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Mikhael S, Daoud G. Navigating Metabolic Challenges in Ovarian Cancer: Insights and Innovations in Drug Repurposing. Cancer Med 2025; 14:e70681. [PMID: 39969135 PMCID: PMC11837049 DOI: 10.1002/cam4.70681] [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: 10/29/2024] [Revised: 01/16/2025] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Ovarian cancer (OC) is the most lethal gynecological malignancy and a major global health concern, often diagnosed at advanced stages with poor survival rates. Despite advancements in treatment, resistance to standard chemotherapy remains a critical challenge with limited treatment options available. In recent years, the role of metabolic reprogramming in OC has emerged as a key factor driving tumor progression, therapy resistance, and poor clinical outcomes. METHODS This review explores the intricate connections between metabolic syndrome, enhanced glycolysis, and altered lipid metabolism within OC cells, which fuel the aggressive nature of the disease. We discuss how metabolic pathways are rewired in OC to support uncontrolled cell proliferation, survival under hypoxic conditions, and evasion of cell death mechanisms, positioning metabolic alterations as central to disease progression. The review also highlights the potential of repurposed metabolic-targeting drugs, such as metformin and statins, which have shown promise in preclinical studies for their ability to disrupt these altered metabolic pathways. CONCLUSION Drug repurposing offers a promising strategy to overcome chemoresistance and improve patient outcomes. Future research should focus on unraveling the complex metabolic networks in OC to develop innovative, targeted therapies that can enhance treatment efficacy and patient survival.
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Affiliation(s)
- Sara Mikhael
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of MedicineAmerican University of BeirutBeirutLebanon
| | - Georges Daoud
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of MedicineAmerican University of BeirutBeirutLebanon
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Wang X, Bao H, Huang YC, Barua A, Lai CM, Sun J, Zhou Y, Cong F, Gong S, Chang CH, Deng WM. Sex-dimorphic tumor growth is regulated by tumor microenvironmental and systemic signals. SCIENCE ADVANCES 2024; 10:eads4229. [PMID: 39642218 PMCID: PMC11623276 DOI: 10.1126/sciadv.ads4229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/01/2024] [Indexed: 12/08/2024]
Abstract
Tumor growth and progression involve coordinated regulation by internal, microenvironmental, and systemic signals and often display conspicuous sexual dimorphism. The mechanisms governing the integration and coordination of these signals, along with their sex-based differences, remain largely unknown. Using a Drosophila tumor model originating from nonreproductive tissue, we show that female-biased tumor growth involves multifaceted communications among tumor cells, hemocytes, and neuroendocrine insulin-producing cells (IPCs). Notch-active tumor cells recruit hemocytes carrying the tumor necrosis factor-α (TNF-α) homolog Eiger to the tumor microenvironment (TME), activating the c-Jun N-terminal kinase (JNK) pathway in tumor cells, instigating the sexually dimorphic up-regulation of cytokine Unpaired 2 (Upd2). Upd2, in turn, exerts a distal influence by modulating the release of a Drosophila insulin-like peptide (Dilp2) from IPCs. Dilp2 then activates the insulin signaling in the tumor, thereby fostering sexual-dimorphic tumor growth. Together, these findings reveal a relay mechanism involving the TME and systemic signals that collectively control the sexual dimorphism of tumor growth.
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Affiliation(s)
- Xianfeng Wang
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Hongcun Bao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Yi-Chun Huang
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Anindita Barua
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | | | - Jie Sun
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Youfang Zhou
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Fei Cong
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | | | | | - Wu-Min Deng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
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Asiri A, Al Qarni A, Bakillah A. The Interlinking Metabolic Association between Type 2 Diabetes Mellitus and Cancer: Molecular Mechanisms and Therapeutic Insights. Diagnostics (Basel) 2024; 14:2132. [PMID: 39410536 PMCID: PMC11475808 DOI: 10.3390/diagnostics14192132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 09/15/2024] [Accepted: 09/16/2024] [Indexed: 10/20/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) and cancer share common risk factors including obesity, inflammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate the PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and anti-apoptosis. The inhibition of the PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy; however, drug resistance poses a major problem in clinical settings resulting in limited efficacy of agents; thus, combination treatments with therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.
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Affiliation(s)
- Abutaleb Asiri
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ali Al Qarni
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ahmed Bakillah
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
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Kajabwangu R, Izudi J, Bazira J, Ssedyabane F, Turanzomwe S, Birungi A, Ngonzi J, Bajunirwe F, Randall TC. Effect of metabolic syndrome and its components on the risk and prognosis of cervical cancer: A literature review. Gynecol Oncol Rep 2024; 54:101438. [PMID: 39035032 PMCID: PMC11260376 DOI: 10.1016/j.gore.2024.101438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 06/13/2024] [Accepted: 06/17/2024] [Indexed: 07/23/2024] Open
Abstract
Despite the global implementation of preventive strategies against Human Papilloma Virus (HPV) infection, the incidence of invasive cervical cancer rose by nearly 1.3-fold, from 471,000 annual cases in 2000 to 604,000 cases in 2020. With over 340,000 deaths annually, cervical cancer is the fourth leading cause of cancer mortality in women globally. There is a need to understand other factors besides HPV such as metabolic syndrome (MetS) that potentially influence the onset and progression of cervical cancer. In this narrative review, we describe evidence showing that Metabolic syndrome (MetS) increases the risk for cervical cancer and worsens its prognosis. Combined screening for MetS and cervical cancer has potential to significantly reduce morbidity and mortality in women with cervical cancer.
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Affiliation(s)
- Rogers Kajabwangu
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara Uganda
| | - Jonathan Izudi
- Department of Community Health, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara Uganda
| | - Joel Bazira
- Department of Medical Microbiology, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara Uganda
| | - Frank Ssedyabane
- Department of Medical Laboratory Science, Faculty of Medicine, Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda
| | - Stuart Turanzomwe
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara Uganda
| | - Abraham Birungi
- Department of Pathology, Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda
| | - Joseph Ngonzi
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara Uganda
| | - Francis Bajunirwe
- Department of Community Health, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara Uganda
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Zhao H, Wu K. Effect of hyperglycemia on the occurrence and prognosis of colorectal cancer. Am J Transl Res 2024; 16:2070-2081. [PMID: 38883369 PMCID: PMC11170586 DOI: 10.62347/nyhh3132] [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: 03/03/2024] [Accepted: 04/29/2024] [Indexed: 06/18/2024]
Abstract
Hyperglycemic status is associated with the development and prognosis of colorectal cancer (CRC), although the exact mechanisms are not fully understood. Hyperglycemia can promote the development of CRC by influencing cell proliferation and apoptosis, inflammatory responses, oxidative stress, immunomodulation, angiogenesis, and other pathways. In terms of prognosis, hyperglycemia may affect the survival and recurrence of CRC patients as well as chemotherapy resistance, but the results of related studies are not consistent. Hypoglycemic treatment may have a positive impact on the prognosis of CRC patients, but its specific effects need further research. Therefore, this article systematically explores the relationship between hyperglycemia and CRC, analyzes the impact of hyperglycemia on the occurrence and prognosis of CRC, and discusses the role of managing hyperglycemia in CRC.
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Affiliation(s)
- Hongxing Zhao
- Department of Radiology, First Affiliated Hospital of Huzhou University Huzhou 313000, Zhejiang, China
| | - Kangzhong Wu
- Department of General Surgery, First Affiliated Hospital of Huzhou University Huzhou 313000, Zhejiang, China
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Jeong S, Poudyal S, Klagges S, Kuhnt T, Papsdorf K, Hambsch P, Wach J, Güresir E, Nägler F, Rühle A, Nicolay NH, Seidel C. Diabetes Mellitus Is a Strong Independent Negative Prognostic Factor in Patients with Brain Metastases Treated with Radiotherapy. Cancers (Basel) 2023; 15:4845. [PMID: 37835539 PMCID: PMC10571851 DOI: 10.3390/cancers15194845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 09/07/2023] [Accepted: 09/29/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Brain metastases (BM) cause relevant morbidity and mortality in cancer patients. The presence of cerebrovascular diseases can alter the tumor microenvironment, cellular proliferation and treatment resistance. However, it is largely unknown if the presence of distinct cerebrovascular risk factors may alter the prognosis of patients with BM. METHODS Patients admitted for the radiotherapy of BM at a large tertiary cancer center were included. Patient and survival data, including cerebrovascular risk factors (diabetes mellitus (DM), smoking, arterial hypertension, peripheral arterial occlusive disease, hypercholesterolemia and smoking) were recorded. RESULTS 203 patients were included. Patients with DM (n = 39) had significantly shorter overall survival (OS) (HR 1.75 (1.20-2.56), p = 0.003, log-rank). Other vascular comorbidities were not associated with differences in OS. DM remained prognostically significant in the multivariate Cox regression including established prognostic factors (HR 1.92 (1.20-3.06), p = 0.006). Furthermore, subgroup analyses revealed a prognostic role of DM in patients with non-small cell lung cancer, both in univariate (HR 1.68 (0.97-2.93), p = 0.066) and multivariate analysis (HR 2.73 (1.33-5.63), p = 0.006), and a trend in melanoma patients. CONCLUSION DM is associated with reduced survival in patients with BM. Further research is necessary to better understand the molecular mechanisms and therapeutic implications of this important interaction.
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Affiliation(s)
- Seong Jeong
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
| | - Soniya Poudyal
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
| | | | - Thomas Kuhnt
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
| | - Kirsten Papsdorf
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
| | - Peter Hambsch
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
| | - Johannes Wach
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
- Department of Neurosurgery, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Erdem Güresir
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
- Department of Neurosurgery, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Franziska Nägler
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
| | - Alexander Rühle
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
| | - Nils H. Nicolay
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
| | - Clemens Seidel
- Department of Radiation Oncology, University of Leipzig Medical Center, 04103 Leipzig, Germany (S.P.); (T.K.)
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, 04103 Leipzig, Germany; (J.W.)
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Sharma N, Dhingra R. Clinical potentials of metformin in cancer therapy. JOURNAL OF DIABETOLOGY 2023; 14:186-192. [DOI: 10.4103/jod.jod_84_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/28/2023] [Indexed: 01/05/2025] Open
Abstract
Abstract
Diabetes is a prevalent metabolic disorder that results in several comorbidities including cancer. Cancer becomes the most severe complication of diabetes patients. Growing evidence proved that impaired glucose homeostasis is an independent risk factor for the occurrence of various types of cancers including liver, pancreatic, gastric (stomach), colorectal, kidney, and breast cancers, and influences cancer prognosis. Diabetes mellitus and cancer have a bidirectional relationship, thus there is a need to look for drugs that can be beneficial in treating both diseases. Therefore, more research is focusing on evaluating the role of antihyperglycemic agents in the treatment of various types of cancers. Metformin, an FDA-approved first-line antihyperglycemic agent can be used as a monotherapy or as an adjuvant to chemotherapeutic agents in the treatment of various types of cancer. However, the exact mechanism of metformin as an anticancer agent is still unknown, the majority of the described putative mechanisms focus on promoting the activity of the AMP-activated protein kinase (AMPK) pathway. This review article thus gives insights into the prognosis of cancer in diabetes patients and aims to explore the possible mechanism of action of metformin in the prevention and treatment of cancer.
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Affiliation(s)
- Nidhi Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Sohna, Haryana, India
| | - Richa Dhingra
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Sohna, Haryana, India
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Dubois N, Muñoz-Garcia J, Heymann D, Renodon-Cornière A. High glucose exposure drives intestinal barrier dysfunction by altering its morphological, structural and functional properties. Biochem Pharmacol 2023; 216:115765. [PMID: 37619641 DOI: 10.1016/j.bcp.2023.115765] [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: 05/12/2023] [Revised: 08/07/2023] [Accepted: 08/21/2023] [Indexed: 08/26/2023]
Abstract
High dietary glucose consumption and hyperglycemia can result in chronic complications. Several studies suggest that high glucose (HG) induces dysfunction of the intestinal barrier. However, the precise changes remain unclear. In our study, we used in vitro models composed of Caco-2 and/or HT29-MTX cells in both monoculture and co-culture to assess the effects of long-term HG exposure on the morphological, structural, and functional properties of the intestinal barrier. Cells were grown in medium containing normal physiologic glucose (NG, 5.5 mM) or a clinically relevant HG (25 mM) concentration until 21 days. Results demonstrated that HG induced morphological changes, with the layers appearing denser and less organized than under physiological conditions, which is in accordance with the increased migration capacity of Caco-2 cells and proliferation properties of HT29-MTX cells. Although we mostly observed a small decrease in mRNA and protein expressions of three junction proteins (ZO-1, OCLN and E-cad) in both Caco-2 and HT29-MTX cells cultured in HG medium, confocal microscopy showed that HG induced a remarkable reduction in their immunofluorescence intensity, triggering disruption of their associated structural network. In addition, we highlighted that HG affected different functionalities (permeability, mucus production and alkaline phosphatase activity) of monolayers with Caco-2 and HT29-MTX cells. Interestingly, these alterations were stronger in co-culture than in monoculture, suggesting a cross-relationship between enterocytes and goblet cells. Controlling hyperglycemia remains a major therapeutical method for reducing damage to the intestinal barrier and improving therapies.
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Affiliation(s)
- Nolwenn Dubois
- Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Laboratory, 44805 Saint-Herblain, France
| | - Javier Muñoz-Garcia
- Nantes Université, CNRS, US2B, UMR 6286, F-44322 Nantes, France; Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Laboratory, 44805 Saint-Herblain, France
| | - Dominique Heymann
- Nantes Université, CNRS, US2B, UMR 6286, F-44322 Nantes, France; Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Laboratory, 44805 Saint-Herblain, France; The University of Sheffield, Dept of Oncology and Metabolism, S102RX Sheffield, UK
| | - Axelle Renodon-Cornière
- Nantes Université, CNRS, US2B, UMR 6286, F-44322 Nantes, France; Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Laboratory, 44805 Saint-Herblain, France.
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Lovin BD, Wilkinson AJ, Qing Y, Hernandez M, Nader ME, Raza S, DeMonte F, Gidley PW. The Effect of Metformin on Vestibular Schwannoma Growth: A Systematic Review and Meta-analysis. Laryngoscope 2023; 133:2066-2072. [PMID: 36744870 PMCID: PMC10404300 DOI: 10.1002/lary.30601] [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: 10/28/2022] [Revised: 01/18/2023] [Accepted: 01/22/2023] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To systematically review and evaluate metformin's potential impact on vestibular schwannoma (VS) growth. DATA SOURCES PubMed, Cochrane Library, and Embase. REVIEW METHODS A retrospective cohort study was performed on sporadic VS patients undergoing initial observation who had at least two magnetic resonance imaging studies. Patients were stratified by metformin use during the observation period. Primary endpoint was VS growth, defined as at least a 2 mm increase in diameter. Survival free of tumor growth was evaluated between groups. Systematic review and meta-analysis were performed to produce a pooled odds ratio [OR]. Study heterogeneity was assessed and post-hoc power analysis was performed. RESULTS A total of 123 patients were included, of which 17% were taking metformin. Median patient age was 56.6 years (range, 25.1-84.5). There were no statistically significant differences between the groups. Survival analysis did not demonstrate a statistically significant difference in time to VS growth between groups (hazard ratio = 0.61, 95% confidence interval [CI] = 0.29-1.29). Furthermore, logistic regression analysis did not demonstrate a statistically significant difference between groups in the odds of VS growth (OR = 0.46, 95% CI = 0.17-1.27). Systematic review identified 3 studies. Meta-analysis suggested that metformin reduces the odds of developing VS growth (pooled OR = 0.45, 95% CI = 0.29-0.71). Studies demonstrated low between-study heterogeneity. Power analysis demonstrated a sample size of 220 patients with equal randomization would be required to prospectively identify a true difference with 80% power. CONCLUSIONS Metformin use may reduce the odds of VS growth. A randomized trial would be ideal to identify an unbiased estimate of metformin's effect on VS growth. Laryngoscope, 133:2066-2072, 2023.
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Affiliation(s)
- Benjamin D Lovin
- Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Alex J Wilkinson
- McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA
| | - Yun Qing
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mike Hernandez
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marc-Elie Nader
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Shaan Raza
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Franco DeMonte
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Paul W Gidley
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Dey S, Murmu N, Mondal T, Saha I, Chatterjee S, Manna R, Haldar S, Dash SK, Sarkar TR, Giri B. Multifaceted entrancing role of glucose and its analogue, 2-deoxy-D-glucose in cancer cell proliferation, inflammation, and virus infection. Biomed Pharmacother 2022; 156:113801. [DOI: 10.1016/j.biopha.2022.113801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/29/2022] [Accepted: 10/02/2022] [Indexed: 11/30/2022] Open
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Haluszka E, Niclis C, Diaz MDP, Osella AR, Aballay LR. Higher dietary glycaemic index, intake of high glycaemic index foods and insulin load are associated with the risk of breast cancer, with differences according to body mass index in women from Córdoba, Argentina. Nutr Res 2022; 104:108-117. [DOI: 10.1016/j.nutres.2022.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 01/10/2023]
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Obukhova L, Nikiforova O, Kontorshchikova C, Medyanik I, Orlinskaya N, Grishin A, Kontorshchikov M, Shchelchkova N. Carbohydrate Metabolism Parameters of Adult Glial Neoplasms According to Immunohistochemical Profile. Biomedicines 2022; 10:biomedicines10051007. [PMID: 35625744 PMCID: PMC9138280 DOI: 10.3390/biomedicines10051007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 11/16/2022] Open
Abstract
This research aimed to investigate the interrelationship of carbohydrate metabolism parameters and immunohistochemical characteristics of glial tumors. Tumor tissue, peritumoral area, and adjacent noncancerous tissue fragments of 20 patients with gliomas of varying degrees of anaplasia were analyzed. The greatest differences in the carbohydrate metabolism compared to adjacent noncancerous tissues were identified in the tumor tissue: reduction in the levels of lactate and glycogen synthase kinase-3β. Significant differences with adjacent noncancerous tissues for the peritumoral zone were not found. The activity of the carbohydrate metabolism enzymes was different depending on the immunohistochemical glioma profile, especially from Ki 67 level. Bioinformatic analysis of the interactions of immunohistochemical markers of gliomas and carbohydrate metabolism enzymes using the databases of STRING, BioGrid, and Signor revealed the presence of biologically significant interactions with glycogen synthase kinase 3β, hexokinase, glucose-6-phosphate dehydrogenase, and transketolase. The established interconnection of glycolysis with methylation of the promoter of O-6-methylguanine-DNA-methyltransferase (MGMT) of gliomas can be used to increase chemotherapy efficiency.
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Khanlarkhani N, Azizi E, Amidi F, Khodarahmian M, Salehi E, Pazhohan A, Farhood B, Mortezae K, Goradel NH, Nashtaei MS. Metabolic risk factors of ovarian cancer: a review. JBRA Assist Reprod 2022; 26:335-347. [PMID: 34751020 PMCID: PMC9118962 DOI: 10.5935/1518-0557.20210067] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 08/29/2021] [Indexed: 11/20/2022] Open
Abstract
Ovarian cancer continues to be the leading cause of death from gynecological cancers. Despite inconsistent results, patients with metabolic abnormalities, including obesity and diabetes mellitus (DM), have poorer outcomes, showing a correlation with ovarian cancer incidence and ovarian cancer survival. Since ovarian cancer is the most common cancer in women, and considering the increasing prevalence of obesity and DM, this paper reviews the literature regarding the relationship between the aforementioned metabolic derangements and ovarian cancer, with a focus on ovarian cancer incidence, mortality, and likely mechanisms behind them. Several systematic reviews and meta-analyses have shown that obesity is associated with a higher incidence and poorer survival in ovarian cancer. Although more studies are required to investigate the etiological relation of DM and ovarian cancer, sufficient biological evidence indicates poorer outcomes and shorter survival in DM women with ovarian cancer. A variety of pathologic factors may contribute to ovarian cancer risk, development, and survival, including altered adipokine expression, increased levels of circulating growth factors, altered levels of sex hormones, insulin resistance, hyperinsulinemia, and chronic inflammation. Thus, obesity and DM, as changeable risk factors, can be targeted for intervention to prevent ovarian cancer and improve its outcomes.
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Affiliation(s)
- Neda Khanlarkhani
- Department of Physiology and Pharmacology, Karolinska Institute, Sweden
| | - Elham Azizi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fardin Amidi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahshad Khodarahmian
- Infertility department, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ensieh Salehi
- Department of Gynecology, School of Medicine, Fertility and Infertility Research Center, Dr. Ali Shariati Hospital, Shahid Mohammadi Hospital, Hormozgan University of Medical Sciences, Hormozgan, Iran
| | - Azar Pazhohan
- Infertility Center, Academic Center for Education, Culture and Research, East Azarbaijan, Tabriz, Iran. / Department of Midwifery, Urmia Branch, Islamic Azad University, Urmia, Iran
| | - Bagher Farhood
- Departments of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Keywan Mortezae
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Shabani Nashtaei
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. / Infertility Department, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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14
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Adnan M, Jeon BB, Chowdhury MHU, Oh KK, Das T, Chy MNU, Cho DH. Network Pharmacology Study to Reveal the Potentiality of a Methanol Extract of Caesalpinia sappan L. Wood against Type-2 Diabetes Mellitus. Life (Basel) 2022; 12:277. [PMID: 35207564 PMCID: PMC8880704 DOI: 10.3390/life12020277] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/22/2022] Open
Abstract
Caesalpinia sappan L. (CS) is widely used to treat diabetic complications in south-east Asia, specifically in traditional Chinese medicine. This study intends to explain the molecular mechanism of how chemical constituents of CS interrelate with different signaling pathways and receptors involved in T2DM. GC-MS was employed to identify the chemical compounds from the methanol extract of CS wood (MECSW). Lipinski's rule of five was applied, and 33 bioactive constituents have been screened from the CS extract. After that, 124 common targets and 26 compounds associated with T2DM were identified by mining several public databases. Protein-protein interactions and compound-target network were constructed using the STRING database and Cytoscape tool. Protein-protein interactions were identified in 121 interconnected nodes active in T2DM and peroxisome proliferator-activated receptor gamma (PPARG) as key target receptors. Furthermore, pathway compound target (PCT) analysis using the merger algorithm plugin of Cytoscape revealed 121 nodes from common T2DM targets, 33 nodes from MECSW compounds and 9 nodes of the KEGG pathway. Moreover, network topology analysis determined "Fisetin tetramethyl ether" as the key chemical compound. The DAVID online tool determined seven signaling receptors, among which PPARG was found most significant in T2DM progression. Gene ontology and KEGG pathway analysis implied the involvement of nine pathways, and the peroxisome proliferator-activated receptor (PPAR) pathway was selected as the hub signaling pathway. Finally, molecular docking and quantum chemistry analysis confirmed the strong binding affinity and reactive chemical nature of fisetin tetramethyl ether with target receptors exceeding that of the conventional drug (metformin), PPARs agonist (rosiglitazone) and co-crystallized ligands, indicating that fisetin could be a potential drug of choice in T2DM management. This study depicts the interrelationship of the bioactive compounds of MECSW with the T2DM-associated signaling pathways and target receptors. It also proposes a more pharmaceutically effective substance, fisetin tetramethyl ether, over the standard drug that activates PPARG protein in the PPAR signaling pathway of T2DM.
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Affiliation(s)
- Md. Adnan
- Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea; (M.A.); (B.-B.J.); (K.-K.O.)
| | - Byeong-Bae Jeon
- Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea; (M.A.); (B.-B.J.); (K.-K.O.)
| | - Md. Helal Uddin Chowdhury
- Ethnobotany and Pharmacognosy Lab, Department of Botany, University of Chittagong, Chattogram 4331, Bangladesh;
| | - Ki-Kwang Oh
- Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea; (M.A.); (B.-B.J.); (K.-K.O.)
| | - Tuhin Das
- Department of Microbiology, University of Chittagong, Chattogram 4331, Bangladesh;
| | - Md. Nazim Uddin Chy
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh;
| | - Dong-Ha Cho
- Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea; (M.A.); (B.-B.J.); (K.-K.O.)
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15
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Kushchayeva Y, Kushchayev S, Jensen K, Brown RJ. Impaired Glucose Metabolism, Anti-Diabetes Medications, and Risk of Thyroid Cancer. Cancers (Basel) 2022; 14:cancers14030555. [PMID: 35158824 PMCID: PMC8833385 DOI: 10.3390/cancers14030555] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary An epidemiologic link exists between obesity, insulin resistance, diabetes, and some cancers, such as breast cancer and colon cancer. The prevalence of obesity and diabetes is increasing, and additional epidemiologic data suggest that there may be a link between obesity and risk of thyroid abnormalities. Factors that may link obesity and diabetes with thyroid proliferative disorders include elevated circulating levels of insulin, increased body fat, high blood sugars, and exogenous insulin use. However, mechanisms underlying associations of obesity, diabetes, and thyroid proliferative disorders are not yet fully understood. The present manuscript reviews and summarizes current evidence of mechanisms and epidemiologic associations of obesity, insulin resistance, and use of anti-diabetes medications with benign and malignant proliferative disorders of the thyroid. Abstract The prevalence of obesity is progressively increasing along with the potential high risk for insulin resistance and development of type 2 diabetes mellitus. Obesity is associated with increased risk of many malignancies, and hyperinsulinemia has been proposed to be a link between obesity and cancer development. The incidence of thyroid cancer is also increasing, making this cancer the most common endocrine malignancy. There is some evidence of associations between obesity, insulin resistance and/or diabetes with thyroid proliferative disorders, including thyroid cancer. However, the etiology of such an association has not been fully elucidated. The goal of the present work is to review the current knowledge on crosstalk between thyroid and glucose metabolic pathways and the effects of obesity, insulin resistance, diabetes, and anti-hyperglycemic medications on the risk of thyroid cancer development.
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Affiliation(s)
- Yevgeniya Kushchayeva
- Diabetes and Endocrinology Center, University of South Florida, Tampa, FL 33612, USA
- Correspondence:
| | - Sergiy Kushchayev
- Department of Radiology, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Kirk Jensen
- F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA;
| | - Rebecca J. Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;
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16
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Guo JZ, Wu QJ, Liu FH, Gao C, Gong TT, Li G. Review of Mendelian Randomization Studies on Endometrial Cancer. Front Endocrinol (Lausanne) 2022; 13:783150. [PMID: 35615721 PMCID: PMC9124776 DOI: 10.3389/fendo.2022.783150] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 03/30/2022] [Indexed: 01/04/2023] Open
Abstract
Endometrial cancer (EC) is a common gynecological cancer. In some parts of the world, the incidence and mortality of EC are on the rise. Understanding the risk factors of EC is necessary to prevent the occurrence of this disease. Observational studies have revealed the association between certain modifiable environmental risk factors and EC risk. However, due to unmeasured confounding, measurement errors, and reverse causality, observational studies sometimes have limited ability to judge robust causal inferences. In recent years, Mendelian randomization (MR) analysis has received extensive attention, providing valuable insights for cancer-related research, and is expected to identify potential therapeutic interventions. In MR analysis, genetic variation (alleles are randomly assigned during meiosis and are usually independent of environmental or lifestyle factors) is used instead of modifiable exposure to study the relationship between risk factors and disease. Therefore, MR analysis can make causal inference about exposure and disease risk. This review briefly describes the key principles and assumptions of MR analysis; summarizes published MR studies on EC; focuses on the correlation between different risk factors and EC risks; and discusses the application of MR methods in EC research. The results of MR studies on EC showed that type 2 diabetes, uterine fibroids, higher body mass index, higher plasminogen activator inhibitor-1 (PAI-1), higher fasting insulin, early insulin secretion, longer telomere length, higher testosterone and higher plasma cortisol levels are associated with increased risk of EC. In contrast, later age of menarche, higher circulatory tumor necrosis factor, higher low-density lipoprotein cholesterol, and higher sex hormone-binding globulin levels are associated with reduced risk of EC. In general, despite some limitations, MR analysis still provides an effective way to explore the causal relationship between different risk factors and EC.
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Affiliation(s)
- Jian-Zeng Guo
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qi-Jun Wu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fang-Hua Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
- Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chang Gao
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
- Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ting-Ting Gong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Gang Li, ; Ting-Ting Gong,
| | - Gang Li
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Gang Li, ; Ting-Ting Gong,
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17
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Yu GH, Jiang Z. Progress in understanding of relationship between diabetes and colorectal cancer. Shijie Huaren Xiaohua Zazhi 2021; 29:1323-1333. [DOI: 10.11569/wcjd.v29.i23.1323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Several epidemiological studies have suggested that diabetes is closely associated with an increased risk of colorectal cancer and diabetes could be regarded as an independent risk factor for colorectal cancer. Potential pathophysiological mechanisms connecting diabetes and colorectal cancer include hyperglycemia, hyperinsulinemia, and insulin-like growth factor axis, chronic inflammation and oxidative stress, gastrointestinal motility disorder, and impaired immunological surveillance. Meanwhile, multiple studies have revealed that diabetes is negatively related to the prognosis of patients with colorectal cancer. This review mainly summarizes the current studies concerning the linkages between diabetes and colorectal cancer and the underlying pathophysiological mechanisms, so as to provide a theoretical basis for rational use of antidiabetic drugs and early diagnosis of diabetes-related colorectal cancer.
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Affiliation(s)
- Guan-Hua Yu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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18
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Sublethal concentrations of high glucose prolong mitotic arrest in a spindle assembly checkpoint activity dependent manner in budding yeast. Biologia (Bratisl) 2021. [DOI: 10.1007/s11756-021-00912-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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19
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Lin CY, Chang CB, Wu RC, Chao A, Lee YS, Tsai CN, Chen CH, Yen CF, Tsai CL. Glucose Activates Lysine-Specific Demethylase 1 through the KEAP1/p62 Pathway. Antioxidants (Basel) 2021; 10:antiox10121898. [PMID: 34942999 PMCID: PMC8750790 DOI: 10.3390/antiox10121898] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 12/30/2022] Open
Abstract
Endometrial cancer incidence increases annually. Several risk factors, including high glucose intake, are associated with endometrial cancer. We investigated whether glucose affects lysine-specific demethylase 1 (LSD1) expression and the responsible molecular mechanisms. A high concentration of glucose stimulated p62 phosphorylation and increased LSD1 protein expression. Knockdown of p62 or treatment with mammalian target of rapamycin (mTOR), transforming growth factor-β activated kinase 1 (TAK1), casein kinase 1 (CK1), and protein kinase C (PKC) inhibitors abrogated glucose-regulated LSD1 expression. Unphosphorylated p62 and LSD1 formed a complex with Kelch-like ECH-associated protein 1 (KEAP1) and were degraded by the KEAP1-dependent proteasome. Phosphorylated p62 increased LSD1 protein expression by escaping the KEAP1 proteasome complex. LSD1 and KEAP1 interaction was enhanced in the presence of the nuclear factor erythroid 2-related factor 2 (NRF2) protein. LSD1 also participated in antioxidant gene regulation with NRF2. In diabetic mice, increasing LSD1and phospho-p62 expression was observed in uterine epithelial cells. Our results indicate that glucose induces p62 phosphorylation through mTOR, TAK1, CK1, and PKC kinases. Subsequently, phospho-p62 competitively interacts with KEAP1 and releases NRF2–LSD1 from the KEAP1 proteasome complex. Our findings may have public health implications for the prevention of endometrial cancer.
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Affiliation(s)
- Chiao-Yun Lin
- Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-Y.L.); (C.-B.C.); (A.C.)
| | - Chen-Bin Chang
- Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-Y.L.); (C.-B.C.); (A.C.)
- Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan;
| | - Ren-Chin Wu
- Department of Pathology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan;
| | - Angel Chao
- Gynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-Y.L.); (C.-B.C.); (A.C.)
- Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan;
| | - Yun-Shien Lee
- Department of Biotechnology, Ming-Chuan University, Taoyuan 333, Taiwan;
| | - Chi-Neu Tsai
- Department of Surgery, Graduate Institute of Clinical Medical Sciences, Chang-Gung University, New Taipei Municipal Tucheng Hospital, New Taipei City 236, Taiwan;
| | - Chih-Hao Chen
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Keelung, Chang Gung University College of Medicine, Taoyuan 333, Taiwan;
| | - Chih-Feng Yen
- Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan;
| | - Chia-Lung Tsai
- Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Correspondence:
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20
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Shahid RK, Ahmed S, Le D, Yadav S. Diabetes and Cancer: Risk, Challenges, Management and Outcomes. Cancers (Basel) 2021; 13:5735. [PMID: 34830886 PMCID: PMC8616213 DOI: 10.3390/cancers13225735] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/03/2021] [Accepted: 11/12/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Diabetes mellitus and cancer are commonly coexisting illnesses, and the global incidence and prevalence of both are rising. Cancer patients with diabetes face unique challenges. This review highlights the relationship between diabetes and cancer and various aspects of the management of diabetes in cancer patients. METHODS A literature search using keywords in PubMed was performed. Studies that were published in English prior to July 2021 were assessed and an overview of epidemiology, cancer risk, outcomes, treatment-related hyperglycemia and management of diabetes in cancer patients is provided. RESULTS Overall, 8-18% of cancer patients have diabetes as a comorbid medical condition. Diabetes is a risk factor for certain solid malignancies, such as pancreatic, liver, colon, breast, and endometrial cancer. Several novel targeted compounds and immunotherapies can cause hyperglycemia. Nevertheless, most patients undergoing cancer therapy can be managed with an appropriate glucose lowering agent without the need for discontinuation of cancer treatment. Evidence suggests that cancer patients with diabetes have higher cancer-related mortality; therefore, a multidisciplinary approach is important in the management of patients with diabetes and cancer for a better outcome. CONCLUSIONS Future studies are required to better understand the underlying mechanism between the risk of cancer and diabetes. Furthermore, high-quality prospective studies evaluating management of diabetes in cancer patients using innovative tools are needed. A patient-centered approach is important in cancer patients with diabetes to avoid adverse outcomes.
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Affiliation(s)
- Rabia K. Shahid
- Department of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada;
| | - Shahid Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK S7N 4H4, Canada; (D.L.); (S.Y.)
| | - Duc Le
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK S7N 4H4, Canada; (D.L.); (S.Y.)
| | - Sunil Yadav
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK S7N 4H4, Canada; (D.L.); (S.Y.)
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21
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Type 2 Diabetes Mellitus and Cancer: Epidemiology, Physiopathology and Prevention. Biomedicines 2021; 9:biomedicines9101429. [PMID: 34680546 PMCID: PMC8533606 DOI: 10.3390/biomedicines9101429] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 01/01/2023] Open
Abstract
Individuals with type 2 diabetes mellitus are at greater risk of developing cancer and of dying from it. Both diseases are age-related, contributing to the impact of population aging on the long-term sustainability of health care systems in European Union countries. The purpose of this narrative review was to describe, from epidemiological, pathophysiological and preventive perspectives, the links between type 2 diabetes mellitus and the most prevalent cancers in these patients. Multiple metabolic abnormalities that may occur in type 2 diabetes mellitus, particularly obesity, could explain the increased cancer risk. In addition, the effectiveness of drugs commonly used to treat type 2 diabetes mellitus (e.g., metformin and thiazolidinediones) has been broadly evaluated in cancer prevention. Thus, a better understanding of the links between type 2 diabetes mellitus and cancer will help to identify the contributing factors and the pathophysiological pathways and to design personalized preventive strategies. The final goal is to facilitate healthy aging and the prevention of cancer and other diseases related with type 2 diabetes mellitus, which are among the main sources of disability and death in the European Union and worldwide.
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22
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Xia B, Peng J, Enrico DT, Lu K, Cheung EC, Kuo Z, He Q, Tang Y, Liu A, Fan D, Zhang C, He Y, Pan Y, Yuan J. Metabolic syndrome and its component traits present gender-specific association with liver cancer risk: a prospective cohort study. BMC Cancer 2021; 21:1084. [PMID: 34620113 PMCID: PMC8499577 DOI: 10.1186/s12885-021-08760-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 08/28/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND & AIMS Little is known on the gender-specific effect and potential role of non-linear associations between metabolic syndrome (MetS) components and liver cancer risk. We evaluated these associations based on the UK Biobank cohort. METHODS We included 474,929 individuals without previous cancer based on the UK Biobank cohort. Gender-specific hazard ratios (HRs) and 95% confidence interval (CIs) were calculated by Cox proportional hazards regression, adjusting for potential confounders. Non-linear associations for individual MetS components were assessed by the restricted cubic spline method. RESULTS Over a median follow-up of 6.6 years, we observed 276 cases of liver cancer (175 men, 101 women). MetS [HR 1.48, 95% CI 1.27-1.72] and central obesity [HR 1.65, 95% CI 1.18-2.31] were associated with higher risk of liver cancer in men but not in women. Participants with hyperglycaemia has higher risk of liver cancer. High waist circumference and blood glucose were dose-dependently associated with increased liver cancer risk in both genders. For high density lipoprotein (HDL) cholesterol (both genders) and blood pressure (women), U-shaped associations were observed. Low HDL cholesterol (< 1.35 mmol/L) in men and high HDL cholesterol in women (> 1.52 mmol/L) were associated with increased liver cancer risk. CONCLUSIONS MetS components showed gender-specific linear or U- shaped associations with the risk of liver cancer. Our study might provide evidence for individualized management of MetS for preventing liver cancer.
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Affiliation(s)
- Bin Xia
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.,Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.,Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Jianjun Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - De Toni Enrico
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Kuiqing Lu
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.,Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Eddie C Cheung
- Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.,Division of Gastroenterology, Davis School of Medicine, University of California, Oakland, USA
| | - Zichong Kuo
- Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Qiangsheng He
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.,Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.,Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yan Tang
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.,Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Anran Liu
- Department of Clinical Nutrition, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Die Fan
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.,Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Changhua Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yulong He
- Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Precision Medicine Center, Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
| | - Jinqiu Yuan
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China. .,Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China. .,Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
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23
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Kumar Das B, Gadad PC. Impact of diabetes on the increased risk of hepatic cancer: An updated review of biological aspects. DIABETES EPIDEMIOLOGY AND MANAGEMENT 2021; 4:100025. [DOI: 10.1016/j.deman.2021.100025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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24
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Hyperglycemic conditions proliferate triple negative breast cancer cells: role of ornithine decarboxylase. Breast Cancer Res Treat 2021; 190:255-264. [PMID: 34529197 DOI: 10.1007/s10549-021-06388-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 09/06/2021] [Indexed: 01/18/2023]
Abstract
PURPOSE Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose (HG) conditions. METHODS Studies were performed with varying concentrations of glucose (5-25 mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A. RESULTS There was a significant increase in proliferation with HG (25 mM) at 48-72 h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5 mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells. CONCLUSIONS Our cellular findings indicate that polyamine inhibition should be explored in patient population as a target for future chemotherapeutics in diabetic breast cancer.
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Yim C, Mansell K, Hussein N, Arnason T. Current cancer therapies and their influence on glucose control. World J Diabetes 2021; 12:1010-1025. [PMID: 34326951 PMCID: PMC8311484 DOI: 10.4239/wjd.v12.i7.1010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/11/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.
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Affiliation(s)
- Carly Yim
- Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Kerry Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Nassrein Hussein
- Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Terra Arnason
- Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
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Georgescu DE, Patrascu T, Georgescu TF, Tulin A, Mosoia L, Bacalbasa N, Stiru O, Georgescu MT. Diabetes Mellitus as a Prognostic Factor for Locally Advanced Rectal Cancer. In Vivo 2021; 35:2495-2501. [PMID: 34182536 DOI: 10.21873/invivo.12530] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/29/2021] [Accepted: 05/31/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM Currently, the impact of diabetes mellitus (DM) on rectal cancer patients is complex and just partly elucidated. The purpose of this study was to investigate the impact of diabetes mellitus on rectal cancer patients focusing on tumor differentiation grade, neoadjuvant chemoradiotherapy (NACRT) response, disease-free (DFS) and overall (OS) survival. PATIENTS AND METHODS Our study's population consisted of a group of 53 patients diagnosed with locally advanced rectal cancer, who underwent NACRT, followed by radical oncological surgery. This patient population was further divided into two groups according to diabetes presence. RESULTS Downstaging rates, local control, DFS, and OS were lower in the DM subgroup compared to the non-DM locally advanced rectal cancer patients. CONCLUSION The presence of DM at the time of diagnosis of locally advanced rectal cancer patients may be a negative predictive factor for response to neoadjuvant therapy, distant metastases, and local recurrences rates.
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Affiliation(s)
- Dragos Eugen Georgescu
- Department of General Surgery, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,Department of General Surgery, "Dr. Ion Cantacuzino" Clinical Hospital, Bucharest, Romania
| | - Traian Patrascu
- Department of General Surgery, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,Department of General Surgery, "Dr. Ion Cantacuzino" Clinical Hospital, Bucharest, Romania
| | - Teodor Florin Georgescu
- Department of General Surgery, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania; .,Department of General Surgery, Bucharest Clinical Emergency Hospital, Bucharest, Romania
| | - Adrian Tulin
- Department of General Surgery, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,Department of General Surgery, Clinical Emergency Hospital "Prof. Dr. Agrippa Ionescu", Bucharest, Romania
| | - Liviu Mosoia
- Department of General Surgery, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,Department of General Surgery, Central Military Emergency Hospital "Dr. Carol Davila", Bucharest, Romania
| | - Nicolae Bacalbasa
- Department of Obstetrics and Gynecology, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,Department of Visceral Surgery, Center of Excellence in Translational Medicine "Fundeni" Clinical Institute, Bucharest, Romania
| | - Ovidiu Stiru
- Emergency Institute for Cardiovascular Diseases Prof. Dr. C.C. Iliescu, Bucharest, Romania.,Department of Cardio-Thoracic Pathology, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Mihai-Teodor Georgescu
- Department of Radiotherapy II, "Prof. Dr. Alex. Trestioreanu" Institute of Oncology, Bucharest, Romania.,Discipline of Oncology, Department 8 (Radiology, Oncology, Haematology), "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
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Fernandez CJ, George AS, Subrahmanyan NA, Pappachan JM. Epidemiological link between obesity, type 2 diabetes mellitus and cancer. World J Methodol 2021; 11:23-45. [PMID: 34026577 PMCID: PMC8127420 DOI: 10.5662/wjm.v11.i3.23] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/02/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023] Open
Abstract
There exists a complex interaction between obesity, type 2 diabetes mellitus (T2DM) and cancer, and an increase in the incidence of cancer is expected with the growing obesity-diabetes pandemic. The association of cancer with diabetes mellitus and obesity appears to be site-specific, the highest risk being for post-menopausal breast cancer, endometrial cancer, and colorectal cancer. Moreover, there is worsening of hyperglycaemia with the onset of cancer, evidencing a bi-directional link between cancer and diabetes mellitus and the need for monitoring for diabetes in cancer survivors. In this review, we look at the epidemiological evidence from observational studies and Mendelian randomization studies linking obesity, diabetes, and cancer, as well as the complex pathophysiological mechanisms involved, including insulin resistance with associated hyperinsulinaemia, the effect of chronic low-grade inflammation, and the effect of various adipokines that are associated with obesity and T2DM. Additionally, we describe the novel therapeutic strategies, based on their role on the discrete pathophysiological mechanisms involved in the tumourigenesis.
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Affiliation(s)
- Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Annu Susan George
- Department of Medical Oncology, VPS Lakeshore Hospital, Cochin 682040, India
| | | | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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Interactions of a Water-Soluble Glycofullerene with Glucose Transporter 1. Analysis of the Cellular Effects on a Pancreatic Tumor Model. NANOMATERIALS 2021; 11:nano11020513. [PMID: 33670509 PMCID: PMC7922475 DOI: 10.3390/nano11020513] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/11/2021] [Accepted: 02/16/2021] [Indexed: 12/12/2022]
Abstract
In recent years, carbon nanomaterials have been intensively investigated for their possible applications in biomedical studies, especially as drug delivery vehicles. Several surface modifications can modulate the unique molecular structure of [60]fullerene derivatives, as well as their physicochemical properties. For this reason, covalent modifications that would enable a greater water solubilization of the fullerene buckyball have been rapidly investigated. The most exciting applications of fullerene nanomaterials are as drug delivery vectors, photosensitizers in photodynamic therapy (PDT), astransfection or MRI contrast agents, antimicrobials and antioxidants. From these perspectives, the glucose derivatives of [60]fullerene seem to be an interesting carbon nanomaterial for biological studies. It is well-known that cancer cells are characterized by an increased glucose uptake and it has also been previously reported that the glucose transporters (GLUTs) are overexpressed in several types of cancers, which make them attractive molecular targets for many drugs. This study explored the use of a highly water-soluble glycofullerene (called Sweet-C60) in pancreatic cancer studies. Here, we describe the PANC-1 cell proliferation, migration, metabolic activity and glycolysis rate after incubations with different concentrations of Sweet-C60. The final results did not show any influence of the Sweet-C60 on various cancer cellular events and glycolysis, suggesting that synthesized glycofullerene is a promising drug delivery vehicle for treating pancreatic cancer.
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Das BK, Knott RM, Gadad PC. Metformin and asarone inhibit HepG2 cell proliferation in a high glucose environment by regulating AMPK and Akt signaling pathway. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2021. [DOI: 10.1186/s43094-021-00193-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Abstract
Background
Metabolic dysregulation is one of the hallmarks of tumor cell proliferation. Evidence indicates the potential role of the 5′adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B/Akt signaling pathway in regulating cell proliferation, survival, and apoptosis. The present study explores the effect of metformin HCl and the combination of α- and β-asarone on the proliferation of HepG2 cells in the presence of high glucose levels simulating the diabetic-hepatocellular carcinoma (HCC) condition.
Results
The metformin and asarone reduced HepG2 cell viability in a dose-dependent manner and induced morphological changes as indicated by methyl thiazolyl tetrazolium (MTT) assay. The metformin and asarone arrested the cells at the G0/G1 phase, upregulated the expression of AMPK, and downregulated Akt expression in high glucose conditions as identified by the flow cytometry technique. Further, the upregulated AMPK led to a decrease in the expression of phosphoenolpyruvate carboxykinase-2 (PCK-2) and sterol regulatory element-binding protein-1 (SREBP-1).
Conclusion
The anti-proliferative effect of metformin and asarone in the diabetic-HCC condition is mediated via AMPK and Akt pathway.
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Medeiros LMD, Stahlschmidt R, Ferracini AC, Souza CMD, Juliato CRT, Mazzola PG. Switching of Hormone Therapies in Breast Cancer Women. REVISTA BRASILEIRA DE GINECOLOGIA E OBSTETRÍCIA 2021; 43:185-189. [PMID: 33465792 PMCID: PMC10183841 DOI: 10.1055/s-0040-1719149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
OBJECTIVE The objective of the present study was to analyze the reasons that led to hormone therapies (HTs) regimen changes in women with breast cancer. METHODS This was a retrospective cross-sectional study from a single-institution Brazilian cancer center with patient records diagnosed with breast cancer between January 2012 and January 2017. RESULTS From 1,555 women who were in treatment with HT, 213 (13.7%) women had HT switched, either tamoxifen to anastrozole or vice-versa. Most women included in the present study who switched HT were > 50 years old, postmenopausal, Caucasian, and had at least one comorbidity. From the group with therapy change, 'disease progression' was reason of change in 124 (58.2%) cases, and in 65 (30.5%) patients, 'presence of side effects' was the reason. From those women who suffered with side effects, 24 (36.9%) had comorbidities. CONCLUSION The present study demonstrated a low rate of HT switch of tamoxifen to anastrozole. Among the reasons for changing therapy, the most common was disease progression, which includes cancer recurrence, metastasis or increased tumor. Side effects were second; furthermore, age and comorbidities are risk factors for side effects.
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Affiliation(s)
| | - Rebeca Stahlschmidt
- Graduate Program in Medical Sciences, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
| | - Amanda Canato Ferracini
- Graduate Program in Medical Sciences, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
| | - Cinthia Madeira de Souza
- Graduate Program in Medical Sciences, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
| | - Cassia Raquel Teatin Juliato
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
| | - Priscila Gava Mazzola
- Faculty of Pharmaceutical Sciences, Universidade de Campinas (Unicamp), Campinas, SP, Brazil
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Spanier G, Ugele I, Nieberle F, Symeou L, Schmidhofer S, Brand A, Meier J, Spoerl S, Krupar R, Rümmele P, Siska P, Renner K, Peter K, Gerken M, Beckhove P, Reichert TE, Kreutz M, Singer K. The predictive power of CD3 + T cell infiltration of oral squamous cell tumors is limited to non-diabetic patients. Cancer Lett 2020; 499:209-219. [PMID: 33276040 DOI: 10.1016/j.canlet.2020.11.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/04/2020] [Accepted: 11/21/2020] [Indexed: 12/31/2022]
Abstract
Diabetes mellitus type II (DM) and immune cell infiltration determine patient outcome in many tumor entities. Here we studied a possible link between the metabolic and immune cell status of OSCC patients. Glucose transporter (GLUT) 1 mRNA expression was elevated in all tumor samples, whereas other glycolytic markers such as lactate dehydrogenase (LDH) A or monocarboxylate transporter (MCT) 1 were increased in tumor samples from patients with diabetes and these patients had a significantly worse prognosis compared to non-diabetic patients. Analyses of immune cell infiltration in tumors from diabetic and non-diabetic patients revealed an increased leukocyte (CD45+) infiltration compared to normal mucosa only in non-diabetic patients. In line, the amount of CD3+ T cells per mm2 tumor tissue, was elevated in patients without diabetes and crucial for patient outcome in OSCC patients without diabetes, as compared to healthy mucosa using fluorescence immunohistochemistry in tissue microarrays of 229 patients. Our results demonstrate that diabetes is a prognostic factor for OSCC patients and associates with decreased leukocyte and CD3+ infiltration indicating that metabolic differences between diabetic and non-diabetic patients may alter tumor-infiltrating T cells and thereby determine patient outcome.
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Affiliation(s)
- Gerrit Spanier
- Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Ines Ugele
- Department of Otorhinolaryngology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Felix Nieberle
- Regensburg Center for Interventional Immunology, University of Regensburg, 93053, Regensburg, Germany
| | - Luisa Symeou
- Department of Otorhinolaryngology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Sandra Schmidhofer
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Almut Brand
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Johannes Meier
- Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Steffen Spoerl
- Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Rosemarie Krupar
- Institute of Pathology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Petra Rümmele
- Institute of Pathology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Peter Siska
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Kathrin Renner
- Regensburg Center for Interventional Immunology, University of Regensburg, 93053, Regensburg, Germany; Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Katrin Peter
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Michael Gerken
- Tumor Center - Institute for Quality Management and Health Services Research, University of Regensburg, 93053, Regensburg, Germany
| | - Philipp Beckhove
- Regensburg Center for Interventional Immunology, University of Regensburg, 93053, Regensburg, Germany
| | - Torsten E Reichert
- Department of Cranio-Maxillofacial Surgery, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Marina Kreutz
- Regensburg Center for Interventional Immunology, University of Regensburg, 93053, Regensburg, Germany; Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany.
| | - Katrin Singer
- Department of Otorhinolaryngology, University Hospital Regensburg, 93053, Regensburg, Germany; Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
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Myosin light chain kinase is a potential target for hypopharyngeal cancer treatment. Biomed Pharmacother 2020; 131:110665. [PMID: 32920510 PMCID: PMC8122670 DOI: 10.1016/j.biopha.2020.110665] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/08/2020] [Accepted: 08/20/2020] [Indexed: 02/07/2023] Open
Abstract
Hypopharyngeal cancer is squamous cell carcinoma (SCC) with the worst prognosis among the head and neck cancers. Overall, the 5-year survival rate remains poor although diagnostic imaging, radiation, chemotherapy, and surgical techniques have been improved. The mortality of patients with hypopharyngeal cancer is partly due to an increased likelihood of developing a second primary malignancy and metastasis. In this study, we found that MLCK expression, compared to healthy tissue, was up-regulated in hypopharyngeal tumor tissue. Of particular interest, a low 5-year survival rate was positively correlated with MLCK expression. We hypothesized that MLCK might be a target for hypopharyngeal cancer prognosis and treatment. In order to explore the function of MLCK in the development of cancer, we knockdown MLCK in hypopharyngeal cancer FaDu cells. The results showed that MLCK knockdown reduced the migration and invasion of FaDu cells. 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) is the derivative of all-trans retinoic acid (ATRA), which was able to reduce both MLCK expression and activity in FaDu cells. ATPR induced FaDu cells apoptosis in a dose-dependent manner and also inhibited cell growth both in vivo and in vitro. Further experiments showed that overexpression of MLCK reduced ATPR induced-migration inhibition while increase of ATPR induced apoptosis, which suggested that MLCK was involved in ATPR's anti-cancer function. In conclusion, MLCK is a novel prognostic marker and therapeutic target for hypopharyngeal cancer. By targeting MLCK, ATPR exhibits its potential application in the treatment of this type of cancer.
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Xia B, He Q, Pan Y, Gao F, Liu A, Tang Y, Chong C, Teoh AYB, Li F, He Y, Zhang C, Yuan J. Metabolic syndrome and risk of pancreatic cancer: A population‐based prospective cohort study. Int J Cancer 2020; 147:3384-3393. [PMID: 32580250 DOI: 10.1002/ijc.33172] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Bin Xia
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Qiangsheng He
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yihang Pan
- Precision Medicine Center. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Fang Gao
- Perioperative, Critical Care and Trauma Trials Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Anran Liu
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Department of Nutriology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yan Tang
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Charing Chong
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - Anthony Y B Teoh
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - Fangping Li
- Department of Endocrinology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yulong He
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Changhua Zhang
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Jinqiu Yuan
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
- Precision Medicine Center. Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
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Petrelli F, Ghidini M, Rausa E, Ghidini A, Cabiddu M, Borgonovo K, Ghilardi M, Parati MC, Pietrantonio F, Sganzerla P, Bossi AC. Survival of Colorectal Cancer Patients With Diabetes Mellitus: A Meta-Analysis. Can J Diabetes 2020; 45:186-197.e2. [PMID: 33039329 DOI: 10.1016/j.jcjd.2020.06.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 06/03/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Diabetes mellitus (DM) is associated with an elevated risk of various cancers, including colorectal cancer (CRC). Similarly, pre-existing DM may also influence prognosis among patients with CRC. We performed a systematic review and meta-analysis to assess the association between DM and risk of death and relapse after a diagnosis of CRC. METHODS PubMed, Scopus, Web of Science, The Cochrane Library and Embase were searched from inception until July 2019 for studies reporting prognosis of patients with DM and CRC. The primary outcome of the study refers to overall mortality in patients with vs without diabetes. Secondary endpoints were cancer-specific mortality and progression or relapse-free survival. The risk of death and relapse are reported as hazard ratio (HR) with 95% confidence interval (CI), and an HR >1 was associated with worst outcome in patients with diabetes compared to those without diabetes. RESULTS Mortality and relapse associated with DM in patients with CRC were evaluated among 5,267,980 participants (total of 82 studies). Overall, concomitant diagnosis of CRC and DM were associated with an independent increased risk of overall mortality (HR, 1.21; 95% CI, 1.17 to 1.25; p<0.01) and CSM (HR, 1.11; 95% CI, 1.05 to 1.17; p<0.01). Patients were also at increased risk of relapse (HR, 1.09; 95% CI, 1.02 to 1.16; p<0.01). CONCLUSIONS In CRC patients with DM, diabetes decreased survival and increased the risk of relapse. Adequate control of lifestyle choices, more intensive follow ups, use of some oral antidiabetics, dietary restrictions, physical activity and monitoring of diabetes-associated complications are measures for reducing mortality in this setting.
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Affiliation(s)
- Fausto Petrelli
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Italy.
| | - Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
| | - Emanuele Rausa
- Surgical Oncology Unit, ASST Bergamo Ovest, Treviglio, Bergamo, Italy
| | | | - Mary Cabiddu
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Karen Borgonovo
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Mara Ghilardi
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Maria Chiara Parati
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Filippo Pietrantonio
- Oncology Unit, Fondazione IRCCS, Istituto Nazionale Tumori di Milano, Milano, Italia
| | - Paolo Sganzerla
- Cardiology Unit, ASST Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Antonio Carlo Bossi
- Endocrine Diseases Unit‒Diabetes Regional Center, ASST Bergamo Ovest, Treviglio, Bergamo, Italy
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Associations between metabolic syndrome and gynecologic cancer. Obstet Gynecol Sci 2020; 63:215-224. [PMID: 32489965 PMCID: PMC7231948 DOI: 10.5468/ogs.2020.63.3.215] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/01/2020] [Accepted: 01/16/2020] [Indexed: 12/21/2022] Open
Abstract
Metabolic syndrome (MetS) is a group of risk factors that causes cardiovascular and diabetic morbidity and mortality, which is diagnosed by central obesity, dyslipidemia, hyperglycemia, and hypertension. Increasing epidemiological data and experimental results indicate that the presence of MetS increases the incidence of common malignancies and related mortality. Epidemiological studies have previously reported an association of endometrial cancer occurrence with MetS. Aromatization of androstenedione to estrogen, insulin resistance, and diabetes can cause increased levels of free estrogen, and the detrimental effect of elevated estrogen as a carcinogen is well studied in endometrial cancer. Medications used to manage MetS such as metformin and statins are suggested to reduce endometrial cancer risk and improve survival. Some large population-based epidemiological studies have suggested that the MetS is related to an increased risk of cervical carcinoma. MetS may contribute to viral-host interactions, which lead to persistent human papilloma virus (HPV) infection, although limited epidemiological data are available. Specific effects of obesity and diabetes on the occurrence of ovarian cancer have been suggested. However, the direct correlation between MetS and ovarian cancer is still lacking. Previous retrospective studies reported that the use of metformin, statins, and beta-blockers could be associated with cancer prevention or better prognosis. Proper diagnosis and management of the MetS should be a part of the strategies undertaken to prevent and treat gynecologic cancer. So far, only limited data is available on this subject, and further clinical and fundamental research is required to further clarify the effect of these therapies on gynecologic cancer treatment.
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Lega IC, Lipscombe LL. Review: Diabetes, Obesity, and Cancer-Pathophysiology and Clinical Implications. Endocr Rev 2020; 41:5625127. [PMID: 31722374 DOI: 10.1210/endrev/bnz014] [Citation(s) in RCA: 163] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023]
Abstract
Obesity and diabetes have both been associated with an increased risk of cancer. In the face of increasing obesity and diabetes rates worldwide, this is a worrying trend for cancer rates. Factors such as hyperinsulinemia, chronic inflammation, antihyperglycemic medications, and shared risk factors have all been identified as potential mechanisms underlying the relationship. The most common obesity- and diabetes-related cancers are endometrial, colorectal, and postmenopausal breast cancers. In this review, we summarize the existing evidence that describes the complex relationship between obesity, diabetes, and cancer, focusing on epidemiological and pathophysiological evidence, and also reviewing the role of antihyperglycemic agents, novel research approaches such as Mendelian Randomization, and the methodological limitations of existing research. In addition, we also describe the bidirectional relationship between diabetes and cancer with a review of the evidence summarizing the risk of diabetes following cancer treatment. We conclude this review by providing clinical implications that are relevant for caring for patients with obesity, diabetes, and cancer and provide recommendations for improving both clinical care and research for patients with these conditions.
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Affiliation(s)
- Iliana C Lega
- Department of Medicine, Women's College Hospital, Toronto, ON, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,IC/ES, Toronto, ON, Canada
| | - Lorraine L Lipscombe
- Department of Medicine, Women's College Hospital, Toronto, ON, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,IC/ES, Toronto, ON, Canada.,Institute for Health Policy, Management and Evaluation, University of Toronto; Toronto, ON, Canada
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38
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Role of the Wnt signalling pathway in the development of endothelial disorders in response to hyperglycaemia. Expert Rev Mol Med 2019; 21:e7. [PMID: 31796147 DOI: 10.1017/erm.2019.8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Diabetes mellitus (DM) is the most common metabolic disease. A WHO report from 2016 indicates that 422 million people worldwide suffer from DM or hyperglycaemia because of impaired glucose metabolism. Chronic hyperglycaemia leads to micro- and macrovessel damage, which may result in life-threatening complications. The Wnt pathway regulates cell proliferation and survival by modulating the expression of genes that control cell differentiation. Three linked Wnt pathways have been discovered thus far: a β-catenin-dependent pathway and two pathways independent of β-catenin - the planar cell polarity pathway and calcium-dependent pathway. The Wnt pathway regulates genes associated with inflammation, cell cycle, angiogenesis, fibrinolysis and other molecular processes. AREAS COVERED This review presents the current state of knowledge regarding the contribution of the Wnt pathway to endothelial ageing under hyperglycaemic conditions and provides new insights into the molecular basis of diabetic endothelial dysfunction. CONCLUSION The β-catenin-dependent pathway is a potential target in the prophylaxis and treatment of early-stage diabetes-related vascular complications. However, the underlying molecular mechanisms remain largely undetermined and require further investigation.
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Vanhove K, Graulus GJ, Mesotten L, Thomeer M, Derveaux E, Noben JP, Guedens W, Adriaensens P. The Metabolic Landscape of Lung Cancer: New Insights in a Disturbed Glucose Metabolism. Front Oncol 2019; 9:1215. [PMID: 31803611 PMCID: PMC6873590 DOI: 10.3389/fonc.2019.01215] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 10/24/2019] [Indexed: 12/12/2022] Open
Abstract
Metabolism encompasses the biochemical processes that allow healthy cells to keep energy, redox balance and building blocks required for cell development, survival, and proliferation steady. Malignant cells are well-documented to reprogram their metabolism and energy production networks to support rapid proliferation and survival in harsh conditions via mutations in oncogenes and inactivation of tumor suppressor genes. Despite the histologic and genetic heterogeneity of tumors, a common set of metabolic pathways sustain the high proliferation rates observed in cancer cells. This review with a focus on lung cancer covers several fundamental principles of the disturbed glucose metabolism, such as the “Warburg” effect, the importance of the glycolysis and its branching pathways, the unanticipated gluconeogenesis and mitochondrial metabolism. Furthermore, we highlight our current understanding of the disturbed glucose metabolism and how this might result in the development of new treatments.
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Affiliation(s)
- Karolien Vanhove
- UHasselt, Faculty of Medicine and Life Sciences, LCRC, Diepenbeek, Belgium.,Department of Respiratory Medicine, Algemeen Ziekenhuis Vesalius, Tongeren, Belgium
| | - Geert-Jan Graulus
- Biomolecule Design Group, Institute for Materials Research, Hasselt University, Diepenbeek, Belgium
| | - Liesbet Mesotten
- UHasselt, Faculty of Medicine and Life Sciences, LCRC, Diepenbeek, Belgium.,Department of Nuclear Medicine, Ziekenhuis Oost Limburg, Genk, Belgium
| | - Michiel Thomeer
- UHasselt, Faculty of Medicine and Life Sciences, LCRC, Diepenbeek, Belgium.,Department of Respiratory Medicine, Ziekenhuis Oost Limburg, Genk, Belgium
| | - Elien Derveaux
- UHasselt, Faculty of Medicine and Life Sciences, LCRC, Diepenbeek, Belgium
| | - Jean-Paul Noben
- Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Wanda Guedens
- Biomolecule Design Group, Institute for Materials Research, Hasselt University, Diepenbeek, Belgium
| | - Peter Adriaensens
- Biomolecule Design Group, Institute for Materials Research, Hasselt University, Diepenbeek, Belgium.,Applied and Analytical Chemistry, Institute for Materials Research, Hasselt University, Diepenbeek, Belgium
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40
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Dworzański J, Drop B, Kliszczewska E, Strycharz-Dudziak M, Polz-Dacewicz M. Prevalence of Epstein-Barr virus, human papillomavirus, cytomegalovirus and herpes simplex virus type 1 in patients with diabetes mellitus type 2 in south-eastern Poland. PLoS One 2019; 14:e0222607. [PMID: 31550259 PMCID: PMC6759159 DOI: 10.1371/journal.pone.0222607] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 09/03/2019] [Indexed: 12/11/2022] Open
Abstract
A microbiota is a complex ecosystem of microorganisms consisting of bacteria, viruses, protozoa, and fungi living in different niches of the human body, which plays an essential role in many metabolic functions. Modifications in the microbiota composition can lead to several diseases, including metabolic disorders. The aim of this study was to analyze the prevalence of four viruses which can cause persistent infections-Epstein-Barr virus (EBV), human papillomavirus (HPV), cytomegalovirus (CMV), and herpes simplex virus type 1 (HSV-1) in patients with diabetes mellitus type 2 (DM2). Blood, saliva and oral swabs were collected from all the study participants. The nested-PCR technique was used to detect the viral DNA. DNA of at least one virus was detected in 71.1% of diabetic patients and in 30% of individuals without diabetes. In patients with diabetes EBV DNA was detected the most frequently (25.4%), followed by HPV- 19.1%, HSV- 10.4% and CMV- 5.2%. A higher percentage of EBV+HPV co-infection was found among men (30.8%). EBV DNA was statistically more often detected in patients living in rural areas (53.7%), while HPV (91.5%) and EBV+HPV co-infection (22.2%) prevailed among patients from urban areas. In patients with a DM2 history longer than 10 years viral infection was detected more frequently. The prevalence of EBV, HPV and the EBV+HPV co-infection was significantly higher in diabetic patients than in individuals without diabetes. The frequency of these infections depended on the duration of the disease (DM2).
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Affiliation(s)
| | - Bartłomiej Drop
- Department of Information Technology and Medical Statistics, Medical University of Lublin, Lublin, Poland
| | - Ewa Kliszczewska
- Department of Virology, Medical University of Lublin, Lublin, Poland
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41
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Schwartz SS, Grant SFA, Herman ME. Intersections and Clinical Translations of Diabetes Mellitus with Cancer Promotion, Progression and Prognosis. Postgrad Med 2019; 131:597-606. [PMID: 31419922 DOI: 10.1080/00325481.2019.1657358] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The association between cancer and dysglycemia has been well documented. It is underappreciated, however, that sustained dysglycemia could potentially be a catalyst toward a pro-cancer physiologic milieu and/or increase the burden of cancer. Hyperglycemia, hyperinsulinemia and energy metabolism at large impact a cascade of growth pathways, epi/genetic modifications, and mitochondrial changes that could feasibly link to tumor processes. Oxidative stress is a recurring motif in cell dysfunction: in diabetes, oxidative stress and reactive oxygen species (ROS) feature prominently in the damage and demise of pancreatic beta cells, as well as cell damage contributing to diabetes-related complications. Oxidative stress may be one intersection at which metabolic and oncogenic processes cross paths with deleterious results in the development of precancer, cancer, and cancer progression. This would augur for tight glucose control. Regrettably, some medical societies have recently relaxed hemoglobin A1c targets. A framework for the hyperglycemic state is presented that helps account and translate the full scope of effects of dysglycemia to ultimately improve clinical best practices.
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Affiliation(s)
- Stanley S Schwartz
- Main Line Health System, Wynnewood, PA, USA.,University of Pennsylvania, Philadelphia, PA, USA
| | - Struan F A Grant
- Center for Spatial and Functional Genomics, Divisions of Human Genetics and Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Mary E Herman
- Montclair State University, Upper Montclair, NJ, USA.,Social Alchemy Ltd. Building Research Competency in the Developing World, Edgewater, NJ, USA
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42
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Rankovic A, Adolphe JL, Verbrugghe A. Role of carbohydrates in the health of dogs. J Am Vet Med Assoc 2019; 255:546-554. [PMID: 31429654 DOI: 10.2460/javma.255.5.546] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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43
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Nagy T, Fisi V, Frank D, Kátai E, Nagy Z, Miseta A. Hyperglycemia-Induced Aberrant Cell Proliferation; A Metabolic Challenge Mediated by Protein O-GlcNAc Modification. Cells 2019; 8:E999. [PMID: 31466420 PMCID: PMC6769692 DOI: 10.3390/cells8090999] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 08/26/2019] [Accepted: 08/26/2019] [Indexed: 12/13/2022] Open
Abstract
Chronic hyperglycemia has been associated with an increased prevalence of pathological conditions including cardiovascular disease, cancer, or various disorders of the immune system. In some cases, these associations may be traced back to a common underlying cause, but more often, hyperglycemia and the disturbance in metabolic balance directly facilitate pathological changes in the regular cellular functions. One such cellular function crucial for every living organism is cell cycle regulation/mitotic activity. Although metabolic challenges have long been recognized to influence cell proliferation, the direct impact of diabetes on cell cycle regulatory elements is a relatively uncharted territory. Among other "nutrient sensing" mechanisms, protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification emerged in recent years as a major contributor to the deleterious effects of hyperglycemia. An increasing amount of evidence suggest that O-GlcNAc may significantly influence the cell cycle and cellular proliferation. In our present review, we summarize the current data available on the direct impact of metabolic changes caused by hyperglycemia in pathological conditions associated with cell cycle disorders. We also review published experimental evidence supporting the hypothesis that O-GlcNAc modification may be one of the missing links between metabolic regulation and cellular proliferation.
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Affiliation(s)
- Tamás Nagy
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary.
| | - Viktória Fisi
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
| | - Dorottya Frank
- Department of Dentistry, Oral and Maxillofacial Surgery, Medical School, University of Pécs, H-7621 Pécs, Hungary
| | - Emese Kátai
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
| | - Zsófia Nagy
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
| | - Attila Miseta
- Department of Laboratory Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary
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Abstract
Cancer cells overexpress several transcription factors and motor proteins, such as NFkB and kinesin, to accommodate their high energy demand as well as migratory needs via enhanced glycolysis. We hypothesize that high glucose drives cancer progression and cell aggressiveness by decreasing actin expression, increasing NFkB, and kinesin expressions, and by activating Epithelial Mesenchymal Transition (EMT). Using lowly metastatic MCF-7 and highly metastatic MDA-MB231 (MB231) breast cancer cells - highly incident cancer types - we establish how glucose metabolism regulates actin and the biochemical changes that lead to alterations of cell mechanical properties. We find that higher glucose (15 and 30 mM) increases glycolytic enzymes, glucose uptake, migration speed, kinesin, Ki-67, and NFkB expressions (biomarkers), and hybrid EMT phenotype activation (adhesion molecules/cadherins). Downregulation of actin, increased expressions of motor protein and NFkB, and decreased nuclear stiffness - induced by higher glucose - result in a significant increase in the migration speed. Moreover, glucose deprivation using the glucose analog 2-deoxyglucose decreases significantly the migration speed in both cancer cells. Thus, higher glucose promotes a more aggressive phenotype that promises to be a new target for cancer therapy and can help prevent cancer progression in diabetic patients by inhibiting glucose activated mechanisms.
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Affiliation(s)
- Julianna M Santos
- Mechanical Engineering Department, Texas Tech University, Lubbock, Texas, USA
| | - Fazle Hussain
- Mechanical Engineering Department, Texas Tech University, Lubbock, Texas, USA
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45
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High Glucose Concentrations Negatively Regulate the IGF1R/Src/ERK Axis through the MicroRNA-9 in Colorectal Cancer. Cells 2019; 8:cells8040326. [PMID: 30965609 PMCID: PMC6523516 DOI: 10.3390/cells8040326] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 04/05/2019] [Accepted: 04/06/2019] [Indexed: 01/20/2023] Open
Abstract
Studies have revealed that people with hyperglycemia have a high risk of colorectal cancer (CRC). Hyperglycemia may be responsible for supplying energy to CRC cells. However, the potential molecular mechanism for this association remains unclear. Furthermore, microRNA-9 (miR-9) has a tumor-suppressive function in CRC. Aberrant reduced expression of miR-9 is involved in the development and progression of malignancy caused by a high glucose (HG) concentration. In this study, we used an HG concentration to activate miR-9 downregulation in CRC cells. Our results indicated that miR-9 decreased the insulin-like growth factor-1 receptor (IGF1R)/Src signaling pathway and downstream cyclin B1 and N-cadherin but upregulated E-cadherin. The HG concentration not only promoted cell proliferation, increased the G1 population, and modulated epithelial-to-mesenchymal transition (EMT) protein expression and morphology but also promoted the cell migration and invasion ability of SW480 (low metastatic potential) and SW620 (high metastatic potential) cells. In addition, low glucose concentrations could reverse the effect of the HG concentration in SW480 and SW620 cells. In conclusion, our results provide new evidence for multiple signaling pathways being regulated through hyperglycemia in CRC. We propose that blood sugar control may serve as a potential strategy for the clinical management of CRC.
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46
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Hu Q, Li C, Wang S, Li Y, Wen B, Zhang Y, Liang K, Yao J, Ye Y, Hsiao H, Nguyen TK, Park PK, Egranov SD, Hawke DH, Marks JR, Han L, Hung MC, Zhang B, Lin C, Yang L. LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition. Cell Res 2019; 29:286-304. [PMID: 30631154 PMCID: PMC6461864 DOI: 10.1038/s41422-018-0134-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 12/07/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the structural conservation of PTEN with dual-specificity phosphatases, there have been no reports regarding the regulatory mechanisms that underlie this potential dual-phosphatase activity. Here, we report that K27-linked polyubiquitination of PTEN at lysines 66 and 80 switches its phosphoinositide/protein tyrosine phosphatase activity to protein serine/threonine phosphatase activity. Mechanistically, high glucose, TGF-β, CTGF, SHH, and IL-6 induce the expression of a long non-coding RNA, GAEA (Glucose Aroused for EMT Activation), which associates with an RNA-binding E3 ligase, MEX3C, and enhances its enzymatic activity, leading to the K27-linked polyubiquitination of PTEN. The MEX3C-catalyzed PTENK27-polyUb activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase activity. With this altered enzymatic activity, PTENK27-polyUb dephosphorylates the phosphoserine/threonine residues of TWIST1, SNAI1, and YAP1, leading to accumulation of these master regulators of EMT. Animals with genetic inhibition of PTENK27-polyUb, by a single nucleotide mutation generated using CRISPR/Cas9 (PtenK80R/K80R), exhibit inhibition of EMT markers during mammary gland morphogenesis in pregnancy/lactation and during cutaneous wound healing processes. Our findings illustrate an unexpected paradigm in which the lncRNA-dependent switch in PTEN protein serine/threonine phosphatase activity is important for physiological homeostasis and disease development.
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Affiliation(s)
- Qingsong Hu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Chunlai Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Shouyu Wang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Department of hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Yajuan Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Bo Wen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yanyan Zhang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Institute of Immunology, Third Military Medical University, 400038, Chongqing, China
| | - Ke Liang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jun Yao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Youqiong Ye
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School, Houston, TX, 77030, USA
| | - Heidi Hsiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Tina K Nguyen
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Peter K Park
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sergey D Egranov
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - David H Hawke
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jeffrey R Marks
- Department of Surgery, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Leng Han
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School, Houston, TX, 77030, USA
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Program in Cancer Biology, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Bing Zhang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chunru Lin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Program in Cancer Biology, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Liuqing Yang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Program in Cancer Biology, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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Zheng P, Wang X, Hong Z, Shen F, Zhang Q. Preoperative fasting hyperglycemia is an independent prognostic factor for postoperative survival after gallbladder carcinoma radical surgery. Cancer Manag Res 2019; 11:1425-1432. [PMID: 30863153 PMCID: PMC6388958 DOI: 10.2147/cmar.s192273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Preoperative high blood glucose levels are closely associated with poor performance and high mortality in cancer patients. This study was designed to investigate the relationship between preoperative fasting hyperglycemia and the prognosis of patients with gallbladder cancer (GBC) after undergoing GBC radical surgery. PATIENTS AND METHODS A retrospective analysis of 83 eligible patients who underwent GBC radical surgery between 2007 and 2016 was performed. Factors affecting overall survival (OS) and recurrence-free survival (RFS) were analyzed by univariate and multivariate analyses. RESULTS Of the 83 patients, 35 (42.2%) had preoperative fasting hyperglycemia. The median OS of the enrolled patients was 12 months. The median OS in patients with fasting hyperglycemia before surgery was 18 months, which was shorter than for patients with normal fasting blood glucose levels before surgery (47 months, P<0.001). Preoperative fasting hyperglycemia was associated with shorter survival times in univariate analyses (HR, 3.215; 95% CI, 1.846-5.601; P<0.001). Multivariate analysis showed that patients with preoperative fasting hyperglycemia had a lower OS (HR, 2.832; 95% CI, 1.480-5.418; P=0.002) and RFS (HR, 2.051; 95% CI, 1.127-3.733; P=0.019) than patients with normal preoperative fasting blood glucose levels. CONCLUSION Preoperative fasting hyperglycemia is an independent indicator of poor prognosis in GBC patients after GBC radical surgery.
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Affiliation(s)
- Peng Zheng
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xiaoqian Wang
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China,
| | - Zhong Hong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Feixia Shen
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China,
| | - Qiyu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China,
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Blood glucose, glucose balance, and disease-specific survival after prostate cancer diagnosis in the Finnish Randomized Study of Screening for Prostate Cancer. Prostate Cancer Prostatic Dis 2019; 22:453-460. [PMID: 30679762 DOI: 10.1038/s41391-018-0123-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 10/15/2018] [Accepted: 11/03/2018] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Diabetes mellitus has been linked with adverse prostate cancer (PCa) outcomes. However, role of hyperglycemia in PCa progression is unclear. We evaluated the link between hyperglycemia and PCa survival among Finnish PCa patients. METHODS The study cohort included 1770 men with data on fasting glucose and diagnosed with PCa within the Finnish Randomized Study of Screening for PCa in 1995-2009. Additionally, 1398 men had data on glycated hemoglobin (HbA1c). Information on fasting glucose and HbA1c measurements was obtained from the regional laboratory database. Antidiabetic medication use was obtained from the prescription database of the Social Insurance Institution (SII). Time-dependent Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals for PCa death among diabetic, impaired glucose tolerant, and normoglycemic men. RESULTS During median follow-up of 9.9 years after the diagnosis, 182 men died from PCa. After adjustment for tumor stage, Gleason grade, and PSA level at diagnosis, diabetic fasting glucose level after PCa diagnosis was associated with elevated risk of PCa death compared to normoglycemic men (HR 1.67 95% CI 1.18-2.36). The risk association was strongest among participants with localized cancer at diagnosis; HR 2.39, 95% CI 1.45-3.93. The risk elevation was observed for glucose measurements taken up to 5 years earlier. Diabetic glucose levels measured before the diagnosis were not associated with PCa death. CONCLUSION Our study cohort suggests an increased risk of PCa death in men with diabetic fasting blood glucose levels, supporting the role of hyperglycemia as a risk factor for PCa progression.
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49
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High Glucose-Induced ROS Production Stimulates Proliferation of Pancreatic Cancer via Inactivating the JNK Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6917206. [PMID: 30584464 PMCID: PMC6280312 DOI: 10.1155/2018/6917206] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 08/06/2018] [Accepted: 09/23/2018] [Indexed: 12/31/2022]
Abstract
Aberrant glucose metabolism of diabetes mellitus or hyperglycemia stimulates pancreatic tumorigenesis and progression. Hyperglycemic environment can increase the ROS level of tumors, but the role of upregulation of ROS levels in pancreatic cancer (PC) still remains controversial. Here, the same as other reports, we demonstrate that high glucose promoted pancreatic cancer cell growth and resulted in an increase in the level of ROS. However, it is interesting that the phosphorylation of JNK was reduced. When treating PC cells with N-acetyl-L-cysteine (NAC), the intracellular ROS generation is repressed, but the expression of phosphorylation of JNK and c-Jun increased. Moreover, the JNK inhibitor SP600125 significantly promoted cell proliferation and suppressed cell apoptosis of pancreatic cancer cells under high glucose conditions. Collectively, high levels of ROS induced by high glucose conditions stimulated the proliferation of pancreatic cancer cells, and it may be achieved by inactivating the JNK pathway.
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50
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Cignarelli A, Genchi VA, Caruso I, Natalicchio A, Perrini S, Laviola L, Giorgino F. Diabetes and cancer: Pathophysiological fundamentals of a 'dangerous affair'. Diabetes Res Clin Pract 2018; 143:378-388. [PMID: 29679627 DOI: 10.1016/j.diabres.2018.04.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 03/27/2018] [Accepted: 04/03/2018] [Indexed: 02/06/2023]
Abstract
Diabetes and cancer are worldwide chronic diseases with a major impact on the quality and expectancy of life. Metabolic abnormalities observed during the onset and progression of diabetes may have a critical role on the initiation and progression of carcinogenesis. To date, there are no conclusive data on the mechanisms underlying the relationship between diabetes and any type of human cancer. However, recent evidence suggests that both hyperglycemia and hyperinsulinemia in diabetes could elicit cell damage responses, such as glucotoxicity, lipotoxicity and oxidative stress, which participate in the cell transformation process raising the risk of cancer development. In addition, clinical trials have revealed that several anti-diabetes therapies may potentially affect the risk of cancer though largely undefined mechanisms. In this review, we highlight epidemiological and pathophysiological aspects of diabetes, which may influence cancer initiation and progression.
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Affiliation(s)
- Angelo Cignarelli
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Valentina Annamaria Genchi
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Irene Caruso
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Annalisa Natalicchio
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Sebastio Perrini
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Luigi Laviola
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
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