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Alhusayen R, Dienes S, Lam M, Alavi A, Alikhan A, Aleshin M, Bahashwan E, Daveluy S, Goldfarb N, Garg A, Gulliver W, Jaleel T, Kimball AB, Kirchhof MG, Kirby J, Lenczowski J, Lev-Tov H, Lowes MA, Lara-Corrales I, Micheletti R, Okun M, Orenstein L, Poelman S, Piguet V, Porter M, Resnik B, Sibbald C, Shi V, Sayed C, Wong SM, Zaenglein A, Veillette H, Hsiao JL, Naik HB. North American clinical practice guidelines for the medical management of hidradenitis suppurativa in special patient populations. J Am Acad Dermatol 2025; 92:825-852. [PMID: 39725212 DOI: 10.1016/j.jaad.2024.11.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/16/2024] [Accepted: 11/23/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Hidradenitis suppurativa (HS) affects different patient populations that require unique considerations in their management. However, no HS guidelines for these populations exist. OBJECTIVE To provide evidence-based consensus recommendations for patients with HS in 7 special patient populations: (i) pregnancy, (ii) breastfeeding, (iii) pediatrics, (iv) malignancy, (v) tuberculosis infection, (vi) hepatitis B or C infection, and (vii) HIV disease. METHODS Recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation system to ascertain level of evidence and selected through a modified Delphi consensus process. RESULTS One hundred eighteen expert consensus statements are provided for the management of patients with HS across these 7 special patient populations.
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Affiliation(s)
- Raed Alhusayen
- Sunnybrook Research Institute, Toronto, Ontario, Canada; Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Serena Dienes
- Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Megan Lam
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Afsaneh Alavi
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota
| | - Ali Alikhan
- Sutter Medical Foundation, Sacramento, California
| | - Maria Aleshin
- Department of Dermatology, Stanford University School of Medicine, Stanford, California
| | - Emad Bahashwan
- Division of Dermatology, Faculty of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Steve Daveluy
- Department of Dermatology, Wayne State University School of Medicine, Detroit, Michigan
| | - Noah Goldfarb
- Department of Dermatology, University of Minnesota, Minneapolis, Minnesota
| | - Amit Garg
- Department of Dermatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York
| | - Wayne Gulliver
- Department of Dermatology, Memorial University of Newfoundland, St. John's, Canada
| | - Tarannum Jaleel
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina
| | - Alexa B Kimball
- Clinical Laboratory for Epidemiology and Applied Research in Skin (CLEARS), Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Department of Dermatology, Harvard Medical School, Boston, Massachusetts
| | - Mark G Kirchhof
- Division of Dermatology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Division of Dermatology, Department of Medicine, Ottawa Hospital, Ottawa, Ontario, Canada
| | - Joslyn Kirby
- Incyte Corporation, Wilmington, Delaware; Department of Dermatology, Penn State Health, Hershey, Pennsylvania
| | | | - Hadar Lev-Tov
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, Florida
| | - Michelle A Lowes
- Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York
| | - Irene Lara-Corrales
- Division of Dermatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Robert Micheletti
- Departments of Dermatology and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Lauren Orenstein
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
| | - Susan Poelman
- Division of Dermatology, University of Calgary and Beacon Dermatology, Calgary, Alberta, Canada
| | - Vincent Piguet
- Division of Dermatology, Department of Medicine, University of Toronto and Women's College Hospital, Toronto, Ontario, Canada
| | - Martina Porter
- Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Barry Resnik
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, Florida; Resnik Skin Institute, Miami, Florida
| | - Cathryn Sibbald
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Dermatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Vivian Shi
- Department of Dermatology, University of Washington, Seattle, Washington
| | - Christopher Sayed
- Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Se Mang Wong
- Department of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrea Zaenglein
- Department of Dermatology, Penn State Health, Hershey, Pennsylvania; Penn State Children's Hospital, Hershey, Pennsylvania
| | - Helene Veillette
- Division of Dermatology, Department of Medicine, CHU de Québec-Université Laval, Québec, Canada
| | - Jennifer L Hsiao
- Department of Dermatology, University of Southern California, Los Angeles, California
| | - Haley B Naik
- Department of Dermatology, University of California, San Francisco, California
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Cheraghpour M, Hatami B, Singal AG. Lifestyle and Pharmacologic Approaches to Prevention of Metabolic Dysfunction-associated Steatotic Liver Disease-related Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2025; 23:685-694.e6. [PMID: 39800201 DOI: 10.1016/j.cgh.2024.09.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 09/19/2024] [Accepted: 09/30/2024] [Indexed: 01/15/2025]
Abstract
Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate pharmacologic approach for individuals with MASLD may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.
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Affiliation(s)
- Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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Hawkins C, Waddilove E, Matthews PC, Delphin M. Impact of metformin on HBV replication: No evidence of suppression in vitro. J Clin Virol 2025; 177:105781. [PMID: 40120569 DOI: 10.1016/j.jcv.2025.105781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/12/2025] [Accepted: 03/15/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Outcomes of chronic Hepatitis B (CHB) infection have been increasingly associated with various metabolic syndromes, including metabolic-dysfunction associated steatotic liver disease (MASLD), with a potential for impact on liver disease progression. There is some evidence that metformin, a widely used anti-diabetic drug, may reduce hepatocellular carcinoma (HCC) incidence in people living with Hepatitis B Virus (HBV), but with little to no evidence of impact on the virus itself in vivo. However, previous in vitro studies suggest metformin may have a direct impact on HBV replication, although the mechanism remains unclear. OBJECTIVES We aimed to investigate the impact of metformin on HBV replication in vitro. STUDY DESIGN Hepatocyte cell lines constitutively expressing HBV (HepAD38) were treated once or thrice with escalating doses of metformin, using lamivudine and water as controls. We monitored cellular cytotoxicity as well as HBV biomarkers (HBeAg, HBsAg, HBV DNA and RNA) throughout the assay. RESULTS We did not observe any impact of metformin on HBV replication after a single dose or three repeated treatments. CONCLUSIONS In HepAD38 cells, HBV replication is not impacted by metformin treatment. This contrasts with prior in vitro data but is in line with clinical evidence that suggests metformin acts through an influence on liver disease progression rather than a direct antiviral impact on HBV itself.
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Affiliation(s)
- Cyrus Hawkins
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | | | - Philippa C Matthews
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Division of Infection and Immunity, University College London, Gower Street, London WC1E 6BT, UK; Department of Infectious Diseases, University College London Hospital, Euston Road, London NW1 2BU, UK
| | - Marion Delphin
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
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López-Cánovas JL, Naranjo-Martínez B, Diaz-Ruiz A. Fasting in combination with the cocktail Sorafenib:Metformin blunts cellular plasticity and promotes liver cancer cell death via poly-metabolic exhaustion. Cell Oncol (Dordr) 2025; 48:161-182. [PMID: 38990489 PMCID: PMC11850423 DOI: 10.1007/s13402-024-00966-2] [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] [Accepted: 05/31/2024] [Indexed: 07/12/2024] Open
Abstract
PURPOSE Dual-Interventions targeting glucose and oxidative metabolism are receiving increasing attention in cancer therapy. Sorafenib (S) and Metformin (M), two gold-standards in liver cancer, are known for their mitochondrial inhibitory capacity. Fasting, a glucose-limiting strategy, is also emerging as chemotherapy adjuvant. Herein, we explore the anti-carcinogenic response of nutrient restriction in combination with sorafenib:metformin (NR-S:M). RESULTS Our data demonstrates that, independently of liver cancer aggressiveness, fasting synergistically boosts the anti-proliferative effects of S:M co-treatment. Metabolic and Cellular plasticity was determined by the examination of mitochondrial and glycolytic activity, cell cycle modulation, activation of cellular apoptosis, and regulation of key signaling and metabolic enzymes. Under NR-S:M conditions, early apoptotic events and the pro-apoptotic Bcl-xS/Bcl-xL ratio were found increased. NR-S:M induced the highest retention in cellular SubG1 phase, consistent with the presence of DNA fragments from cellular apoptosis. Mitochondrial functionality, Mitochondrial ATP-linked respiration, Maximal respiration and Spare respiratory capacity, were all found blunted under NR-S:M conditions. Basal Glycolysis, Glycolytic reserve, and glycolytic capacity, together with the expression of glycogenic (PKM), gluconeogenic (PCK1 and G6PC3), and glycogenolytic enzymes (PYGL, PGM1, and G6PC3), were also negatively impacted by NR-S:M. Lastly, a TMT-proteomic approach corroborated the synchronization of liver cancer metabolic reprogramming with the activation of molecular pathways to drive a quiescent-like status of energetic-collapse and cellular death. CONCLUSION Altogether, we show that the energy-based polytherapy NR-S:M blunts cellular, metabolic and molecular plasticity of liver cancer. Notwithstanding the in vitro design of this study, it holds a promising therapeutic tool worthy of exploration for this tumor pathology.
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Affiliation(s)
- Juan L López-Cánovas
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain
| | - Beatriz Naranjo-Martínez
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain
| | - Alberto Diaz-Ruiz
- Laboratory of Cellular and Molecular Gerontology, Precision Nutrition and Aging Program, Institute IMDEA Food (CEI UAM+CSIC), Crta. de Canto Blanco nº 8, Madrid, E-28049, Spain.
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, Spain.
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Choi D, Lee JG, Heo SH, Cho MK, Nam HS, Lee SH, Lee YJ. Curcumin and Its Potential to Target the Glycolytic Behavior of Lactate-Acclimated Prostate Carcinoma Cells with Docetaxel. Nutrients 2024; 16:4338. [PMID: 39770959 PMCID: PMC11677565 DOI: 10.3390/nu16244338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Dysregulated cellular metabolism is known to be associated with drug resistance in cancer treatment. Methods: In this study, we investigated the impact of cellular adaptation to lactic acidosis on intracellular energy metabolism and sensitivity to docetaxel in prostate carcinoma (PC) cells. The effects of curcumin and the role of hexokinase 2 (HK2) in this process were also examined. Results: PC-3AcT and DU145AcT cells that preadapted to lactic acid displayed increased growth behavior, increased dependence on glycolysis, and reduced sensitivity to docetaxel compared to parental PC-3 and DU145 cells. Molecular analyses revealed activation of the c-Raf/MEK/ERK pathway, upregulation of cyclin D1, cyclin B1, and p-cdc2Thr161, and increased levels and activities of key regulatory enzymes in glycolysis, including HK2, in lactate-acclimated cells. HK2 knockdown resulted in decreased cell growth and glycolytic activity, decreased levels of complexes I-V in the mitochondrial electron transport chain, loss of mitochondrial membrane potential, and depletion of intracellular ATP, ultimately leading to cell death. In a xenograft animal model, curcumin combined with docetaxel reduced tumor size and weight, induced downregulation of glycolytic enzymes, and stimulated the upregulation of apoptotic and necroptotic proteins. This was consistent with the in vitro results from 2D monolayer and 3D spheroid cultures, suggesting that the efficacy of curcumin is not affected by docetaxel. Conclusions: Overall, our findings suggest that metabolic plasticity through enhanced glycolysis observed in lactate-acclimated PC cells may be one of the underlying causes of docetaxel resistance, and targeting glycolysis by curcumin may provide potential for drug development that could improve treatment outcomes in PC patients.
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Affiliation(s)
- Dongsic Choi
- Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan 31511, Republic of Korea; (D.C.); (S.-H.L.)
| | - Jun Gi Lee
- Biochemistry and Molecular Biology, Marquette University, Milwaukee, WI 53233, USA;
| | - Su-Hak Heo
- Department of Medicinal Bioscience, College of Biomedical and Health Science, Konkuk University Glocal Campus, Chungju 27478, Republic of Korea;
| | - Moon-Kyen Cho
- Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan 31151, Republic of Korea; (M.-K.C.); (H.-S.N.)
| | - Hae-Seon Nam
- Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan 31151, Republic of Korea; (M.-K.C.); (H.-S.N.)
| | - Sang-Han Lee
- Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan 31511, Republic of Korea; (D.C.); (S.-H.L.)
| | - Yoon-Jin Lee
- Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan 31511, Republic of Korea; (D.C.); (S.-H.L.)
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Park Y, Kang D, Sinn DH, Kim H, Hong YS, Cho J, Gwak GY. Effect of renin-angiotensin system inhibitor in incident cancer among chronic hepatitis B patients: An emulated target trial using a nationwide cohort. J Renin Angiotensin Aldosterone Syst 2024; 25. [DOI: 10.1177/14703203241294037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Background Although the renin-angiotensin system (RAS) has been reported to be associated with cancer development, the anticancer effects of RAS inhibitors (RASi) remain controversial. Objectives This study aimed to investigate the effect of RASi use on cancer incidence in chronic hepatitis B (CHB) patients. Design We designed a series of pragmatic trials for each week and followed the patients until the cancer diagnosis, death, or end of follow-up. Methods We analyzed CHB patients aged 40–84 years from the nationwide database between 2009 and 2017. We used 3:1 propensity score matching. Results Among 15,477 RASi non-users and 5263 RASi users, 2002 developed cancer. The adjusted hazard ratio (HR) for all cancer in RASi users was 0.89 [95% confidence interval (CI): 0.81–0.99]. The adjusted HR (95% CI) of hepatocellular carcinoma (HCC) and extrahepatic cancer were 0.79 (0.65–0.96) and 0.93 (0.82–1.04), respectively. When RASi was further divided, the adjusted HR (95% CI) for cancer of the angiotensin-converting enzyme inhibitor user and the angiotensin II receptor blocker user were 0.66 (0.50–0.87) and 0.93 (0.84–1.03), respectively. Conclusion RASi use was associated with a decreased incidence of all cancers, particularly HCC, in CHB patients, suggesting a chemopreventive effect of RASi in this population.
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Affiliation(s)
- Yewan Park
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Danbee Kang
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - Dong Hyun Sinn
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, Korea
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyunsoo Kim
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - Yun Soo Hong
- Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Juhee Cho
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
- Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Susman S, Santoso B, Makary MS. Locoregional Therapies for Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease. Biomedicines 2024; 12:2226. [PMID: 39457538 PMCID: PMC11504147 DOI: 10.3390/biomedicines12102226] [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: 09/01/2024] [Revised: 09/17/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide with an average five-year survival rate in the US of 19.6%. With the advent of HBV and HCV treatment and prevention, along with the rising rates of obesity, nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome are set to overtake infectious causes as the most common cause of HCC. While surgical resection and transplantation can be curative when amenable, the disease is most commonly unresectable on presentation, and other treatment approaches are the mainstay of therapy. In these patients, locoregional therapies have evolved as a vital tool in both palliation for advanced disease and as a bridge to surgical resection and transplantation. In this review, we will be exploring the primary locoregional therapies for HCC in patients with NAFLD, including transarterial chemoembolization (TACE), bland transarterial embolization (TAE), transarterial radioembolization (TARE), and percutaneous ablation.
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Affiliation(s)
- Stephen Susman
- Department of Radiology, Yale University Medical Center, New Haven, CT 06510, USA
| | - Breanna Santoso
- Heritage College of Osteopathic Medicine, Ohio University, Dublin, OH 43016, USA
| | - Mina S. Makary
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43202, USA
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Su F, Koeberle A. Regulation and targeting of SREBP-1 in hepatocellular carcinoma. Cancer Metastasis Rev 2024; 43:673-708. [PMID: 38036934 PMCID: PMC11156753 DOI: 10.1007/s10555-023-10156-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/10/2023] [Indexed: 12/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic reprogramming. De novo lipogenesis is under the control of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1) and essentially contributes to HCC progression. Here, we summarize the current knowledge on the regulation of SREBP-1 isoforms in HCC based on cellular, animal, and clinical data. Specifically, we (i) address the overarching mechanisms for regulating SREBP-1 transcription, proteolytic processing, nuclear stability, and transactivation and (ii) critically discuss their impact on HCC, taking into account (iii) insights from pharmacological approaches. Emphasis is placed on cross-talk with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) axis, AMP-activated protein kinase (AMPK), protein kinase A (PKA), and other kinases that directly phosphorylate SREBP-1; transcription factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), proliferator-activated receptor γ co-activator 1 (PGC-1), signal transducers and activators of transcription (STATs), and Myc; epigenetic mechanisms; post-translational modifications of SREBP-1; and SREBP-1-regulatory metabolites such as oxysterols and polyunsaturated fatty acids. By carefully scrutinizing the role of SREBP-1 in HCC development, progression, metastasis, and therapy resistance, we shed light on the potential of SREBP-1-targeting strategies in HCC prevention and treatment.
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Affiliation(s)
- Fengting Su
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria
| | - Andreas Koeberle
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria.
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Peppas S, Doumas S, Suvarnakar A, Chou J, Arafat A, Ahmad AI, Lewis JH. Clinical outcomes with metformin use in diabetic patients with compensated cirrhosis: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2024; 36:674-682. [PMID: 38477839 DOI: 10.1097/meg.0000000000002754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2024]
Abstract
BACKGROUND Previous studies have demonstrated a beneficial effect of metformin in patients with cirrhosis, but no improvement in liver histology. AIM To investigate the impact of metformin on mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. METHODS Medline, Embase and Cochrane databases were searched from inception to February 2023 for studies reporting results regarding the impact of metformin on all-cause mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. The risk of bias was assessed by ROBINS-I Cochrane tool. R software 4.3.1 was used for all analyses. RESULTS Six observational studies were included in the final analysis. Metformin use was associated with reduced all-cause mortality or liver transplantation [hazard ratio (HR): 0.55; 95% confidence interval (CI) 0.37-0.82], while no benefit was shown in the prevention of hepatic decompensation (HR: 0.97; 95% CI: 0.77-1.22). In the subgroup analysis, metformin use was associated with reduced all-cause mortality or liver transplantation (HR: 0.50; 95% CI 0.38-0.65) in patients with metabolic-associated steatohepatitis cirrhosis, while two studies reported no survival benefit in patients with cirrhosis due to hepatitis C (HR: 0.39; 95% CI 0.12-1.20). CONCLUSION Metformin use is associated with reduced all-cause mortality, but not with the prevention of hepatic decompensation in people with diabetes with compensated cirrhosis. The mortality benefit is most likely driven by better diabetes and cardiovascular health control.
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Affiliation(s)
- Spyros Peppas
- Department of Medicine, MedStar Washington Hospital Center
| | - Stavros Doumas
- Department of Internal Medicine, MedStar Georgetown University Medical Center
| | | | - Jiling Chou
- MedStar Research Health Institute, Hyattsville, Maryland
| | - Ayah Arafat
- MedStar Research Health Institute, Hyattsville, Maryland
| | - Akram I Ahmad
- Divsion of Gastroenterology & Hepatology, Cleveland Clinic Florida, Weston, Florida
| | - James H Lewis
- Division of Gastroenterology & Hepatology, MedStar Georgetown University Medical Center, Washington, DC, USA
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Galal MA, Al-Rimawi M, Hajeer A, Dahman H, Alouch S, Aljada A. Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int J Mol Sci 2024; 25:4083. [PMID: 38612893 PMCID: PMC11012626 DOI: 10.3390/ijms25074083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Mohammed Al-Rimawi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | | | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Samhar Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
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11
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Quiroz-Aldave JE, Gamarra-Osorio ER, Durand-Vásquez MDC, Rafael-Robles LDP, Gonzáles-Yovera JG, Quispe-Flores MA, Concepción-Urteaga LA, Román-González A, Paz-Ibarra J, Concepción-Zavaleta MJ. From liver to hormones: The endocrine consequences of cirrhosis. World J Gastroenterol 2024; 30:1073-1095. [PMID: 38577191 PMCID: PMC10989500 DOI: 10.3748/wjg.v30.i9.1073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 01/02/2024] [Accepted: 02/06/2024] [Indexed: 03/06/2024] Open
Abstract
Hepatocrinology explores the intricate relationship between liver function and the endocrine system. Chronic liver diseases such as liver cirrhosis can cause endocrine disorders due to toxin accumulation and protein synthesis disruption. Despite its importance, assessing endocrine issues in cirrhotic patients is frequently neglected. This article provides a comprehensive review of the epidemiology, pathophysiology, diagnosis, and treatment of endocrine disturbances in liver cirrhosis. The review was conducted using the PubMed/Medline, EMBASE, and Scielo databases, encompassing 172 articles. Liver cirrhosis is associated with endocrine disturbances, including diabetes, hypoglycemia, sarcopenia, thyroid dysfunction, hypogonadotropic hypogonadism, bone disease, adrenal insufficiency, growth hormone dysfunction, and secondary hyperaldosteronism. The optimal tools for diagnosing diabetes and detecting hypoglycemia are the oral glucose tolerance test and continuous glucose monitoring system, respectively. Sarcopenia can be assessed through imaging and functional tests, while other endocrine disorders are evaluated using hormonal assays and imaging studies. Treatment options include metformin, glucagon-like peptide-1 analogs, sodium-glucose co-transporter-2 inhibitors, and insulin, which are effective and safe for diabetes control. Established standards are followed for managing hypoglycemia, and hormone replacement therapy is often necessary for other endocrine dysfunctions. Liver transplantation can address some of these problems.
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Affiliation(s)
| | | | | | | | | | | | | | - Alejandro Román-González
- Department of Endocrinology, Hospital Universitario de San Vicente Fundación, Medellin 050010, Colombia
- Internal Medicine, Universidad de Antioquia, Medellín 050010, Colombia
| | - José Paz-Ibarra
- School of Medicine, Universidad Nacional Mayor de San Marcos, Lima 15081, Peru
- Department of Endocrinology, Hospital Nacional Edgardo Rebagliati Martins, Lima 15072, Peru
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12
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Shojaeian A, Nakhaie M, Amjad ZS, Boroujeni AK, Shokri S, Mahmoudvand S. Leveraging metformin to combat hepatocellular carcinoma: its therapeutic promise against hepatitis viral infections. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2023.147] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is categorized among the most common primary malignant liver cancer and a primary global cause of death from cancer. HCC tends to affect males 2-4 times more than females in many nations. The main factors that raise the incidence of HCC are chronic liver diseases, hepatotropic viruses like hepatitis B (HBV) and C (HCV), non-alcoholic fatty liver disease, exposure to toxins like aflatoxin, and non-alcoholic steatohepatitis (NASH). Among these, hepatitis B and C are the most prevalent causes of chronic hepatitis globally. Metformin, which is made from a naturally occurring compound called galegine, derived from the plant Galega officinalis (G. officinalis ), has been found to exhibit antitumor effects in a wide range of malignancies, including HCC. In fact, compared to patients on sulphonylureas or insulin, studies have demonstrated that metformin treatment significantly lowers the risk of HCC in patients with chronic liver disease. This article will first describe the molecular mechanism of hepatitis B and C viruses in the development of HCC. Then, we will provide detailed explanations about metformin, followed by a discussion of the association between metformin and hepatocellular carcinoma caused by the viruses mentioned above.
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13
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Sacco M, Ribaldone DG, Saracco GM. Metformin and Hepatocellular Carcinoma Risk Reduction in Diabetic Patients with Chronic Hepatitis C: Fact or Fiction? Viruses 2023; 15:2451. [PMID: 38140692 PMCID: PMC10748230 DOI: 10.3390/v15122451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/07/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Patients with chronic hepatitis C (CHC) and concomitant type 2 diabetes mellitus (DM) show a higher risk of developing hepatocellular carcinoma (HCC). Successful antiviral therapy has reduced the incidence of post-therapy HCC, but the presence of DM still represents an unfavourable predictive factor even in cured patients. Metformin (MET) is recommended as a first-line therapy for DM, and its use is associated with a significant reduction in HCC among diabetic patients with chronic liver disease of different etiology, but very few studies specifically address this issue in patients with CHC. AIM the aim of this review is to evaluate whether the use of MET induces a significant decrease in HCC in diabetic patients with CHC, treated or untreated with antiviral therapy. METHODS A search of PubMed, Medline, Web of Sciences and Embase was conducted for publications evaluating the role of MET in reducing the risk of HCC in patients with DM and CHC, with no language and study type restrictions up to 30 June 2023. Only studies fulfilling the following inclusion criteria were considered: (1) data on the incidence of HCC in the follow-up of diabetic patients with CHC only; (2) follow-up ≥24 months; (3) sufficient data to establish the rate of diabetic patients with CHC treated with metformin or other antidiabetic medications; and (4) data on the type of antiviral treatment and the clinical outcome. RESULTS Three studies met the inclusion criteria. A prospective cohort study considering only patients with DM and untreated advanced CHC, or non-responders to interferon (IFN) therapy, showed that the use of MET was associated with a significant decrease in HCC incidence, liver-related death and liver transplants. A recent retrospective study focusing on a large-scale nationwide cohort of patients with CHC in Taiwan successfully treated with IFN-based therapy stratified patients into 3 groups: non-MET users, MET users and non-diabetic patients, with 5-year cumulative rates of HCC of 10.9%, 2.6% and 3.0%, respectively, showing a significantly higher HCC risk in non-MET users compared with MET users and with non-diabetic patients, while it was not significantly different between MET users and non-diabetic patients. In a recent Italian cohort study focusing on 7007 patients with CHC treated and cured with direct-acting antiviral agents (DAAs), a combined effect of DM and MET therapy was found, showing a higher incidence of HCC in diabetic patients not taking MET compared with those without DM and those with DM taking MET. CONCLUSION according to the current evidence, the use of MET should be encouraged in diabetic patients with CHC in order to reduce the risk of HCC; however, a well-designed randomized controlled trial is needed to establish the generalizability of the beneficial effects of MET in this particular subset of patients.
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Affiliation(s)
| | | | - Giorgio Maria Saracco
- Gastro-Hepatoloy Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (M.S.); (D.G.R.)
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14
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He W, Wang X, Chen M, Li C, Chen W, Pan L, Cui Y, Yu Z, Wu G, Yang Y, Xu M, Dong Z, Ma K, Wang J, He Z. Metformin reduces hepatocarcinogenesis by inducing downregulation of Cyp26a1 and CD8 + T cells. Clin Transl Med 2023; 13:e1465. [PMID: 37997519 PMCID: PMC10668005 DOI: 10.1002/ctm2.1465] [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: 04/14/2023] [Revised: 10/12/2023] [Accepted: 10/19/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer with major challenges in both prevention and therapy. Metformin, adenosine monophosphate-activated protein kinase (AMPK) activator, has been suggested to reduce the incidence of HCC when used for patients with diabetes in preclinical and clinical studies. However, the possible effects of metformin and their mechanisms of action in non-diabetic HCC have not been adequately investigated. METHODS Fah-/- mice were used to construct a liver-injury-induced non-diabetic HCC model for exploring hepatocarcinogenesis and therapeutic potential of metformin. Changes in relevant tumour and biochemical indicators were measured. Bulk and single-cell RNA-sequencing analyses were performed to validate the crucial role of proinflammatory/pro-tumour CD8+ T cells. In vitro and in vivo experiments were performed to confirm Cyp26a1-related antitumour mechanisms of metformin. RESULTS RNA-sequencing analysis showed that chronic liver injury led to significant changes in AMPK-, glucose- and retinol metabolism-related pathways in Fah-/- mice. Metformin prevented the formation of non-diabetic HCC in Fah-/- mice with chronic liver injury. Cyp26a1 ddexpression in hepatocytes was significantly suppressed after metformin treatment. Moreover, downregulation of Cyp26a1 occurred in conjunction with increased levels of all-trans-retinoic acid (atRA), which is involved in the activation of metformin-suppressed hepatocarcinogenesis in Fah-/- mice. In contrast, both CD8+ T-cell infiltration and proinflammatory/pro-tumour cytokines in the liver were significantly upregulated in Fah-/- mice during chronic liver injury, which was notably reversed by either metformin or atRA treatment. Regarding mechanisms, metformin regulated the decrease in Cyp26a1 enzyme expression and increased atRA expression via the AMPK/STAT3/Gadd45β/JNK/c-Jun pathway. CONCLUSIONS Metformin inhibits non-diabetic HCC by upregulating atRA levels and downregulating CD8+ T cells. This is the first reporting that the traditional drug metformin regulates the metabolite atRA via the Cyp26a1-involved pathway. The present study provides a potential application of metformin and atRA in non-diabetic HCC.
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Affiliation(s)
- Weizhi He
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
- Fudan University Shanghai Cancer Center, International Co‐Laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Shanghai Medical College of Fudan University, Institutes of Biomedical SciencesShanghai Key Laboratory of Medical EpigeneticsShanghaiChina
| | - Xicheng Wang
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Miaomiao Chen
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Chong Li
- Zhoupu Community Health Service Center of Pudong New AreaShanghaiChina
| | - Wenjian Chen
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Lili Pan
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Yangyang Cui
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Postgraduate Training Base of Shanghai East HospitalJinzhou Medical UniversityJinzhouLiaoningChina
| | - Zhao Yu
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Guoxiu Wu
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Yang Yang
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Mingyang Xu
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Zhaoxuan Dong
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Keming Ma
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
| | - Jinghan Wang
- Department of Hepatobiliary and Pancreatic SurgeryShanghai East Hospital, Tongji UniversityShanghaiChina
| | - Zhiying He
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East HospitalSchool of Life Sciences and TechnologyTongji University School of MedicineShanghaiChina
- Shanghai Engineering Research Center of Stem Cells Translational MedicineShanghaiChina
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15
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Talamantes S, Lisjak M, Gilglioni EH, Llamoza-Torres CJ, Ramos-Molina B, Gurzov EN. Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Rep 2023; 5:100811. [PMID: 37575883 PMCID: PMC10413159 DOI: 10.1016/j.jhepr.2023.100811] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/01/2023] [Accepted: 05/08/2023] [Indexed: 08/15/2023] Open
Abstract
Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells. In addition, we highlight the role of enzymes in dysregulated metabolic activity and consequent dysfunctional signalling. Finally, we discuss the potential uses and challenges of novel therapeutic strategies to prevent and treat NAFLD/T2D-associated HCC.
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Affiliation(s)
- Stephanie Talamantes
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Michela Lisjak
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Eduardo H. Gilglioni
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
| | - Camilo J. Llamoza-Torres
- Department of Hepatology, Virgen de la Arrixaca University Hospital, Murcia, 30120, Spain
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
| | - Esteban N. Gurzov
- Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université Libre de Bruxelles, Route de Lennik 808, Brussels, 1070, Belgium
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, 30120, Spain
- WELBIO Department, WEL Research Institute, Avenue Pasteur 6, Wavre, 1300, Belgium
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16
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Cigrovski Berkovic M, Giovanardi F, Mrzljak A, Lai Q. Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma: A systematic review and meta-analysis. World J Diabetes 2023; 14:1289-1300. [PMID: 37664473 PMCID: PMC10473950 DOI: 10.4239/wjd.v14.i8.1289] [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: 02/27/2023] [Revised: 04/24/2023] [Accepted: 05/16/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the commonest malignancies associated with significant cancer-related death. The identification of chemo-preventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing. Metformin, a first-line agent used in the treatment of type 2 diabetes mellitus (T2DM), has been associated with inhibition of HCC growth. AIM To determine whether metformin can prevent adverse events (i.e., death, tumor progression, and recurrence) after any HCC treatment in T2DM patients. METHODS A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy. A search of the PubMed and Cochrane Central Register of Con-trolled Trials Databases was conducted. RESULTS A total of 13 studies (n = 14886 patients) were included in this review. With regard to the risk of death, a decreased risk was reported in cases receiving metformin, although this decrease was not statistically significant [odds ratio (OR) = 0.89, P = 0.42]. When only patients treated with curative strategies were considered, a more marked correlation between metformin and favorable cases was reported (OR = 0.70, P = 0.068). When analyzing palliative treatment, there was no statistical significance in terms of the correlation between metformin and favorable cases (OR = 0.74, P = 0.66). As for the risks of progressive disease and recurrence, no obvious correlation between metformin use and reduced risk was reported. When sub-analyses were performed for patients from different regions, the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin (OR = 0.69, P = 0.17), but the same was not seen in patients from Western countries (OR = 1.19, P = 0.31). CONCLUSION Metformin failed to show a marked impact in preventing adverse effects after HCC treatment. A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death, especially in patients from Eastern regions. Great heterogeneity was reported among the different studies. Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.
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Affiliation(s)
- Maja Cigrovski Berkovic
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb, Zagreb 10000, Croatia
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb 10000, Croatia
- Department of Medicine, School of Medicine, Zagreb 10000, Croatia
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
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17
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Abdalla MMI. Serum resistin and the risk for hepatocellular carcinoma in diabetic patients. World J Gastroenterol 2023; 29:4271-4288. [PMID: 37545641 PMCID: PMC10401662 DOI: 10.3748/wjg.v29.i27.4271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/11/2023] [Accepted: 06/27/2023] [Indexed: 07/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is a major contributor to cancer-related fatalities across the globe. Diabetes has been identified as a significant risk factor for HCC, with recent research indicating that the hormone resistin could be involved in the onset and advancement of HCC in diabetic individuals. Resistin is a hormone that is known to be involved in inflammation and insulin resistance. Patients with HCC have been observed to exhibit increased resistin levels, which could be correlated with more severe disease stages and unfavourable prognoses. Nevertheless, the exact processes through which resistin influences the development and progression of HCC in diabetic patients remain unclear. This article aims to examine the existing literature on the possible use of resistin levels as a biomarker for HCC development and monitoring. Furthermore, it reviews the possible pathways of HCC initiation due to elevated resistin and offers new perspectives on comprehending the fundamental mechanisms of HCC in diabetic patients. Gaining a better understanding of these processes may yield valuable insights into HCC’s development and progression, as well as identify possible avenues for prevention and therapy.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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18
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Papadakos SP, Ferraro D, Carbone G, Frampton AE, Vennarecci G, Kykalos S, Schizas D, Theocharis S, Machairas N. The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy? Cancers (Basel) 2023; 15:3161. [PMID: 37370771 PMCID: PMC10295995 DOI: 10.3390/cancers15123161] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/05/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Daniele Ferraro
- HPB Surgery and Liver Transplant Unit, AORN A. Cardarelli, 80131 Naples, Italy; (D.F.); (G.V.)
| | - Gabriele Carbone
- Department of General Surgery and Organ Transplantation, University of Rome “Sapienza”, 00161 Rome, Italy;
| | - Adam Enver Frampton
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK;
- Oncology Section, Surrey Cancer Research Institute, Department of Clinical and Experimental Medicine, FHMS, University of Surrey, The Leggett Building, Daphne Jackson Road, Guildford GU2 7WG, UK
- HPB Surgical Unit, Royal Surrey NHS Foundation Trust, Guildford GU2 7XX, UK
| | - Giovanni Vennarecci
- HPB Surgery and Liver Transplant Unit, AORN A. Cardarelli, 80131 Naples, Italy; (D.F.); (G.V.)
| | - Stylianos Kykalos
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolaos Machairas
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
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19
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Giorda CB, Picariello R, Tartaglino B, Nada E, Costa G, Manti R, Monge L, Gnavi R. HEPATOCELLULAR CARCINOMA IN A LARGE COHORT OF TYPE 2 DIABETES PATIENTS. Diabetes Res Clin Pract 2023; 200:110684. [PMID: 37100229 DOI: 10.1016/j.diabres.2023.110684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/04/2023] [Accepted: 04/19/2023] [Indexed: 04/28/2023]
Abstract
AIMS To elucidate the current burden of hepatocellular carcinoma (HCC) in type 2 diabetes (DM2) with a focus on the associated clinical determinants. METHODS Incidence of HCC between 2009 and 2019 in the diabetic and general population was calculated from regional administrative and hospital databases. Potential determinants of the disease were evaluated with a follow-up study. RESULTS In the DM2 population, the incidence resulted in 8.05 cases per 10,000 yearly. This rate was three times higher than that of the general population. 137158 patients with DM2 and 902 HCC were found for the cohort study. The survival of HCC patients was 1/3 of that of cancer-free diabetic controls. Age, male sex, alcohol abuse, previous viral hepatitis B and C, cirrhosis, low platelet count, elevated GGT / ALT, higher BMI and HbA1c levels were associated with HCC occurrence. Diabetes therapy was not adversely associated with HCC development. CONCLUSION Incidence of HCC in DM2 is more than tripled compared to the general population with high mortality. These figures are higher than those expected from the previous evidence. In parallel with known risk factors for liver disease, such as viruses and alcohol, insulin-resistance characteristics are associated with a higher probability of HCC.
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Affiliation(s)
- Carlo B Giorda
- Metabolism and Diabetes Unit, ASL TO5, Regione Piemonte, Chieri, Italy.
| | | | | | - Elisa Nada
- Metabolism and Diabetes Unit, ASL TO5, Regione Piemonte, Chieri, Italy
| | - Giuseppe Costa
- Epidemiology Unit, ASL TO3, Regione Piemonte, Grugliasco, Italy; Department of Public Health, University of Torino, Torino, Italy
| | - Roberta Manti
- Metabolism and Diabetes Unit, ASL TO5, Regione Piemonte, Chieri, Italy
| | - Luca Monge
- AMD (Clinical Diabetologists Association), Rome
| | - Roberto Gnavi
- Epidemiology Unit, ASL TO3, Regione Piemonte, Grugliasco, Italy
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Romero-Gómez M, Aller R, Ampuero J, Fernández Rodríguez C, Augustín S, Latorre R, Rivera-Esteban J, Martínez Urroz B, Gutiérrez García ML, López SA, Albillos A, Hernández M, Graupera I, Benlloch S, Olveira A, Crespo J, Calleja JL. AEEH «Consensus about detection and referral of hidden prevalent liver diseases». GASTROENTEROLOGIA Y HEPATOLOGIA 2023; 46:236-247. [PMID: 35569541 DOI: 10.1016/j.gastrohep.2022.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Manuel Romero-Gómez
- Servicio de Aparato Digestivo, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina (HUVR/CSIC/US), Universidad de Sevilla, Sevilla, España.
| | - Rocío Aller
- Servicio de Aparato Digestivo, Hospital Clínico Universitario de Valladolid, Universidad de Valladolid, Valladolid, España
| | - Javier Ampuero
- Servicio de Aparato Digestivo, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina (HUVR/CSIC/US), Universidad de Sevilla, Sevilla, España
| | | | - Salvador Augustín
- Servei de Hepatología, Hospital Universitario Vall d'Hebron, Barcelona, España
| | - Raquel Latorre
- Servicio de Aparato Digestivo, Hospital Universitario Son Llàtzer, Palma de Mallorca, Islas Baleares, España
| | | | | | | | - Sonia Alonso López
- Servicio de Aparato Digestivo, Hospital Universitario Gregorio Marañón, Madrid, España
| | - Agustín Albillos
- Servicio de Aparato Digestivo, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Marta Hernández
- Servicio de Aparato Digestivo, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Universidad Autónoma de Madrid, Majadahonda, Madrid, España
| | - Isabel Graupera
- Servicio de Hepatología, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, España
| | - Salvador Benlloch
- Servicio de Aparato Digestivo, Hospital Arnau de Vilanova, Valencia, España; CIBERehd, Instituto de Salud Carlos III, Madrid, España
| | - Antonio Olveira
- Servicio de Aparato Digestivo, Hospital La Paz, Madrid, España
| | - Javier Crespo
- Servicio de Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Valdecilla. IDIVAL, Santander, Cantabria, España
| | - José Luis Calleja
- Servicio de Aparato Digestivo, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Universidad Autónoma de Madrid, Majadahonda, Madrid, España
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Chen J, Jin H, Zhou H, Liu K. Effects of Metformin on Risk and Prognosis of Biliary Tract Cancer: A Systematic Review and Meta-Analysis. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:298. [PMID: 36837499 PMCID: PMC9967261 DOI: 10.3390/medicina59020298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/25/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023]
Abstract
Background and Objectives: Metformin has been found to potentially reduce the risk and improve the prognosis of a variety of tumors, but these findings remain controversial in biliary tract cancer (BTC). Therefore, this systematic review and meta-analysis was conducted to investigate the association between metformin and BTC. Materials and Methods: Two independent researchers comprehensively searched PubMed, Embase, the Cochrane Library, and Web of Science for eligible studies published from their inception to 31 March 2022. Comparisons of risk, overall survival (OS), and disease-free survival (DFS) for patients with BTC were selected as the endpoints of interest and pooled by random or fixed-effects models. Results: Eleven studies with a total of 24,788,738 participants were eligible for this analysis. The overall pooled effects showed no significant differences in biliary tract cancer risk (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.50-1.35, p = 0.436), OS (HR = 0.88, 95% CI: 0.74-1.04, p = 0.135), or DFS (HR = 1.03, 95% CI: 0.79-1.34, p = 0.829) between metformin users and non-users. When restricting participants to those with diabetes, a similar negative result was found, demonstrating that metformin use was not significantly associated with a lower risk of developing BTC compared with a lack of metformin use (HR = 0.65, 95% CI: 0.39-1.07, p = 0.089); notably, the included studies exhibited significant heterogeneity in the selection of participants and the definition of metformin users. Conclusions: Metformin may not be able to reduce the risk of BTC and improve prognosis in certain populations. Based on the limited quantity and quality of the included studies, the present results should be interpreted within their limitations, and further studies are warranted to determine the optimal timing, dose, duration, and scenario of metformin administration.
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Affiliation(s)
| | | | | | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, China
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22
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Metts JL, Trucco M, Weiser DA, Thompson P, Sandler E, Smith T, Crimella J, Sansil S, Thapa R, Fridley BL, Llosa N, Badgett T, Gorlick R, Reed D, Gill J. A phase I trial of metformin in combination with vincristine, irinotecan, and temozolomide in children with relapsed or refractory solid and central nervous system tumors: A report from the national pediatric cancer foundation. Cancer Med 2023; 12:4270-4281. [PMID: 36151773 PMCID: PMC9972017 DOI: 10.1002/cam4.5297] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 08/23/2022] [Accepted: 09/16/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Patients with relapsed and refractory solid and central nervous system (CNS) tumors have poor outcomes and need novel therapeutic options. Vincristine, irinotecan, and temozolomide (VIT) is a common chemotherapy regimen in relapsed pediatric tumors with an established toxicity profile. Metformin shows preclinical anti-cancer activity through multiple pathways. METHODS The objective of this Phase I trial was to establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of metformin in combination with VIT in children with relapsed and refractory solid and CNS tumors. A 3 + 3 design was used to test the addition of metformin at five dose levels (666, 999, 1333, 1666, and 2000 mg/m2 /day). Therapy toxicity, pharmacokinetics, and radiologic response to treatment were evaluated. RESULTS Twenty-six patients (median age 13 years, range 2-18 years) were enrolled with 22 evaluable for toxicity. The most common diagnoses were Ewing sarcoma (n = 8), rhabdomyosarcoma (n = 3) and atypical teratoid/rhabdoid tumor (n = 3). The MTD was exceeded at Dose Level 5 due to two dose-limiting toxicities; both were Grade 3 diarrhea requiring prolonged hospitalization and intravenous fluids. The MTD was not determined due to study closure with less than six patients enrolled at Dose Level 4. Frequently observed toxicities were gastrointestinal (most notably diarrhea) and hematologic. Amongst 16 patients evaluable for best overall response, there was one complete response (Ewing sarcoma), three partial responses (Ewing sarcoma, glioblastoma multiforme, and alveolar rhabdomyosarcoma), and five patients with stable disease. CONCLUSIONS The MTD of VIT with metformin was not determined due to premature study closure. We recommend an RP2D of Dose Level 4, 1666 mg/m2 /day. Radiographic responses were seen in multiple tumor types. Further evaluation for efficacy could be investigated in a Phase II trial.
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Affiliation(s)
- Jonathan L Metts
- Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA
| | - Matteo Trucco
- Cleveland Clinic Children's Hospital, Department of Pediatric Hematology-Oncology & Bone Marrow Transplantation, Cleveland, Ohio, USA
| | - Daniel A Weiser
- Departments of Pediatrics and Genetics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Patrick Thompson
- Division of Pediatric Hematology-Oncology, University of North Carolina Health Care, Chapel Hill, North Carolina, USA
| | - Eric Sandler
- Department of Pediatric Oncology, Nemours Health Systems, Jacksonville, Florida, USA
| | - Tiffany Smith
- Cognitive Research Corporation, St Petersburg, Florida, USA
| | - Jessica Crimella
- Clinical Trials Office Partnerships, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Samer Sansil
- Cancer Pharmacokinetics and Pharmacodynamic Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Ram Thapa
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Brooke L Fridley
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Nicholas Llosa
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Thomas Badgett
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Richard Gorlick
- Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Damon Reed
- Adolescent and Young Adult Program, Department of Interdisciplinary Cancer Management, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
| | - Jonathan Gill
- Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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23
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Garg K, Lingaraj A, Havangi S, Satheesha A, Naidu A, Garg B. Metformin use and Occurrence of Hepatocellular Carcinoma in Patients with Type II Diabetes Mellitus: A Systematic Review. JOURNAL OF RADIATION AND CANCER RESEARCH 2023. [DOI: 10.4103/jrcr.jrcr_65_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
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24
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Onikanni SA, Lawal B, Bakare OS, Ajiboye BO, Ojo OA, Farasani A, Kabrah SM, Batiha GES, Conte-Junior CA. Cancer of the Liver and its Relationship with Diabetes mellitus. Technol Cancer Res Treat 2022; 21:15330338221119743. [PMID: 36533882 PMCID: PMC9772979 DOI: 10.1177/15330338221119743] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
A high increase witnessed in type II diabetes mellitus (T2DM) globally has increasingly posed a serious threat to global increases in liver cancer with the association between diabetes mellitus type II and the survival rate in liver cancer patients showing unstable findings. An increase in the development and progression of chronic liver disease from diabetes mellitus patients may be connected to cancer of the liver with several links such as Hepatitis B and C virus and heavy consumption of alcohol. The link between T2DM patients and liver cancer is centered on non-alcoholic fatty liver disease (NAFLD) which could be a serious threat globally if not clinically addressed. Several reports identified metformin treatment as linked to a lower risk of liver cancer prognosis while insulin treatment or sulphonylureas posed a serious threat. Mechanistically, the biological linkage between diabetes type II mellitus and liver cancer are still complex to understand with only the existence of a relationship between NAFLD and high level of energy intake and diabetes mellitus induces hepatic damage, increased liver weight thereby causes multiple pro-inflammatory cytokines that lead to the development of liver cancer. Therefore, this review gives an account of the pathophysiological importance of liver cancer position with T2DM, with the role of NAFLD as an important factor that bridges them.
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Affiliation(s)
- Sunday Amos Onikanni
- Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria,College of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan,Sunday Amos Onikanni, College of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
| | - Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei,Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei
| | | | - Basiru Olaitan Ajiboye
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Ekiti State, Nigeria
| | - Oluwafemi Adeleke Ojo
- Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo, 232101, Nigeria
| | - Abdullah Farasani
- Biomedical Research Unit, Medical Research Center, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia,Department of Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Saeed M Kabrah
- Department of Laboratory Medicine Faculty of Applied medical sciences, Umm Al-Qura University, Kingdom of Saudi Arabia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, Egypt
| | - Carlos Adam Conte-Junior
- Analytical and Molecular Laboratorial Center (CLAn), Institute of Chemistry (IQ), Federal University of Rio de Janeiro (UFRJ), Cidade Universitária, Rio de Janeiro, RJ, 21941-909, Brazil
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25
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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26
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Plaz Torres MC, Jaffe A, Perry R, Marabotto E, Strazzabosco M, Giannini EG. Diabetes medications and risk of HCC. Hepatology 2022; 76:1880-1897. [PMID: 35239194 PMCID: PMC9790535 DOI: 10.1002/hep.32439] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus is a recognized risk factor for HCC in patients with liver disease, independent from the etiology of their liver disease. Hence, prevention and treatment of type 2 diabetes mellitus and its underlying cause, insulin resistance, should be considered a treatment target for patients with liver disease. The drug armamentarium for diabetes is wide and consists of agents with insulin-sensitizing activity, agents that stimulate insulin secretion, insulin itself, and agents that reduce gastrointestinal and urinary glucose absorption. From an endocrinology perspective, the main goal of treatment is the achievement of euglycemia; however, in patients at risk of, or with known underlying liver disease, the choice of diabetic medication as it relates to potential hepatic carcinogenesis remains complex and should be carefully considered. In the last decade, increasing evidence has suggested that metformin may reduce the risk of HCC, whereas evidence for other classes of diabetic medications, particularly some of the newer agents including the sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, is fewer and often inconsistent. In this review, we aim to summarize the current evidence on the potential effects of the most widely used diabetic agents on liver cancer tumorigenesis.
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Affiliation(s)
- Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Ariel Jaffe
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Rachel Perry
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Section of EndocrinologyDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Department of Cellular and Molecular PhysiologyYale University School of MedicineNew HavenConnecticutUSA
| | - Elisa Marabotto
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Mario Strazzabosco
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
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27
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Roeb E, Canbay A, Bantel H, Bojunga J, de Laffolie J, Demir M, Denzer UW, Geier A, Hofmann WP, Hudert C, Karlas T, Krawczyk M, Longerich T, Luedde T, Roden M, Schattenberg J, Sterneck M, Tannapfel A, Lorenz P, Tacke F. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:1346-1421. [PMID: 36100202 DOI: 10.1055/a-1880-2283] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- E Roeb
- Gastroenterologie, Medizinische Klinik II, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - A Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - H Bantel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - J Bojunga
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin., Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - J de Laffolie
- Allgemeinpädiatrie und Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - M Demir
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
| | - U W Denzer
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Marburg, Deutschland
| | - A Geier
- Medizinische Klinik und Poliklinik II, Schwerpunkt Hepatologie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - W P Hofmann
- Gastroenterologie am Bayerischen Platz - Medizinisches Versorgungszentrum, Berlin, Deutschland
| | - C Hudert
- Klinik für Pädiatrie m. S. Gastroenterologie, Nephrologie und Stoffwechselmedizin, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - T Karlas
- Klinik und Poliklinik für Onkologie, Gastroenterologie, Hepatologie, Pneumologie und Infektiologie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - M Krawczyk
- Klinik für Innere Medizin II, Gastroent., Hepat., Endokrin., Diabet., Ern.med., Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - T Longerich
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - T Luedde
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - M Roden
- Klinik für Endokrinologie und Diabetologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - J Schattenberg
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| | - M Sterneck
- Klinik für Hepatobiliäre Chirurgie und Transplantationschirurgie, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - A Tannapfel
- Institut für Pathologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - P Lorenz
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - F Tacke
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
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28
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Chen Y, Li Q, Ren S, Chen T, Zhai B, Cheng J, Shi X, Song L, Fan Y, Guo D. Investigation and experimental validation of curcumin-related mechanisms against hepatocellular carcinoma based on network pharmacology. J Zhejiang Univ Sci B 2022; 23:682-698. [PMID: 35953761 PMCID: PMC9381327 DOI: 10.1631/jzus.b2200038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/27/2022] [Indexed: 11/11/2022]
Abstract
OBJECTIVES To determine the potential molecular mechanisms underlying the therapeutic effect of curcumin on hepatocellular carcinoma (HCC) by network pharmacology and experimental in vitro validation. METHODS The predictive targets of curcumin or HCC were collected from several databases. the identified overlapping targets were crossed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Two of the candidate pathways were selected to conduct an experimental verification. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay was used to determine the effect of curcumin on the viability of HepG2 and LO2 cells. The apoptosis and autophagy of HepG2 cells were respectively detected by flow cytometry and transmission electron microscopy. Besides, western blot and real-time polymerase chain reaction (PCR) were employed to verify the p53 apoptotic pathway and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) autophagy pathway. HepG2 cells were pretreated with pifithrin-α (PFT-α) and GSK690693 for further investigation. RESULTS The 167 pathways analyzed by KEGG included apoptosis, autophagy, p53, and AMPK pathways. The GO enrichment analysis demonstrated that curcumin was involved in cellular response to drug, regulation of apoptotic pathway, and so on. The in vitro experiments also confirmed that curcumin can inhibit the growth of HepG2 cells by promoting the apoptosis of p53 pathway and autophagy through the AMPK pathway. Furthermore, the protein and messenger RNA (mRNA) of the two pathways were downregulated in the inhibitor-pretreated group compared with the experimental group. The damage-regulated autophagy modulator (DRAM) in the PFT-α-pretreated group was downregulated, and p62 in the GSK690693-pretreated group was upregulated. CONCLUSIONS Curcumin can treat HCC through the p53 apoptotic pathway and the AMPK/Unc-51-like kinase 1 (ULK1) autophagy pathway, in which the mutual transformation of autophagy and apoptosis may occur through DRAM and p62.
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Affiliation(s)
- Yang Chen
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Qian Li
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Sisi Ren
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Ting Chen
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Bingtao Zhai
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Jiangxue Cheng
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Xiaoyan Shi
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Liang Song
- Medical Experimental Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Yu Fan
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
- Shaanxi Provincial Key Laboratory of TCM Constitution and Disease Prevention, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Dongyan Guo
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China. ,
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29
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Cao JZ, Wang ZG, Yu J, Tao YP, Yang Y, Liu H, Zhou WP, Lu J, Huang Q. Antidiabetic treatment improves prognosis after radical resection in hepatocellular carcinoma patients with diabetes mellitus: a retrospective cohort study from 2000 to 2013. J Gastrointest Oncol 2022; 13:1330-1339. [PMID: 35837203 PMCID: PMC9274028 DOI: 10.21037/jgo-22-478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/14/2022] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND It remains unclear whether diabetic medications, such as metformin and insulin, affect the post-liver resection prognosis of hepatocellular carcinoma (HCC) patients complicated with diabetes mellitus (DM). This study try to find out the prognostic factors in HCC patients with DM and provide a better antidiabetic therapy after liver resection. METHODS Patients presenting with HCC complicated with DM undergoing liver resection were enrolled in this study. They were examined and followed up every 3-6 months after surgery. Patients were divided into the antidiabetic treatment group and no antidiabetic treatment group according to whether they received medications for diabetes or not. Then patients in the antidiabetic treatment group were further divided into insulin group, metformin group, insulin plus metformin group and others group, according to the medications they received. Overall survival (OS) and recurrence-free survival (RFS) were compared among two groups and four subgoups. Comparative and multivariate analyses were performed to investigate the effects of DM medication on the prognosis of these HCC patients, using Cox proportional hazards model. RESULTS The 1-, 3-, 5-, and 7-year OS rates for the antidiabetic treatment group were 87.5%, 75.5%, 48.7%, and 29.1%, respectively, and for the no antidiabetic treatment group, the OS rates were 85.4%, 57.7%, 33.6%, and 19.1%, respectively (P=0.007). The 1-, 3-, 5-, 7-year RFS rates for the antidiabetic treatment group were 76.4%, 53.5%, 28.5%, and 17.5%, respectively, and for the no antidiabetic treatment group, the RFS rates were 69.5%, 32.5%, 16.5%, and 10.7%, respectively (P=0.001). In subgroup analysis, There was no significant difference in either RFS (P=0.934) nor OS (P=0.412) among the different types of antidiabetic treatment regimens. Cox proportional hazard regression analysis revealed that tumor size (HR: 1.048), tumor number (HR: 1.626), vascular invasion (HR: 2.074, P=0.003), satellite tumor (HR: 1.592), Edmondson classification (HR: 1.468) and antidiabetic treatment (HR: 0.722) were independent prognostic factors of DFS, while tumor size (HR: 1.048), tumor number (HR: 1.779), vascular invasion (HR: 2.545), Edmondson classification (HR: 1.596) and antidiabetic treatment (HR: 0.713) were independent prognostic factors of OS. CONCLUSIONS For HCC patients with DM, antidiabetic treatment should be recommended aggressively in order to improve the surgical outcome, regardless of which antidiabetic drugs are used.
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Affiliation(s)
- Jing-Zhu Cao
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhen-Guang Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jian Yu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yuan-Ping Tao
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- National Liver Tissue Bank, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jin Lu
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Qin Huang
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
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High-Concentration Metformin Reduces Oxidative Stress Injury and Inhibits the Growth and Migration of Clear Cell Renal Cell Carcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:1466991. [PMID: 35592685 PMCID: PMC9113878 DOI: 10.1155/2022/1466991] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/23/2022] [Accepted: 03/28/2022] [Indexed: 12/21/2022]
Abstract
Objective To explore the mechanism of metformin in treating CCRCC. Methods Prospective cohort study was conducted. SOD and cyclin D in six CCRCC samples donated by volunteers were detected to compare the degree of oxidative stress injury and the status of cell proliferation. 786-0 CCRCC cells were cultured in vitro with different concentrations of metformin, and MTT assay and Transwell cell migration and wound healing assay were used to detect their proliferation and migration. After culture, SOD and cyclin D in 786-0 CCRCC cells were also detected. Results In the edge tissue, SOD was lower than in the tumor nest and normal tissue, and cyclin D was highly expressed. In grade II CCRCC, SOD was higher than in grade IV CCRCC, but cyclin D was also highly expressed in grade IV CCRCC. The cell proliferation rate and density of the metformin group were lower than the control group, while in the high-concentration metformin group, it was lower than medium- and low-concentration groups. After culture, the migration of 786-0 cells in the metformin group was significantly lower than that in the control group, the wound healing rate was decreased, and the migration and wound healing rates in the high-concentration metformin group were significantly lower than those in the medium- and low-concentration groups. However, the SOD of the metformin group was higher than the control group, but the cyclin D was lower, while the SOD was higher than medium- and low-concentration groups in the high-concentration group, but the cyclin D was lower after cultured. Conclusion High-concentration metformin can reduce oxidative stress injury, increase the expression of SOD in CCRCC, and reduce cyclin D in CCRCC to inhibit proliferation and migration, which has optimistic prospects and application value in controlling the progression of CCRCC.
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Li CQ, Liu ZQ, Liu SS, Zhang GT, Jiang L, Chen C, Luo DQ. Transcriptome Analysis of Liver Cancer Cell Huh-7 Treated With Metformin. Front Pharmacol 2022; 13:822023. [PMID: 35401213 PMCID: PMC8985428 DOI: 10.3389/fphar.2022.822023] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/18/2022] [Indexed: 12/24/2022] Open
Abstract
Metformin is a kind of widely used antidiabetic drug that regulates glucose homeostasis by inhibiting liver glucose production and increasing muscle glucose uptake. Recently, some studies showed that metformin exhibits anticancer properties in a variety of cancers. Although several antitumor mechanisms have been proposed for metformin action, its mode of action in human liver cancer remains not elucidated. In our study, we investigated the underlying molecular mechanisms of metformin's antitumor effect on Huh-7 cells of hepatocellular carcinoma (HCC) in vitro. RNA sequencing was performed to explore the effect of metformin on the transcriptome of Huh-7 cells. The results revealed that 4,518 genes (with log2 fold change > 1 or < −1, adjusted p-value < 0.05) were differentially expressed in Huh-7 cells with treatment of 25-mM metformin compared with 0-mM metformin, including 1,812 upregulated and 2,706 downregulated genes. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses identified 54 classical pathways that were significantly enriched, and 16 pathways are closely associated with cancer, such as cell cycle, DNA replication, extracellular matrix–receptor interaction, and so on. We selected 11 differentially expressed genes, which are closely associated with HCC, to validate their differential expressions through a quantitative real-time reverse transcription-polymerase chain reaction. The result exhibited that the genes of fatty acid synthase, mini-chromosome maintenance complex components 6 and 5, myristoylated alanine-rich C-kinase substrate, fatty acid desaturase 2, C-X-C motif chemokine ligand 1, bone morphogenetic protein 4, S-phase kinase-associated protein 2, kininogen 1, and proliferating cell nuclear antigen were downregulated, and Dual-specificity phosphatase-1 is significantly upregulated in Huh-7 cells with treatment of 25-mM metformin. These differentially expressed genes and pathways might play a crucial part in the antitumor effect of metformin and might be potential targets of metformin treating HCC. Further investigations are required to evaluate the metformin mechanisms of anticancer action in vivo.
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Affiliation(s)
- Chun-Qing Li
- Key Laboratory of Microbial Diversity Research and Application of Hebei Province, College of Life Science, Hebei University, Baoding, China
| | - Zhi-Qin Liu
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Science, Hebei University, Baoding, China
| | - Sha-Sha Liu
- Key Laboratory of Microbial Diversity Research and Application of Hebei Province, College of Life Science, Hebei University, Baoding, China.,College of Science and Technology, Hebei Agricultural University, Huanghua, China
| | - Gao-Tao Zhang
- Key Laboratory of Microbial Diversity Research and Application of Hebei Province, College of Life Science, Hebei University, Baoding, China
| | - Li Jiang
- Key Laboratory of Microbial Diversity Research and Application of Hebei Province, College of Life Science, Hebei University, Baoding, China
| | - Chuan Chen
- Key Laboratory of Microbial Diversity Research and Application of Hebei Province, College of Life Science, Hebei University, Baoding, China
| | - Du-Qiang Luo
- Key Laboratory of Microbial Diversity Research and Application of Hebei Province, College of Life Science, Hebei University, Baoding, China
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Di Ciaula A, Bonfrate L, Krawczyk M, Frühbeck G, Portincasa P. Synergistic and Detrimental Effects of Alcohol Intake on Progression of Liver Steatosis. Int J Mol Sci 2022; 23:2636. [PMID: 35269779 PMCID: PMC8910376 DOI: 10.3390/ijms23052636] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
| | - Leonilde Bonfrate
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
| | - Marcin Krawczyk
- Department of Medicine II Saarland University Medical Center, Saarland University, 66424 Homburg, Germany;
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain;
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 31009 Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31009 Pamplona, Spain
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
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Li Q, Xu H, Sui C, Zhang H. Impact of metformin use on risk and mortality of hepatocellular carcinoma in diabetes mellitus. Clin Res Hepatol Gastroenterol 2022; 46:101781. [PMID: 34332136 DOI: 10.1016/j.clinre.2021.101781] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/22/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND The views regarding the associations between metformin use and hepatocellular carcinoma (HCC) among diabetes mellitus (DM) patients are divisive. Thus we summarized all available published studies evaluating the relationship between metformin therapy and HCC survival and risk, and aim to conduct an updated meta-analysis study to more accurately clarify the association. METHODS We searched for articles regarding impact of metformin use on risk and mortality of HCC in DM and published before April 2021 in databases (PubMed and Web of Science). We used STATA 12.0 software to compute odds ratios (ORs)/relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) to generate a computed effect size and 95% CI. RESULTS The present study showed that metformin use was associated with a decreased risk of HCC in DM with a random effects model (OR/RR = 0.59, 95% CI 0.51-0.68, I2 = 96.5%, p < 0.001). In addition, the study indicated that metformin use was associated with a decreased all-cause mortality of HCC in DM with a random effects model (HR = 0.74, 95% CI 0.66-0.83, I2 = 49.6%, p = 0.037). CONCLUSION In conclusion, our studies support that the use of metformin in DM patients is significantly associated with reduced risk and all-cause mortality of HCC. And more prospective studies focusing on the metformin therapy as a protective factor for HCC are needed to verify the accuracy of the findings.
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Affiliation(s)
- Qiaomei Li
- Department of Hepatic Surgery, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China
| | - Hairong Xu
- Second department of biliary tract, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China
| | - Chengjun Sui
- Department of special treatment, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China
| | - Hongjuan Zhang
- Department of Oncology Biotherapy, The Third Affiliated Hospital of Naval Medical University, No. 700 North Moyu road, Jiading district, 201805 Shanghai, China.
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Abd El-Fattah EE, Saber S, Youssef ME, Eissa H, El-Ahwany E, Amin NA, Alqarni M, Batiha GES, Obaidullah AJ, Kaddah MMY, Ahmed Gaafar AG, Mourad AAE, Mostafa-Hedeab G, Abdelhamid AM. AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma. Front Pharmacol 2022; 12:720173. [PMID: 35095479 PMCID: PMC8790251 DOI: 10.3389/fphar.2021.720173] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 12/21/2021] [Indexed: 12/20/2022] Open
Abstract
HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.
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Affiliation(s)
- Eslam E Abd El-Fattah
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Mahmoud E Youssef
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Hanan Eissa
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Eman El-Ahwany
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Noha A Amin
- Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mohammed Alqarni
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Ahmad J Obaidullah
- Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.,Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohamed M Y Kaddah
- Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab, Egypt
| | - Ahmed Gaafar Ahmed Gaafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt
| | - Ahmed A E Mourad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt
| | - Gomaa Mostafa-Hedeab
- Pharmacology Department and Health Research Unit, Medical College, Jouf University, Jouf, Saudi Arabia.,Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt
| | - Amir Mohamed Abdelhamid
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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Bakrania A, Zheng G, Bhat M. Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment. Pharmaceutics 2021; 14:41. [PMID: 35056937 PMCID: PMC8779722 DOI: 10.3390/pharmaceutics14010041] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2-9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Medical Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada
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36
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Prevention of NAFLD-associated HCC: Role of lifestyle and chemoprevention. J Hepatol 2021; 75:1217-1227. [PMID: 34339764 DOI: 10.1016/j.jhep.2021.07.025] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
In many countries worldwide, the burden of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. Preventive strategies are needed to counteract this trend. In this review, we provide an overview of the evidence on preventive strategies in NAFLD-associated HCC. We consider the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, antidiabetic treatments and statins is summarised. The role of adjuvant therapies for tertiary prevention of HCC is briefly reviewed.
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Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis. Clin Gastroenterol Hepatol 2021; 19:2148-2160.e14. [PMID: 32798709 DOI: 10.1016/j.cgh.2020.08.026] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. METHODS We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. RESULTS Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2-receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61-0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35-0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. CONCLUSIONS Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2-receptor blocker exposure.
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Padda J, Khalid K, Khedr A, Tasnim F, Al-Ewaidat OA, Cooper AC, Jean-Charles G. Non-Alcoholic Fatty Liver Disease and Its Association With Diabetes Mellitus. Cureus 2021; 13:e17321. [PMID: 34557367 PMCID: PMC8449987 DOI: 10.7759/cureus.17321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2021] [Indexed: 11/29/2022] Open
Abstract
There is a bidirectional relationship between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). The liver has a vital role in the pathophysiology of both diseases as it leads to the development of insulin resistance (IR), which in turn results in NAFLD and T2DM. It has been shown that T2DM increases the risk of NAFLD progression. Furthermore, the presence of NAFLD raises the probability of T2DM complications, which explains the increased rates of NAFLD screening in patients with T2DM. In addition, there are common management options for the two diseases. Lifestyle changes can play a role in the initial management of both diseases. Medications that are used to treat T2DM are also used in the management of NAFLD, such as metformin, thiazolidinediones (TZD), glucagon-like peptide-1 (GLP-1) analogues, and dipeptidyl peptidase-4 (DPP4) inhibitors. Bariatric surgery is often used as a last resort and has shown promising results. Lifestyle interventions with diet and exercise are important postoperatively to maintain the weight loss. There are many novel treatments that are being investigated for the treatment of NAFLD, targeting multiple pathophysiologic pathways. This review aims to shed some light on the intricate relationship between NAFLD and T2DM and how IR links both diseases. We also try to raise awareness among clinicians about this relationship and how the presence of one disease should raise a high index of suspicion for the existence of the other.
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Affiliation(s)
| | | | - Anwar Khedr
- Internal Medicine, JC Medical Center, Orlando, USA
| | | | | | | | - Gutteridge Jean-Charles
- Internal Medicine, JC Medical Center, Orlando, USA.,Internal Medicine, Advent Health & Orlando Health Hospital, Orlando, USA
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Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo. Cancers (Basel) 2021; 13:cancers13184612. [PMID: 34572837 PMCID: PMC8468269 DOI: 10.3390/cancers13184612] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 01/14/2023] Open
Abstract
Simple Summary Recent studies have shown that metformin combined with clinical chemotherapeutic drugs could cause decreased cell toxicity and attenuate tumor resistance in various types of cancer. The aim of the present study was to elucidate whether combined treatment with metformin and everolimus has a synergistic anticancer effect in human cervical cancer in vitro and in vivo. The results showed that this combined treatment synergistically inhibited the growth of human cervical cancer cell lines and xenografts in nude mice, and induced caspase-dependent apoptosis, promoting sub-G1- and G0/G1-phase arrest and enhancing mtROS production. Combined treatment also synergistically inactivated PI3K/AKT signaling and activated MAPKs signaling in cervical cancer. Our data suggested that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combined treatment provides a novel therapeutic strategy for patients with cervical cancer. Abstract Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.
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Yip TC, Chan RNC, Wong VW, Tse Y, Liang LY, Hui VW, Zhang X, Li G, Chan HL, Wong GL. Association of metformin use on metabolic acidosis in diabetic patients with chronic hepatitis B-related cirrhosis and renal impairment. Health Sci Rep 2021; 4:e352. [PMID: 34401527 PMCID: PMC8358231 DOI: 10.1002/hsr2.352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/01/2021] [Accepted: 07/22/2021] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND AND AIMS Metformin is an oral anti-hyperglycemic recommended by the American Diabetes Association (ADA) as a preferred initial pharmacologic agent for type 2 diabetes. Metabolic acidosis is a rare yet severe side effect of it. We examined the association of metformin use and dosage on the risk of metabolic acidosis in diabetic patients with different degrees of chronic hepatitis B (CHB)-related cirrhosis and chronic kidney disease (CKD). METHODS Metabolic acidosis was defined by blood pH ≤7.35, together with lactate >5 mmol/L or arterial bicarbonate ≤18 mmol/L or venous bicarbonate ≤21 mmol/L, and/or diagnosis codes. Child-Pugh class and CKD stage were included in the model as time-dependent covariates. Age, gender, comorbidities, and use of relevant medications were adjusted as covariates. Maximum daily dose of metformin was classified into ≤1000 mg and >1000 mg. RESULTS We identified 4431 diabetic patients with CHB-related cirrhosis between 2000 and 2017 from a territory-wide database in Hong Kong. The risk of metabolic acidosis increased with Child-Pugh class B and C cirrhosis regardless of CKD stage (adjusted subdistribution hazard ratio [aSHR] ranged from 3.50 to 86.16). Metformin use was associated with a higher risk in patients with Child-Pugh class B or C cirrhosis and stage 3A CKD or above (aSHR ranged from 1.55 to 2.46). In stage 4/5 CKD, a daily dose of metformin ≤1000 mg was still associated with a higher risk of metabolic acidosis regardless of the severity of cirrhosis (aSHR ranged from 2.45 to 3.92). CONCLUSION In conclusion, patients with Child-Pugh class B cirrhosis or above were at a higher risk of metabolic acidosis. Metformin further increased the risk in patients with Child-Pugh class B cirrhosis or above and stage 3A CKD or above. Dose adjustment in stage 4/5 CKD did not reduce the risk of metabolic acidosis.
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Affiliation(s)
- Terry Cheuk‐Fung Yip
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
- Medical Data Analytics Centre (MDAC)The Chinese University of Hong KongHong KongChina
- Institute of Digestive Disease, The Chinese University of Hong KongHong KongChina
| | - Raymond Ngai Chiu Chan
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
| | - Vincent Wai‐Sun Wong
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
- Medical Data Analytics Centre (MDAC)The Chinese University of Hong KongHong KongChina
- Institute of Digestive Disease, The Chinese University of Hong KongHong KongChina
| | - Yee‐Kit Tse
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
- Medical Data Analytics Centre (MDAC)The Chinese University of Hong KongHong KongChina
- Institute of Digestive Disease, The Chinese University of Hong KongHong KongChina
| | - Lilian Yan Liang
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
| | - Vicki Wing‐Ki Hui
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
| | - Xinrong Zhang
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
| | - Guan‐Lin Li
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
| | - Henry Lik‐Yuen Chan
- Medical Data Analytics Centre (MDAC)The Chinese University of Hong KongHong KongChina
- Faculty of MedicineThe Chinese University of Hong KongHong KongChina
- Department of Internal MedicineUnion HospitalHong Kong
| | - Grace Lai‐Hung Wong
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina
- Medical Data Analytics Centre (MDAC)The Chinese University of Hong KongHong KongChina
- Institute of Digestive Disease, The Chinese University of Hong KongHong KongChina
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Abstract
As liver is one of the primary organs involved in glucose homeostasis, it is not surprising that patients with liver dysfunction in chronic liver disease usually develop impaired glucose tolerance and subsequently overt diabetes later in their natural course. Diabetes that develops after the onset of cirrhosis of liver is usually referred to as hepatogenous diabetes (HD). It is an underrecognized and a hallmark endocrinological event in chronic liver disease. HD is associated with a higher risk of developing hepatic decompensations, such as ascites, variceal bleeding, hepatic encephalopathy, renal dysfunction, refractory ascites, and hepatocellular carcinoma along with reduced survival rates than normoglycemic patients with cirrhosis of liver. It is quite different from type 2 diabetes mellitus with the absence of classical risk factors, dissimilar laboratory profiles, and decreased incidence of microvascular complications. Furthermore, the management of patients with HD is challenging because of altered pharmacokinetics of most antidiabetic drugs and increased risk of hypoglycemia and other adverse effects. Hence, a clear understanding of the epidemiology, pathophysiology, clinical implications, laboratory diagnosis, and management of HD is essential for both hepatologists as well as endocrinologists, which is narrated briefly in this review.
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Affiliation(s)
- Preetam Nath
- Department of Gastroenterology & Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha 751024, India
| | - Anil C. Anand
- Department of Gastroenterology & Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha 751024, India
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42
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Leng W, Jiang J, Chen B, Wu Q. Metformin and Malignant Tumors: Not Over the Hill. Diabetes Metab Syndr Obes 2021; 14:3673-3689. [PMID: 34429626 PMCID: PMC8380287 DOI: 10.2147/dmso.s326378] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/06/2021] [Indexed: 12/11/2022] Open
Abstract
Malignant tumors are a major cause of death, and their incidence is increasing worldwide. Although the survival rate for some cancers has improved, treatments for other malignant tumors are limited, and their mortality rate continues to increase. People with type 2 diabetes have a higher risk of malignant tumors and a higher mortality rate than those without diabetes. Metformin is a commonly used hypoglycemic drug. In recent years, a growing number of studies have indicated that metformin has antitumor effects and increases the sensitivity of malignant tumors to chemotherapy. However, the effect of metformin on different tumors is currently controversial, and the mechanism of metformin's antitumor action is not fully understood. Insights into the effect of metformin on malignant tumors and the possible mechanism may contribute to the development of antitumor drugs.
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Affiliation(s)
- Weiling Leng
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Juan Jiang
- Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, People’s Republic of China
| | - Bing Chen
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Qinan Wu
- Endocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing, People’s Republic of China
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43
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Management of diabetes mellitus in patients with cirrhosis: An overview and joint statement. DIABETES & METABOLISM 2021; 47:101272. [PMID: 34363981 DOI: 10.1016/j.diabet.2021.101272] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/25/2021] [Accepted: 07/12/2021] [Indexed: 12/18/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a frequent comorbidity in patients with cirrhosis that is projected to rise in prevalence due to the worldwide burden of obesity, insulin-resistance and non-alcoholic fatty liver disease. The management of T2DM in patients with cirrhosis is complex given the requirement for accurate adaptation according to the level of liver function impairment, with lack of summary of the little evidence available in the literature. Here, we summarise the data available with respect to the epidemiology and the impact of T2DM in patients with cirrhosis, as well as those on the management of T2DM in these patients. We provide guidance for the diagnosis of T2DM and the monitoring of glycaemic control in patients with cirrhosis, and for the management of nutrition and pharmacological treatments in relation to the level of liver dysfunction.
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44
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Rodríguez-Escaja C, Á Navascués C, González-Diéguez L, Cadahía V, Varela M, de Jorge MÁ, Castaño-García A, Rodríguez M. Diabetes is not associated with an increased risk of hepatocellular carcinoma in patients with alcoholic or hepatitis C virus cirrhosis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 113:505-511. [PMID: 33244982 DOI: 10.17235/reed.2020.6953/2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS diabetes has been reported as a risk factor for hepatocellular carcinoma (HCC) in population-based studies but there are controversial data in patients with cirrhosis. Metformin could have a protective role in HCC development. The aim of this study was to determine the influence of diabetes on the risk of developing HCC in patients with alcohol- and hepatitis C virus (HCV)-related cirrhosis. METHODS a cohort of 982 Caucasian patients were analyzed with alcoholic or HCV cirrhosis, included from 1992 to 2014 in a HCC surveillance program and prospectively followed. The influence of diabetes on the development of HCC was analyzed by Kaplan Meier analysis and adjusted with a Cox regression for relevant co-factors. RESULTS after a median follow-up of 49.5 (24.0-96.0) months, 156 patients (15.8 %) developed HCC. There were no differences in the cumulative incidences of HCC after 20 years between diabetic and non-diabetic patients in the global (53.5 % vs 45.4 %; p = 0.26), alcoholic (50.4 % vs 45.4 %; p = 0.21) or HCV (60 % vs 43.1 %; p = 0.57) cirrhosis series. Diabetes did not constitute a risk factor after adjusting for other potential co-factors, neither in the whole series (hazard ratio [HR]: 1.12, 95 % CI: 0.78-1.51; p = 0.26), alcoholic (HR: 1.160, 95 % CI: 0.74-1.82; p = 0.50) or HCV cirrhosis cohort (HR: 1.17, 95 % CI: 0.63-2.19; p = 0.60). These figures did not change after excluding patients treated with metformin. CONCLUSIONS in Caucasian patients with alcoholic or HCV cirrhosis, diabetes is not a risk factor for developing HCC. This lack of an association does not seem to be a consequence of the protective effect of metformin.
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Affiliation(s)
- Carlos Rodríguez-Escaja
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Carmen Á Navascués
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Luisa González-Diéguez
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Valle Cadahía
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - María Varela
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Miguel Ángel de Jorge
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Andrés Castaño-García
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
| | - Manuel Rodríguez
- Liver Unit. Division of Gastroenterology and Hepat, Hospital Universitario Central de Asturias, España
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45
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Zahra MH, Afify SM, Hassan G, Nawara HM, Kumon K, Seno A, Seno M. Metformin suppresses self-renewal and stemness of cancer stem cell models derived from pluripotent stem cells. Cell Biochem Funct 2021; 39:896-907. [PMID: 34268768 DOI: 10.1002/cbf.3661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/24/2021] [Accepted: 06/29/2021] [Indexed: 11/09/2022]
Abstract
Metformin exhibits anti-cancer activities in various types of tumours while it is prescribed as the first-line drug for type 2 diabetes. Since new evidence has recently suggested that metformin could target cancer stem cells (CSCs) and prevent their recurrence, repositioning of metformin could be considered as a candidate for anti-CSC agent. In this study, we assessed the effect of metformin on the cancer stem cells developed from induced pluripotent stem cells. As the result, metformin significantly suppressed the self-renewal ability of CSCs when assessed by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and cell counting methods exhibiting the IC50 as approximately 20 mM, which suppressed tube formation by CSCs on Matrigel reducing the angiogenic potential of CSCs. Cell cycle analysis showed that metformin reduced the percentage of cells in the S phase increasing the percentage of cells in G0/G1 phase. Moreover, the tumorigenicity of CSCs was found to be attenuated when the cells were injected with metformin. From these results, we concluded that metformin could be promising for targeted therapy by repositioning the widely available drugs with safety. SIGNIFICANCE OF THE STUDY: Metformin could target CSCs and prevent their recurrence, repositioning of metformin could be considered as a candidate for the anti-CSC agent. In this paper, we assessed the effect of metformin on the CSCs developed from induced pluripotent stem cells. Here, we show that metformin suppresses the self-renewal and tube formation abilities of CSCs. We also show that metformin reduces the percentage of cells in the S phase increasing the percentage of cells in G0/G1 phase. Moreover, the tumorigenicity of CSCs was found to be attenuated when grafted in vivo after treatment with metformin.
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Affiliation(s)
- Maram H Zahra
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
| | - Said M Afify
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan.,Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Menoufia, Egypt
| | - Ghmkin Hassan
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan.,Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus, Syria
| | - Hend M Nawara
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
| | - Kazuki Kumon
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
| | - Akimasa Seno
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
| | - Masaharu Seno
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
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46
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El Shorbagy S, abuTaleb F, Labib HA, Ebian H, Harb OA, Mohammed MS, Rashied HA, Elbana KA, Haggag R. Prognostic Significance of VEGF and HIF-1 α in Hepatocellular Carcinoma Patients Receiving Sorafenib Versus Metformin Sorafenib Combination. J Gastrointest Cancer 2021; 52:269-279. [PMID: 32212089 DOI: 10.1007/s12029-020-00389-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major health problem. HCC burden has been increasing in Egypt in the past 10 years. Most HCC cases are diagnosed at an advanced stage with limited treatment options. Sorafenib is the standard therapy for advanced HCC, but the effectiveness is not satisfied. Metformin may decrease the risk of HCC development in diabetic patients, reduces tumor invasion, and augments sensitivity to sorafenib; however, safety and efficacy of combined treatment are still unclear. As HCC is characterized by high vascularity, and vascular endothelial growth factor (VEGF) plays an important role in vascularization, many studies questioned if VEGF and HIF-1 α could offer information about HCC response to sorafenib. We conducted this study to assess the benefits from adding metformin to HCC treatment, and appraise the role of VEGF and HIF-1 α in HCC prognosis. METHOD This was a prospective, randomized study in which 80 advanced measurable patients consecutively treated with sorafenib plus metformin (arm A) or sorafenib alone (arm B), prognostic value of plasma, and tissue levels of VEGF and HIF-1 α were evaluated. RESULTS We enrolled 61 men and 19 women with a median age of 60 years (range 49-68 years). Fifty-seven patients had Child-Pugh A while 23 had early B, the most common etiology of liver disease was hepatitis C (86%). Sixty percent of patients were diabetic. No significant difference was detected between arm A and arm B regarding response to treatment (p = 0.5), time to disease progression (p = 0.3), or overall survival (p = 0.6). Low VEGF and HIF-1 α plasma levels were significantly associated with better treatment response (p < 0.001 for both), and higher OS (p < 0.001). Patients with high expressions of VEGF and HIF in HCC tissue had significantly poor treatment outcome (p < 0.001, p = 0.03, respectively), and poor OS (p < 0.001, p < 0.001, respectively). CONCLUSIONS No superior efficacy of adding metformin to sorafenib in HCC treatment. VEGF and HIF-1 α had promising prognostic value in HCC.
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Affiliation(s)
- Shereen El Shorbagy
- Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Fouad abuTaleb
- Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Hany A Labib
- Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Huda Ebian
- Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ola A Harb
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mona Saeed Mohammed
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Khaled A Elbana
- Internal Medicine department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Rasha Haggag
- Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt.
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47
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Cunha Júnior AD, Bragagnoli AC, Costa FO, Carvalheira JBC. Repurposing metformin for the treatment of gastrointestinal cancer. World J Gastroenterol 2021; 27:1883-1904. [PMID: 34007128 PMCID: PMC8108031 DOI: 10.3748/wjg.v27.i17.1883] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/13/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus type 2 and cancer share many risk factors. The pleiotropic insulin-dependent and insulin-independent effects of metformin might inhibit pathways that are frequently amplified in neoplastic tissue. Particularly, modulation of inflammation, metabolism, and cell cycle arrest are potential therapeutic cancer targets utilized by metformin to boost the anti-cancer effects of chemotherapy. Studies in vitro and in vivo models have demonstrated the potential of metformin as a chemo- and radiosensitizer, besides its chemopreventive and direct therapeutic activity in digestive system (DS) tumors. Hence, these aspects have been considered in many cancer clinical trials. Case-control and cohort studies and associated meta-analyses have evaluated DS cancer risk and metformin usage, especially in colorectal cancer, pancreatic cancer, and hepatocellular carcinoma. Most clinical studies have demonstrated the protective role of metformin in the risk for DS cancers and survival rates. On the other hand, the ability of metformin to enhance the actions of chemotherapy for gastric and biliary cancers is yet to be investigated. This article reviews the current findings on the anti-cancer mechanisms of metformin and its apparatus from pre-clinical and ongoing studies in DS malignancies.
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Affiliation(s)
- Ademar Dantas Cunha Júnior
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | | | - Felipe Osório Costa
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
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48
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Abstract
PURPOSE OF REVIEW Mitochondria have a major impact on virtually all processes linked to oncogenesis. Thus, mitochondrial metabolism inhibition has emerged as a promising anticancer strategy. In this review, we discuss the anticancer potential of mitochondrial inhibitors, with particular focus on metformin, in the context of more effective, targeted therapeutic modalities, and diagnostic strategies for cancer patients. RECENT FINDINGS Metformin has gained interest as an antitumor agent. However, promising results have not been translated into remarkable advances in the clinical practice. Recent findings emphasize the need of providing a metabolic context in which mitochondrial inhibitors may elicit its anticancerous effects. In addition, mitochondria are critical regulators in orchestrating immune responses. Thus, the immunomodulatory effect of mitochondrial inhibitors should also be taken into account to optimize its clinical use. Targeting mitochondrial metabolic network represents a promising therapeutic strategy in cancer. However, there is a need to define the metabolic context in which mitochondrial inhibitors are more effective, as well as how the cross-talk between many immunological functions and mitochondrial functionality may be exploited for a therapeutic benefit in cancer patients.
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49
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Campbell C, Wang T, McNaughton AL, Barnes E, Matthews PC. Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis. J Viral Hepat 2021; 28:493-507. [PMID: 33305479 PMCID: PMC8581992 DOI: 10.1111/jvh.13452] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer mortality worldwide and is a leading cause of death in individuals with chronic hepatitis B virus (HBV) infection. It is uncertain how the presence of other metabolic factors and comorbidities influences HCC risk in HBV. Therefore, we performed a systematic literature review and meta-analysis to seek evidence for significant associations. MEDLINE, EMBASE and Web of Science databases were searched from 1 January 2000 to 24 June 2020 for studies investigating associations of metabolic factors and comorbidities with HCC risk in individuals with chronic HBV infection, written in English. We extracted data for meta-analysis and generated pooled effect estimates from a fixed-effects model. Pooled estimates from a random-effects model were also generated if significant heterogeneity was present. We identified 40 observational studies reporting on associations of diabetes mellitus (DM), hypertension, dyslipidaemia and obesity with HCC risk. Only DM had a sufficient number of studies for meta-analysis. DM was associated with >25% increase in hazards of HCC (fixed-effects hazards ratio [HR] 1.26, 95% confidence interval (CI) 1.20-1.32, random-effects HR 1.36, 95% CI 1.23-1.49). This association was attenuated towards the null in a sensitivity analysis restricted to studies adjusted for metformin use. In conclusion, in adults with chronic HBV infection, DM is a significant risk factor for HCC, but further investigation of the influence of antidiabetic drug use and glycaemic control on this association is needed. Enhanced screening of individuals with HBV and diabetes may be warranted.
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Affiliation(s)
- Cori Campbell
- Nuffield Department of MedicineUniversity of OxfordOxfordUK
| | - Tingyan Wang
- Nuffield Department of MedicineUniversity of OxfordOxfordUK
| | | | - Eleanor Barnes
- Nuffield Department of MedicineUniversity of OxfordOxfordUK,Department of HepatologyOxford University NHS Foundation TrustJohn Radcliffe HospitalOxfordUK
| | - Philippa C. Matthews
- Nuffield Department of MedicineUniversity of OxfordOxfordUK,Department of Infectious Diseases and MicrobiologyOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK,NIHR BRCJohn Radcliffe HospitalOxfordUK
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50
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Geh D, Manas DM, Reeves HL. Hepatocellular carcinoma in non-alcoholic fatty liver disease-a review of an emerging challenge facing clinicians. Hepatobiliary Surg Nutr 2021; 10:59-75. [PMID: 33575290 DOI: 10.21037/hbsn.2019.08.08] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022]
Abstract
Importance Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of chronic liver disease and is becoming a leading cause of hepatocellular carcinoma (HCC) in many developed countries. This presents major challenges for the surveillance, diagnosis and treatment of HCC. Objective To discuss the clinical challenges faced by clinicians in managing the rising number of NAFLD-HCC cases. Evidence Review MEDLINE, PubMed and Embase databases were searched using the keywords; NAFLD, HCC, surveillance, hepatectomy, liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE), selective internal radiotherapy treatment (SIRT) and sorafenib. Relevant clinical studies were included. Findings Current HCC surveillance programmes are inadequate because they only screen for HCC in patients with cirrhosis, whereas in NAFLD a significant proportion of HCC develops in the absence of cirrhosis. Consequently NAFLD patients often present with a more advanced stage of HCC, with a poorer prognosis. NAFLD-HCC patients also tend to be older and to have more co-morbidities compared to HCC of other etiologies. This limits the use of curative treatments such as liver resection and orthotopic liver transplantation (OLT). Evidence suggests that although NAFLD-HCC patients who undergo liver resection or OLT have worse perioperative and short-term outcomes, overall long-term survival is comparable to HCC of other etiologies. This highlights the importance of careful patient selection, pre-habilitation and perioperative planning for NAFLD-HCC patients being considered for surgical treatment. Careful consideration is also important for non-surgical treatments, although the evidence supporting treatment selection is frequently lacking, as these patients tend to be poorly represented in clinical trials. Locoregional therapies such as percutaneous ablation and TACE may be less well tolerated and less effective in NAFLD patients with obesity or diabetes. The tyrosine kinase inhibitor sorafenib may also be less effective. Conclusions and Relevance This review highlights how international guidelines, for which NAFLD traditionally has made up a small part of the evidence base, may not be appropriate for all NAFLD-HCC patients. Future guidelines need to reflect the changing landscape of HCC, by making specific recommendations for the management of NAFLD-HCC.
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Affiliation(s)
- Daniel Geh
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Derek M Manas
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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