherin, vimentin, vascular endothelial growth factor(VEGFR)-3, VEGF-C, and VEGF-D. Overexpression of miR-382 or downregulation of Anxa3 was shown to inhibit colony formation, migration, and invasion abilities of PC cells. Further, tumor xenograft in nude mice in vivo also confirmed the inhibitory role of miR-382 and silenced Anxa3 in lymph node metastasis in PC. Thus, this study provides promising therapeutic targets for PC treatment.NEW & NOTEWORTHY This study focused on the mechanism of miR-382 in epithelial mesenchymal transition and lymph node metastasis in PC in relation to Anxa3 and the PI3K/Akt signaling pathway. We found the inhibitory role of miR-382 in PC in vitro and in vivo.
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Affiliation(s)
- Xiaohui Wan
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Dongrui Guo
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Qi Zhu
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Rongfeng Qu
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, People's Republic of China
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Lancione PJ, Kumar B, Zhao S, Mroz EA, Brock G, Rocco JW, Carrau RL, Agrawal A, Seim N, Kang SY, Ozer E, Old MO. A potential protective effect of metformin in adenoid cystic carcinoma. Oral Oncol 2020; 107:104726. [PMID: 32388409 DOI: 10.1016/j.oraloncology.2020.104726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/14/2020] [Accepted: 04/15/2020] [Indexed: 10/24/2022]
Affiliation(s)
- Peter J Lancione
- The Ohio State University College of Medicine, 370 W 9(th) Ave, Columbus, OH 43210, USA.
| | - Bhavna Kumar
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
| | - Songzhu Zhao
- Department of Biomedical Informatics and Center for Biostatistics, The Ohio State University, 320 Lincoln Tower, 1800 Cannon Drive, Columbus, OH 43210, USA.
| | - Edmund A Mroz
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
| | - Guy Brock
- Department of Biomedical Informatics and Center for Biostatistics, The Ohio State University, 320 Lincoln Tower, 1800 Cannon Drive, Columbus, OH 43210, USA
| | - James W Rocco
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
| | - Ricardo L Carrau
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
| | - Amit Agrawal
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
| | - Nolan Seim
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
| | - Stephen Y Kang
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
| | - Enver Ozer
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
| | - Matthew O Old
- Department of Otolaryngology-Head & Neck Surgery, The Ohio State Wexner Medical Center, 915 Olentangy River Road, Columbus, OH 43212, USA.
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Zhao B, Luo J, Yu T, Zhou L, Lv H, Shang P. Anticancer mechanisms of metformin: A review of the current evidence. Life Sci 2020; 254:117717. [PMID: 32339541 DOI: 10.1016/j.lfs.2020.117717] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 04/15/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023]
Abstract
Metformin, a US Food and Drug Administration-approved "star" drug used for diabetes mellitus type 2, has become a topic of increasing interest to researchers due to its anti-neoplastic effects. Growing evidence has demonstrated that metformin may be a promising chemotherapeutic agent, and several clinical trials of metformin use in cancer treatment are ongoing. However, the anti-neoplastic effects of metformin and its underlying mechanisms have not been fully elucidated. In this review, we present the newest findings on the anticancer activities of metformin, and highlight its diverse anticancer mechanisms. Several clinical trials, as well as the limitations of the current evidence are also demonstrated. This review explores the crucial roles of metformin and provides supporting evidence for the repurposing of metformin as a treatment of cancer.
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Affiliation(s)
- Bin Zhao
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Jie Luo
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Tongyao Yu
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Liangfu Zhou
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Huanhuan Lv
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Peng Shang
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518057, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
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17
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Old wine in new bottles: Drug repurposing in oncology. Eur J Pharmacol 2020; 866:172784. [DOI: 10.1016/j.ejphar.2019.172784] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 11/05/2019] [Accepted: 11/07/2019] [Indexed: 02/07/2023]
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18
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Ranchoux B, Nadeau V, Bourgeois A, Provencher S, Tremblay É, Omura J, Coté N, Abu-Alhayja'a R, Dumais V, Nachbar RT, Tastet L, Dahou A, Breuils-Bonnet S, Marette A, Pibarot P, Dupuis J, Paulin R, Boucherat O, Archer SL, Bonnet S, Potus F. Metabolic Syndrome Exacerbates Pulmonary Hypertension due to Left Heart Disease. Circ Res 2019; 125:449-466. [PMID: 31154939 DOI: 10.1161/circresaha.118.314555] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
RATIONALE Pulmonary hypertension (PH) due to left heart disease (LHD), or group 2 PH, is the most prevalent form of PH worldwide. PH due to LHD is often associated with metabolic syndrome (MetS). In 12% to 13% of cases, patients with PH due to LHD display vascular remodeling of pulmonary arteries (PAs) associated with poor prognosis. Unfortunately, the underlying mechanisms remain unknown; PH-targeted therapies for this group are nonexistent, and the development of a new preclinical model is crucial. Among the numerous pathways dysregulated in MetS, inflammation plays also a critical role in both PH and vascular remodeling. OBJECTIVE We hypothesized that MetS and inflammation may trigger the development of vascular remodeling in group 2 PH. METHODS AND RESULTS Using supracoronary aortic banding, we induced diastolic dysfunction in rats. Then we induced MetS by a combination of high-fat diet and olanzapine treatment. We used metformin treatment and anti-IL-6 (interleukin-6) antibodies to inhibit the IL-6 pathway. Compared with sham conditions, only supracoronary aortic banding+MetS rats developed precapillary PH, as measured by both echocardiography and right/left heart catheterization. PH in supracoronary aortic banding+MetS was associated with macrophage accumulation and increased IL-6 production in lung. PH was also associated with STAT3 (signal transducer and activator of transcription 3) activation and increased proliferation of PA smooth muscle cells, which contributes to remodeling of distal PA. We reported macrophage accumulation, increased IL-6 levels, and STAT3 activation in the lung of group 2 PH patients. In vitro, IL-6 activates STAT3 and induces human PA smooth muscle cell proliferation. Metformin treatment decreased inflammation, IL-6 levels, STAT3 activation, and human PA smooth muscle cell proliferation. In vivo, in the supracoronary aortic banding+MetS animals, reducing IL-6, either by anti-IL-6 antibody or metformin treatment, reversed pulmonary vascular remodeling and improve PH due to LHD. CONCLUSIONS We developed a new preclinical model of group 2 PH by combining MetS with LHD. We showed that MetS exacerbates group 2 PH. We provided evidence for the importance of the IL-6-STAT3 pathway in our experimental model of group 2 PH and human patients.
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Affiliation(s)
- Benoît Ranchoux
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Valérie Nadeau
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Alice Bourgeois
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Steeve Provencher
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Éve Tremblay
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Junichi Omura
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Nancy Coté
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Rami Abu-Alhayja'a
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Valérie Dumais
- Institut universitaire de cardiologie et de pneumologie de Québec Research Center, Laval University, Québec City, Canada (V.D., R.T.N., A.M.)
| | - Renato T Nachbar
- Institut universitaire de cardiologie et de pneumologie de Québec Research Center, Laval University, Québec City, Canada (V.D., R.T.N., A.M.)
| | - Lionel Tastet
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Abdellaziz Dahou
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Sandra Breuils-Bonnet
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - André Marette
- Institut universitaire de cardiologie et de pneumologie de Québec Research Center, Laval University, Québec City, Canada (V.D., R.T.N., A.M.)
| | - Philippe Pibarot
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Jocelyn Dupuis
- Institut de cardiologie de Montréal, Québec, Canada (J.D.)
| | - Roxane Paulin
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Olivier Boucherat
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - Stephen L Archer
- Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A., F.P.)
| | - Sébastien Bonnet
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.)
| | - François Potus
- From the Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Québec City, Canada (B.R., V.N., A.B., S.P., E.T., J.O., N.C., R.A-A., L.T., A.D., S.B.-B., P.P., R.P., O.B., S.B., F.P.).,Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A., F.P.)
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Fujita H, Hirose K, Sato M, Fujioka I, Fujita T, Aoki M, Takai Y. Metformin attenuates hypoxia-induced resistance to cisplatin in the HepG2 cell line. Oncol Lett 2018; 17:2431-2440. [PMID: 30719114 DOI: 10.3892/ol.2018.9869] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 11/14/2018] [Indexed: 12/30/2022] Open
Abstract
Hepatoblastoma is the most commonly occurring liver tumor in children. Preoperative chemotherapy and surgery have improved treatment outcomes; however, further improvements are required in the treatment of advanced cases. Recently, the efficacy of transarterial chemoembolization (TACE) has garnered attention. TACE increases the local concentration of drugs by transcatheterically administering antitumor agents, and induces necrosis in the tumor by embolizing the feeding artery. However, studies have revealed that tumors exhibit resistance to anticancer drugs in hypoxic environments. Metformin is a drug used to treat type 2 diabetes; however, recent reports have indicated that it may also exhibit antitumor effects in various cancer cell lines. These effects are hypothesized to be mediated by the activation of adenosine monophosphate-activated protein kinase and reduction of mammalian target of rapamycin signaling, but these effects occur at high concentrations that are not suitable for use in a clinical setting. The potential efficacy of metformin at increased physiological concentrations has not been evaluated. The present study investigated the therapeutic effect of low concentrations of metformin in combination with cisplatin on liver cancer HepG2 cells in hypoxic conditions. HepG2 cells were treated with cisplatin alone, metformin alone, or a combination of these two drugs and cultured in normoxia or hypoxia. Treatment with either 5 µM cisplatin or 1 mM metformin alone did not significantly affect cell proliferation or apoptosis in hypoxic conditions. However, when 5 µM cisplatin was combined with 1 mM metformin, a significant inhibition of cell proliferation and induction of apoptosis was observed in hypoxic HepG2 cells. In conclusion, a low concentration of metformin attenuates hypoxia-induced resistance to cisplatin in HepG2 cells. Selective delivery of an effective dose of metformin to a hepatoblastoma tumor may be achievable and clinically useful with TACE.
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Affiliation(s)
- Hiromasa Fujita
- Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Katsumi Hirose
- Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.,Department of Radiation Oncology, Southern Tohoku BNCT Research Center, Koriyama, Fukushima 963-8052, Japan
| | - Mariko Sato
- Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Ichitaro Fujioka
- Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Tamaki Fujita
- Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Masahiko Aoki
- Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Yoshihiro Takai
- Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.,Department of Radiation Oncology, Southern Tohoku BNCT Research Center, Koriyama, Fukushima 963-8052, Japan
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Bridgeman SC, Ellison GC, Melton PE, Newsholme P, Mamotte CDS. Epigenetic effects of metformin: From molecular mechanisms to clinical implications. Diabetes Obes Metab 2018; 20:1553-1562. [PMID: 29457866 DOI: 10.1111/dom.13262] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 02/13/2018] [Accepted: 02/13/2018] [Indexed: 12/15/2022]
Abstract
There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP-activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition; however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.
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Affiliation(s)
- Stephanie Claire Bridgeman
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Gaewyn Colleen Ellison
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Phillip Edward Melton
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
- Centre for Genetic Origins of Health and Disease, Faculty of Health and Medical Science, The University of Western Australia, Perth, Western Australia, Australia
| | - Philip Newsholme
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Cyril Desire Sylvain Mamotte
- School of Pharmacy and Biomedical Sciences, and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
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21
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Prognostic value of metformin for non-small cell lung cancer patients with diabetes. World J Surg Oncol 2018; 16:60. [PMID: 29558957 PMCID: PMC5859437 DOI: 10.1186/s12957-018-1362-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 03/09/2018] [Indexed: 12/16/2022] Open
Abstract
Background The anti-cancer role of metformin has been reported in many different kinds of solid tumors, but how it affects non-small cell lung cancer (NSCLC) is currently elusive. The aim of this study was to investigate the influence of metformin treatment on diabetic NSCLC. Methods Two hundred fifty-five patients of diabetic NSCLC receiving therapy in our hospital from 2014 to 2016 were enrolled in our study. The information on clinical diagnosis, pathology, and prognosis as well as the influence of metformin in diabetic NSCLC were collected and assessed. Univariate and multivariate analytical techniques were applied to explore how metformin affect the survival of NSCLC. Results One hundred fifty of the 255 diabetic NSCLC patients took metformin. The median overall survival time (OST) and disease-free survival time (DFST) were significantly prolonged with metformin treatment compared to without metformin treatment (OST 25.0 vs 11.5 months, p = 0.005; DFST 15.6 vs 8.5 months, p = 0.010). Multivariate analysis indicated that metformin treatment could be used to predict the long-term outcome of diabetic NSCLC independently (HR = 0.588, 95% CI 0.466–0.895, p = 0.035). Conclusion Our study revealed that the metformin could help in improving the final outcome of NSCLC patients with diabetes in the long term and thus could be applied to treat NSCLC.
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22
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Zhi D, Zhao X, Dong M, Yan C. miR-493 inhibits proliferation and invasion in pancreatic cancer cells and inversely regulated hERG1 expression. Oncol Lett 2017; 14:7398-7404. [PMID: 29344180 PMCID: PMC5755206 DOI: 10.3892/ol.2017.7178] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 10/03/2017] [Indexed: 12/19/2022] Open
Abstract
The human ether-a-go-go-related potassium channel 1 (hERG1) is a component of the voltage-gated Kv11.1 potassium channel, which has been recently indicated to have a crucial role in the tumorigenesis of multiple tumors, including pancreatic carcinoma. Pancreatic carcinoma is one of the most malignant human cancer types, which has an extremely poor prognosis. The present study demonstrated that the expression levels of hERG1 were markedly elevated in pancreatic cancer tissues and pancreatic cancer cell lines, and that the abnormal hERG1 expression was significantly associated with the proliferation and invasion ability of pancreatic cancer. Furthermore, hERG1 was identified to be a direct target of miR-493, which is generally reduced in pancreatic cancer tissues and cell lines. These findings provide a novel insight into the regulatory mechanism of miR-493/hERG1 in pancreatic cancer cell proliferation and invasion, which may aid the development of novel diagnostic and therapeutic strategies for pancreatic cancer in the future.
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Affiliation(s)
- Duo Zhi
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, P.R. China
| | - Xin Zhao
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, P.R. China
| | - Caichuan Yan
- Department of Cancer Molecular and Biology, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150040, P.R. China
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23
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Wang J, Gao Y, Duan L, Wei S, Liu J, Tian L, Quan J, Zhang Q, Liu J, Yang J. Metformin ameliorates skeletal muscle insulin resistance by inhibiting miR-21 expression in a high-fat dietary rat model. Oncotarget 2017; 8:98029-98039. [PMID: 29228671 PMCID: PMC5716711 DOI: 10.18632/oncotarget.20442] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Accepted: 07/25/2017] [Indexed: 12/19/2022] Open
Abstract
Insulin resistance (IR) plays a major role in the pathogenesis of abdominal obesity, hypertension, coronary heart disease, atherosclerosis and diabetes. miR-21 and TGF-β/smads is closely related to IR. However, it remained elusive whether metformin improved skeletal muscle insulin resistance (IRSM) by regulating miR-21 and its target signal TGF-β1/smads expression. In this study, high-fat diet rats with IR model and IR-skeletal muscle L6 cells (L6-SMCs) model were established, insulin sensitive index (ISI) and Homeostasis model assessment of IR (HOMA-IR) were applied, miR-21 and TGF-β1/smads mRNA expression were examined by RT-PCR, smad3 and smad7 protein were detected by western-blotting and laser scanning confocal microscopy (LSCM), the valid target of miR-21 was detected by luciferase reporter gene assay. Here, we found that metformin dose-dependently decreased miR-21 expression, accompanied by the decrease of HOMA-IR and the increase of HOMA-ISI. Luciferase report gene assay showed that smad7 was an effective target of miR-21. miR-21 overexpression directly downregulated smad7 and indirectly upregulated smad3 expression. Interestingly, miR-21 expression positively correlated with HOMA-IR and negatively correlated with HOMA-ISI. In conclusion, our results demonstrated that metformin improved IRSM by inhibiting miR-21 expression, and that miR-21 may be one of the therapeutic targets for IR.
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Affiliation(s)
- Jinyang Wang
- Department of Endocrinology, Gansu Provincial People's hospital, Lanzhou, China.,Gansu Provincial Key Laboratory of Endocrine and metabolism, Lanzhou, China
| | - Yanbin Gao
- School of Traditional Chinese medical, Capital Medical University, Beijing, China.,Beijing Key Laboratory of TCM Collateral Disease Theory Research, Beijing, China
| | - Lijun Duan
- Department of Gynecology and Obstetrics, Gansu Provincial People's Hospital, Lanzhou, China
| | - Suhong Wei
- Department of Endocrinology, Gansu Provincial People's hospital, Lanzhou, China.,Gansu Provincial Key Laboratory of Endocrine and metabolism, Lanzhou, China
| | - Jing Liu
- Department of Endocrinology, Gansu Provincial People's hospital, Lanzhou, China.,Gansu Provincial Key Laboratory of Endocrine and metabolism, Lanzhou, China
| | - Liming Tian
- Department of Endocrinology, Gansu Provincial People's hospital, Lanzhou, China.,Gansu Provincial Key Laboratory of Endocrine and metabolism, Lanzhou, China
| | - Jinxing Quan
- Department of Endocrinology, Gansu Provincial People's hospital, Lanzhou, China.,Gansu Provincial Key Laboratory of Endocrine and metabolism, Lanzhou, China
| | - Qi Zhang
- Department of Endocrinology, Gansu Provincial People's hospital, Lanzhou, China.,Gansu Provincial Key Laboratory of Endocrine and metabolism, Lanzhou, China
| | - Juxiang Liu
- Department of Endocrinology, Gansu Provincial People's hospital, Lanzhou, China.,Gansu Provincial Key Laboratory of Endocrine and metabolism, Lanzhou, China
| | - Jinkui Yang
- Department of Endocrinology, Beijing Tongren hospital of Capital Medical University, Beijing, China
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24
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El-Ashmawy NE, Khedr NF, El-Bahrawy HA, Abo Mansour HE. Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway. Tumour Biol 2017; 39:1010428317692235. [PMID: 28459206 DOI: 10.1177/1010428317692235] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.
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Affiliation(s)
- Nahla E El-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Naglaa F Khedr
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Hoda A El-Bahrawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Hend E Abo Mansour
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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25
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Xia C, Chen R, Chen J, Qi Q, Pan Y, Du L, Xiao G, Jiang S. Combining metformin and nelfinavir exhibits synergistic effects against the growth of human cervical cancer cells and xenograft in nude mice. Sci Rep 2017; 7:43373. [PMID: 28252027 PMCID: PMC5333097 DOI: 10.1038/srep43373] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 01/23/2017] [Indexed: 12/28/2022] Open
Abstract
Human cervical cancer is the fourth most common carcinoma in women worldwide. However, the emergence of drug resistance calls for continuously developing new anticancer drugs and combination chemotherapy regimens. The present study aimed to investigate the anti-cervical cancer effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, and nelfinavir, an HIV protease inhibitor, when used alone or in combination. We found that both metformin and nelfinavir, when used alone, were moderately effective in inhibiting proliferation, inducing apoptosis and suppressing migration and invasion of human cervical cell lines HeLa, SiHa and CaSki. When used in combination, these two drugs acted synergistically to inhibit the growth of human cervical cancer cells in vitro and cervical cancer cell xenograft in vivo in nude mice, and suppress cervical cancer cell migration and invasion. The protein expression of phosphoinositide 3-kinase catalytic subunit PI3K(p110α), which can promote tumor growth, was remarkably downregulated, while the tumor suppressor proteins p53 and p21 were substantially upregulated following the combinational treatment in vitro and in vivo. These results suggest that clinical use of metformin and nelfinavir in combination is expected to have synergistic antitumor efficacy and significant potential for the treatment of human cervical cancer.
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Affiliation(s)
- Chenglai Xia
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.,Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA
| | - Ruihong Chen
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Jinman Chen
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Qianqian Qi
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA
| | - Yanbin Pan
- Aris Pharmaceuticals Inc., Bristol, PA19007, USA
| | - Lanying Du
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA
| | - Guohong Xiao
- Guangdong Provincial Key Laboratory of Reproductive Medicine, Guangzhou, 510150, China
| | - Shibo Jiang
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.,Laboratory of Medical Molecular Virology of Ministries of Education and Health, College of Basic Medical Science, Fudan University, Shanghai, 200032, China
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26
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Xie W, Wang L, Sheng H, Qiu J, Zhang D, Zhang L, Yang F, Tang D, Zhang K. Metformin Induces Growth Inhibition and Cell Cycle Arrest by Upregulating MicroRNA34a in Renal Cancer Cells. Med Sci Monit 2017; 23:29-37. [PMID: 28045889 PMCID: PMC5226302 DOI: 10.12659/msm.898710] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 05/30/2016] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Metformin is a widely used biguanide drug for the treatment of type 2 diabetes. It has been revaluated as a potential anti-cancer drug with promising activity in various tumors. However, the precise mechanisms underlying the suppression of cancer cells by metformin remain not well understood. MATERIAL AND METHODS In this study, human renal cell carcinoma cell line ACHN was used to investigate the anti-proliferation effect of metformin. A cell counting kit-8 assay was used to detect the cell viability. The cell cycle distribution and apoptosis were analyzed by flow cytometry. The expression of cyclin D1 and p27KIP1 was detected by Western blot. The underlying mechanism involving miRNA34a was further investigated by quantitative RT-PCR and transfection with miRNA inhibitor specific for miRNA34a in ACHN, 769-P, and A498 cells. RESULTS Metformin could significantly inhibit the proliferation of ACHN cells in a dose- and time-dependent manner. In addition, the results showed that metformin induced G0/G1 phase arrest and delayed entry into S phase in ACHN cells. It was shown that metformin downregulates the expression of cyclin D1 and increases the p27KIP1 level. Furthermore, metformin increased ACHN cell death. Lastly, miRNA34a was found to be upregulated by metformin in ACHN, 769-P, and A498 cells. Subsequently, it was demonstrated that inhibition of miRNA34a could partially attenuate the suppressive effect of metformin on renal cancer cell proliferation. CONCLUSIONS The study data revealed that metformin induced cell growth inhibition and cell cycle arrest partially by upregulating miRNA34a in renal cancer cells.
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Affiliation(s)
- Wei Xie
- Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Lei Wang
- Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Halei Sheng
- Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Jing Qiu
- Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Di Zhang
- Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Le Zhang
- Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Fan Yang
- Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Dahai Tang
- Department of Laboratory Medicine, No. 411 Hospital of CPLA, Shanghai, P.R. China
| | - Kebin Zhang
- Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
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27
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Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells. Sci Rep 2016; 6:36721. [PMID: 27830724 PMCID: PMC5103223 DOI: 10.1038/srep36721] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 10/20/2016] [Indexed: 01/02/2023] Open
Abstract
Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells.
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28
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Fujita K, Iwama H, Oura K, Tadokoro T, Hirose K, Watanabe M, Sakamoto T, Katsura A, Mimura S, Nomura T, Tani J, Miyoshi H, Morishita A, Yoneyama H, Okano K, Suzuki Y, Himoto T, Masaki T. Metformin-suppressed differentiation of human visceral preadipocytes: Involvement of microRNAs. Int J Mol Med 2016; 38:1135-40. [PMID: 27600587 PMCID: PMC5029962 DOI: 10.3892/ijmm.2016.2729] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 08/31/2016] [Indexed: 12/12/2022] Open
Abstract
Visceral adipose tissue contributes to the pathophysiology of metabolic syndrome. Metformin has been reported to suppress lipogenesis in a murine preadipocyte cell line. However, the effect of metformin on the differentiation of human visceral adipose tissue remains unknown. MicroRNAs (miRNAs or miRs) have been suggested as therapeutic targets because of their involvement in the differentiation and maturation of fatty cells. The aim of this study was to determine whether metformin suppresses the differentiation of human preadipocytes and to identify miRNAs associated with the regulation of lipid metabolism. Human visceral preadipocytes (HPrAD-vis) were preincubated in growth media and then cultured with differentiation media containing metformin for 1 or 2 weeks. Adipogenic differentiation of the cells was assessed by Oil Red O staining, and soluble adiponectin in the culture media was measured using an enzyme-linked immunosorbent assay. Cell proliferation was assessed using a WST-8 assay, and the gene and protein expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (C/EBPα) was determined by RT-qPCR and western blot analysis, respectively. miRNAs were profiled using human miRNA Oligo chips after total RNA was extracted and labeled. Oil Red O staining showed that metformin suppressed the accumulation of lipid droplets in HPrAD-vis cells. The adiponectin concentration in the culture media was also decreased in metformin-treated cells. The WST-8 assay revealed no effect on proliferation or growth inhibition following metformin treatment, although metformin suppressed the expression of PPARγ and C/EBPα. miRNA profiling further revealed differences between the metformin-treated group and control HPrAD-vis cells. Thus, the findings of the present study demonstrated that metformin suppressed the differentiation of human preadipocytes in vitro and altered the miRNA profile of these cells. Thus, the miRNAs whose expression levels were altered by metformin may contribute to the observed suppression of HPrAD-vis cell differentiation.
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Affiliation(s)
- Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kayo Hirose
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Miwako Watanabe
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Akiko Katsura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hisaaki Miyoshi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
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Fujita K, Iwama H, Miyoshi H, Tani J, Oura K, Tadokoro T, Sakamoto T, Nomura T, Morishita A, Yoneyama H, Masaki T. Diabetes mellitus and metformin in hepatocellular carcinoma. World J Gastroenterol 2016; 22:6100-13. [PMID: 27468203 PMCID: PMC4945972 DOI: 10.3748/wjg.v22.i27.6100] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.
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30
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Tomasetti M, Amati M, Santarelli L, Neuzil J. MicroRNA in Metabolic Re-Programming and Their Role in Tumorigenesis. Int J Mol Sci 2016; 17:E754. [PMID: 27213336 PMCID: PMC4881575 DOI: 10.3390/ijms17050754] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 04/27/2016] [Accepted: 05/11/2016] [Indexed: 12/13/2022] Open
Abstract
The process of metabolic re-programing is linked to the activation of oncogenes and/or suppression of tumour suppressor genes, which are regulated by microRNAs (miRNAs). The interplay between oncogenic transformation-driven metabolic re-programming and modulation of aberrant miRNAs further established their critical role in the initiation, promotion and progression of cancer by creating a tumorigenesis-prone microenvironment, thus orchestrating processes of evasion to apoptosis, angiogenesis and invasion/migration, as well metastasis. Given the involvement of miRNAs in tumour development and their global deregulation, they may be perceived as biomarkers in cancer of therapeutic relevance.
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Affiliation(s)
- Marco Tomasetti
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60020, Italy.
| | - Monica Amati
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60020, Italy.
| | - Lory Santarelli
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60020, Italy.
| | - Jiri Neuzil
- Mitochondria, Apoptosis and Cancer Research Group, School of Medical Science and Menzies Health Institute Queensland, Griffith University, Southport, QLD 4222, Australia.
- Molecular Therapy Group, Institute of Biotechnology, Czech Academy of Sciences, Prague-West 25243, Czech Republic.
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Papanagnou P, Stivarou T, Tsironi M. Unexploited Antineoplastic Effects of Commercially Available Anti-Diabetic Drugs. Pharmaceuticals (Basel) 2016; 9:ph9020024. [PMID: 27164115 PMCID: PMC4932542 DOI: 10.3390/ph9020024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 04/23/2016] [Accepted: 04/28/2016] [Indexed: 02/07/2023] Open
Abstract
The development of efficacious antitumor compounds with minimal toxicity is a hot research topic. Numerous cancer cell targeted agents are evaluated daily in laboratories for their antitumorigenicity at the pre-clinical level, but the process of their introduction into the market is costly and time-consuming. More importantly, even if these new antitumor agents manage to gain approval, clinicians have no former experience with them. Accruing evidence supports the idea that several medications already used to treat pathologies other than cancer display pleiotropic effects, exhibiting multi-level anti-cancer activity and chemosensitizing properties. This review aims to present the anticancer properties of marketed drugs (i.e., metformin and pioglitazone) used for the management of diabetes mellitus (DM) type II. Mode of action, pre-clinical in vitro and in vivo or clinical data as well as clinical applicability are discussed here. Given the precious multi-year clinical experience with these non-antineoplastic drugs their repurposing in oncology is a challenging alternative that would aid towards the development of therapeutic schemes with less toxicity than those of conventional chemotherapeutic agents. More importantly, harnessing the antitumor function of these agents would save precious time from bench to bedside to aid the fight in the arena of cancer.
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Affiliation(s)
- Panagiota Papanagnou
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Orthias Artemidos and Plateon St, Sparti GR-23100, Greece.
| | - Theodora Stivarou
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Orthias Artemidos and Plateon St, Sparti GR-23100, Greece.
| | - Maria Tsironi
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Orthias Artemidos and Plateon St, Sparti GR-23100, Greece.
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