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Bu J, Miao Z, Yang Q. GOT2: New therapeutic target in pancreatic cancer. Genes Dis 2025; 12:101370. [PMID: 40247913 PMCID: PMC12005923 DOI: 10.1016/j.gendis.2024.101370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 04/18/2024] [Accepted: 06/21/2024] [Indexed: 04/19/2025] Open
Abstract
In recent years, the incidence and mortality rates of pancreatic cancer have been steadily increasing, and conventional therapies have shown a high degree of tolerance. Therefore, the search for new therapeutic targets remains a key issue in current research. Mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) is an important component of the malate-aspartate shuttle system, which plays an important role in the maintenance of cellular redox balance and amino acid metabolism, and has the potential to become a promising target for anti-cancer therapy. In this paper, we will elaborate on the metabolic and immune effects of GOT2 in pancreatic cancer based on existing studies, with a view to opening up new avenues for the treatment of pancreatic cancer.
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Affiliation(s)
- Jiarui Bu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Zeyu Miao
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Qing Yang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
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2
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Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, Gao Z, Liu D, He W, Yang LL. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10:69. [PMID: 39966374 PMCID: PMC11836267 DOI: 10.1038/s41392-025-02141-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/08/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Hui Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuo Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Guo
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujing Song
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Fu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenjie Gao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Wei He
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Hao ZN, Tan XP, Zhang Q, Li J, Xia R, Ma Z. Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy. Biomolecules 2024; 14:1646. [PMID: 39766353 PMCID: PMC11674224 DOI: 10.3390/biom14121646] [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: 11/14/2024] [Revised: 12/14/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8+ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies.
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Affiliation(s)
- Zhi-Nan Hao
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Xiao-Ping Tan
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
- The Third Clinical Medical College of Yangtze University, Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou 434023, China
| | - Qing Zhang
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Jie Li
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Ruohan Xia
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Zhaowu Ma
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
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Schmidt M, Vernooij R, van Nuland M, Smeijsters E, Devriese L, Mohammad NH, Hermens T, Stammers J, Swart C, Egberts T, Haitjema S, Lammers L. Impaired liver function: effect on paclitaxel toxicity, dose modifications and overall survival. BMC Cancer 2024; 24:1553. [PMID: 39696046 PMCID: PMC11658450 DOI: 10.1186/s12885-024-13330-2] [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: 05/26/2024] [Accepted: 12/11/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND The anticancer drug paclitaxel is primarily metabolized in the liver. Previous studies have indicated a correlation between impaired liver function and paclitaxel toxicity, which may indicate dose reduction. Since the evidence is limited, the aim of this study was to investigate the effect of impaired liver function on the hematological toxicity of paclitaxel, dose modifications and overall survival (OS). METHODS For this single-center retrospective observational study, patients treated with paclitaxel for breast, esophageal and ovarian cancer at the University Medical Centre Utrecht between 2011 and 2022 were identified from the Utrecht Patient Oriented Database (UPOD). Based on regression analysis, the risk of developing Grade 3/4 hematological toxicity was compared between patients with normal and impaired (based on the NCI criteria for bilirubin and ASAT (aspartate aminotransferase) concentrations) liver function. Additionally, differences in the occurrence of toxicity-related dose modifications and OS were evaluated between the two groups. RESULTS A total of 569 patients were included. Breast cancer patients who were receiving advanced treatment and had mildly impaired liver function (ASAT ≤ 2x ULN, bilirubin ≤ ULN) had an increased risk of developing grade 3/4 neutropenia (HR = 4.39, 95% CI 1.20-16.02; p = 0.03). In addition, patients with impaired liver function treated according to the advanced ovarian cancer regimen had an increased risk of developing grade 3/4 leukopenia (HR = 12.64, 95% CI 2.12-75.22, p = 0.01) and dose modification (treatment discontinuation) (HR = 3.91, 95% CI 1.74-8.79, p < 0.01). Impaired liver function was also associated with decreased OS in inoperable esophageal and advanced ovarian cancer patients (HR = 7.65, 95% CI 2.54-23.1, p < 0.01 and HR = 2.98, 95% CI 1.36-6.54, p < 0.01, respectively). The risk of developing grade 3/4 hematological toxicity during lower-dose paclitaxel treatment protocols was not significantly different in patients with impaired liver function. CONCLUSIONS This study revealed that patients with impaired liver function treated with paclitaxel for breast and ovarian cancer in an advanced setting are at greater risk of developing hematological toxicity than patients with normal liver function at the start of therapy. Furthermore, in patients with ovarian (advanced) or inoperable esophageal cancer, impaired liver function is associated with decreased OS. Within these groups of patients, it is important to weigh the risk of upfront paclitaxel dose modifications versus an adaptive strategy.
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Affiliation(s)
- Marieke Schmidt
- Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands
| | - Robin Vernooij
- Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Merel van Nuland
- Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands
| | - Erin Smeijsters
- Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands
| | - Lot Devriese
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, PO Box 85500, Utrecht, 3508 GA, The Netherlands
| | - Nadia Haj Mohammad
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, PO Box 85500, Utrecht, 3508 GA, The Netherlands
| | - Thom Hermens
- Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands
| | - Julian Stammers
- Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands
| | - Christina Swart
- Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands
| | - Toine Egberts
- Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Saskia Haitjema
- Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Laureen Lammers
- Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508 GA, The Netherlands.
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Soon JW, Manca MA, Laskowska A, Starkova J, Rohlenova K, Rohlena J. Aspartate in tumor microenvironment and beyond: Metabolic interactions and therapeutic perspectives. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167451. [PMID: 39111633 DOI: 10.1016/j.bbadis.2024.167451] [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: 05/10/2024] [Revised: 07/19/2024] [Accepted: 07/31/2024] [Indexed: 08/11/2024]
Abstract
Aspartate is a proteinogenic non-essential amino acid with several essential functions in proliferating cells. It is mostly produced in a cell autonomous manner from oxalacetate via glutamate oxalacetate transaminases 1 or 2 (GOT1 or GOT2), but in some cases it can also be salvaged from the microenvironment via transporters such as SLC1A3 or by macropinocytosis. In this review we provide an overview of biosynthetic pathways that produce aspartate endogenously during proliferation. We discuss conditions that favor aspartate uptake as well as possible sources of exogenous aspartate in the microenvironment of tumors and bone marrow, where most available data have been generated. We highlight metabolic fates of aspartate, its various functions, and possible approaches to target aspartate metabolism for cancer therapy.
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Affiliation(s)
- Julian Wong Soon
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic
| | - Maria Antonietta Manca
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic
| | - Agnieszka Laskowska
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic
| | - Julia Starkova
- CLIP (Childhood Leukaemia Investigation Prague), Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Katerina Rohlenova
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic.
| | - Jakub Rohlena
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic.
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Plaza-Florido A, Gálvez BG, López JA, Santos-Lozano A, Zazo S, Rincón-Castanedo C, Martín-Ruiz A, Lumbreras J, Terron-Camero LC, López-Soto A, Andrés-León E, González-Murillo Á, Rojo F, Ramírez M, Lucia A, Fiuza-Luces C. Exercise and tumor proteome: insights from a neuroblastoma model. Physiol Genomics 2024; 56:833-844. [PMID: 39311839 PMCID: PMC11573273 DOI: 10.1152/physiolgenomics.00064.2024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/10/2024] [Accepted: 09/10/2024] [Indexed: 11/12/2024] Open
Abstract
The impact of exercise on pediatric tumor biology is essentially unknown. We explored the effects of regular exercise on tumor proteome profile (as assessed with liquid chromatography with tandem mass spectrometry) in a mouse model of one of the most aggressive childhood malignancies, high-risk neuroblastoma (HR-NB). Tumor samples of 14 male mice (aged 6-8 wk) that were randomly allocated into an exercise (5-wk combined aerobic and resistance training) or nonexercise control group (6 and 8 mice/group, respectively) were analyzed. The Search Tool for the Retrieval of Interacting Genes/Proteins database was used to generate a protein-protein interaction (PPI) network and enrichment analyses. The Systems Biology Triangle (SBT) algorithm was applied for analyses at the functional category level. Tumors of exercised mice showed a higher and lower abundance of 101 and 150 proteins, respectively, than controls [false discovery rate (FDR) < 0.05]. These proteins were enriched in metabolic pathways, amino acid metabolism, regulation of hormone levels, and peroxisome proliferator-activated receptor signaling (FDR < 0.05). The SBT algorithm indicated that 184 and 126 categories showed a lower and higher abundance, respectively, in the tumors of exercised mice (FDR < 0.01). Categories with lower abundance were involved in energy production, whereas those with higher abundance were related to transcription/translation, apoptosis, and tumor suppression. Regular exercise altered the abundance of hundreds of intratumoral proteins and molecular pathways, particularly those involved in energy metabolism, apoptosis, and tumor suppression. These findings provide preliminary evidence of the molecular mechanisms underlying the potential effects of exercise in HR-NB.NEW & NOTEWORTHY We used liquid chromatography with tandem mass spectrometry to explore the impact of a 5-wk exercise intervention on the tumor proteome profile in a mouse model of one of the most aggressive childhood malignancies, high-risk neuroblastoma. Exercise altered the abundance of hundreds of proteins and pathways, particularly those involved in energy metabolism and tumor suppression. These molecular changes could mediate, at least partly, the potential antitumorigenic effects of exercise.
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Affiliation(s)
- Abel Plaza-Florido
- Pediatric Exercise and Genomics Research Center, Department of Pediatrics, School of Medicine, University of California Irvine, Irvine, California, United States
| | - Beatriz G Gálvez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad Complutense de Madrid, Madrid, Spain
- Research Institute of the Hospital 12 de Octubre, Madrid, Spain
| | - Juan A López
- Proteomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
| | - Alejandro Santos-Lozano
- Research Institute of the Hospital 12 de Octubre, Madrid, Spain
- i+HeALTH, Department of Health Sciences, European University Miguel de Cervantes, Valladolid, Spain
| | - Sandra Zazo
- Department of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS-FJD, UAM)-CIBERONC, Madrid, Spain
| | | | - Asunción Martín-Ruiz
- Department of Cellular Biology, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Jorge Lumbreras
- Proteomics Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Laura C Terron-Camero
- Unidad de Bioinformática, Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Granada, Spain
| | - Alejandro López-Soto
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias, Asturias, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, Asturias, Spain
| | - Eduardo Andrés-León
- Unidad de Bioinformática, Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Granada, Spain
| | - África González-Murillo
- Unidad de Terapias Avanzadas, Oncología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- Fundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Federico Rojo
- Department of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS-FJD, UAM)-CIBERONC, Madrid, Spain
| | - Manuel Ramírez
- Unidad de Terapias Avanzadas, Oncología, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- Fundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Alejandro Lucia
- Research Institute of the Hospital 12 de Octubre, Madrid, Spain
- Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain
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Machuca A, Peñalver GA, Garcia RAF, Martinez-Lopez A, Castillo-Lluva S, Garcia-Calvo E, Luque-Garcia JL. Advancing rhodium nanoparticle-based photodynamic cancer therapy: quantitative proteomics and in vivo assessment reveal mechanisms targeting tumor metabolism, progression and drug resistance. J Mater Chem B 2024; 12:12073-12086. [PMID: 39453320 DOI: 10.1039/d4tb01631a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
Rhodium nanoparticles have been recently discovered as good photosensitizers with great potential in cancer photodynamic therapy by effectively inducing cytotoxicity in cancer cells under near-infrared laser. This study evaluates the molecular mechanisms underlying such antitumoral effect through quantitative proteomics. The results revealed that rhodium nanoparticle-based photodynamic therapy disrupts tumor metabolism by downregulating key proteins involved in ATP synthesis and mitochondrial function, leading to compromised energy production. The treatment also induces oxidative stress and apoptosis while targeting the invasion capacity of cancer cells. Additionally, key proteins involved in drug resistance are also affected, demonstrating the efficacy of the treatment in a multi-drug resistant cell line. In vivo evaluation using a chicken embryo model also confirmed the effectiveness of the proposed therapy in reducing tumor growth without affecting embryo viability.
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Affiliation(s)
- Andres Machuca
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | - Gabriel A Peñalver
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | | | - Angelica Martinez-Lopez
- Department Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - Sonia Castillo-Lluva
- Department Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - Estefania Garcia-Calvo
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | - Jose L Luque-Garcia
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
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Graziani C, Barile A, Antonelli L, Fiorillo A, Ilari A, Vetica F, di Salvo ML, Paiardini A, Tramonti A, Contestabile R. The Z isomer of pyridoxilidenerhodanine 5'-phosphate is an efficient inhibitor of human pyridoxine 5'-phosphate oxidase, a crucial enzyme in vitamin B 6 salvage pathway and a potential chemotherapeutic target. FEBS J 2024; 291:4984-5001. [PMID: 39288205 DOI: 10.1111/febs.17274] [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: 04/17/2024] [Revised: 07/30/2024] [Accepted: 09/02/2024] [Indexed: 09/19/2024]
Abstract
Pyridoxal 5'-phosphate (PLP), the catalytically active form of vitamin B6, acts as a cofactor in many metabolic processes. In humans, PLP is produced in the reactions catalysed by pyridox(am)ine 5'-phosphate oxidase (PNPO) and pyridoxal kinase (PDXK). Both PNPO and PDXK are involved in cancer progression of many tumours. The silencing of PNPO and PDXK encoding genes determines a strong reduction in tumour size and neoplastic cell invasiveness in models of acute myeloid leukaemia (in the case of PDXK) and ovarian and breast cancer (in the case of PNPO). In the present work, we demonstrate that pyridoxilidenerhodanine 5'-phosphate (PLP-R), a PLP analogue that has been tested by other authors on malignant cell lines reporting a reduction in proliferation, inhibits PNPO in vitro following a mixed competitive and allosteric mechanism. We also show that the unphosphorylated precursor of this inhibitor (PL-R), which has more favourable pharmacokinetic properties according to our predictions, is phosphorylated by PDXK and therefore transformed into PLP-R. On this ground, we propose the prototype of a novel prodrug-drug system as a useful starting point for the development of new, potential, antineoplastic agents.
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Affiliation(s)
- Claudio Graziani
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Italy
| | - Anna Barile
- Istituto di Biologia e Patologia Molecolari, Consiglio Nazionale delle Ricerche, Rome, Italy
| | - Lorenzo Antonelli
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Italy
| | - Annarita Fiorillo
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Italy
| | - Andrea Ilari
- Istituto di Biologia e Patologia Molecolari, Consiglio Nazionale delle Ricerche, Rome, Italy
| | | | - Martino Luigi di Salvo
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Italy
| | - Alessandro Paiardini
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Italy
| | - Angela Tramonti
- Istituto di Biologia e Patologia Molecolari, Consiglio Nazionale delle Ricerche, Rome, Italy
| | - Roberto Contestabile
- Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Italy
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
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9
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Bononi G, Di Bussolo V, Tuccinardi T, Minutolo F, Granchi C. A patent review of lactate dehydrogenase inhibitors (2014-present). Expert Opin Ther Pat 2024; 34:1121-1135. [PMID: 39358962 DOI: 10.1080/13543776.2024.2412575] [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: 06/13/2024] [Revised: 09/01/2024] [Accepted: 09/18/2024] [Indexed: 10/04/2024]
Abstract
INTRODUCTION Lactate dehydrogenase (LDH) is a key enzyme in glycolysis responsible for the conversion of pyruvate into lactate and vice versa. Lactate plays a crucial role in tumor progression and metastasis; therefore, reducing lactate production by inhibiting LDH is considered an optimal strategy to tackle cancer. Additionally, dysregulation of LDH activity is correlated with other pathologies, such as cardiovascular and neurodegenerative diseases as well as primary hyperoxaluria, fibrosis and cryptosporidiosis. Hence, LDH inhibitors could serve as potential therapeutics for treating these pathological conditions. AREAS COVERED This review covers patents published since 2014 up to the present in the Espacenet database, concerning LDH inhibitors and their potential therapeutic applications. EXPERT OPINION Over the past 10 years, different compounds have been identified as LDH inhibitors. Some of them are derived from the chemical optimization of already known LDH inhibitors (e.g. pyrazolyl derivatives, quinoline 3-sulfonamides), while others belong to newly identified chemical classes of LDH inhibitors. LDH inhibition has proven to be a promising therapeutic strategy not only for preventing human pathologies, but also for treating animal diseases. The published patents from both academia and the pharmaceutical industry highlight the persistent high interest of the scientific community in developing efficient LDH inhibitors.
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Affiliation(s)
- Giulia Bononi
- Department of Pharmacy, University of Pisa, Pisa, Italy
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10
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Ravi D, Kritharis A, Evens AM. Deciphering the Metabolic Basis and Molecular Circuitry of the Warburg Paradox in Lymphoma. Cancers (Basel) 2024; 16:3606. [PMID: 39518046 PMCID: PMC11545614 DOI: 10.3390/cancers16213606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Background/Objectives: Warburg's metabolic paradox illustrates that malignant cells require both glucose and oxygen to survive, even after converting glucose into lactate. It remains unclear whether sparing glucose from oxidation intersects with TCA cycle continuity and if this confers any metabolic advantage in proliferating cancers. This study seeks to understand the mechanistic basis of Warburg's paradox and its overall implications for lymphomagenesis. Methods: Using metabolomics, we first examined the metabolomic profiles, glucose, and glutamine carbon labeling patterns in the metabolism during the cell cycle. We then investigated proliferation-specific metabolic features of malignant and nonmalignant cells. Finally, through bioinformatics and the identification of appropriate pharmacological targets, we established malignant-specific proliferative implications for the Warburg paradox associated with metabolic features in this study. Results: Our results indicate that pyruvate, lactate, and alanine levels surge during the S phase and are correlated with nucleotide synthesis. By using 13C1,2-Glucose and 13C6,15N2-Glutamine isotope tracers, we observed that the transamination of pyruvate to alanine is elevated in lymphoma and coincides with the entry of glutamine carbon into the TCA cycle. Finally, by using fludarabine as a strong inhibitor of lymphoma, we demonstrate that disrupting the transamination of pyruvate to alanine correlates with the simultaneous suppression of glucose-derived nucleotide biosynthesis and glutamine carbon entry into the TCA cycle. Conclusions: We conclude that the transamination of pyruvate to alanine intersects with reduced glucose oxidation and maintains the TCA cycle as a critical metabolic feature of Warburg's paradox and lymphomagenesis.
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Affiliation(s)
- Dashnamoorthy Ravi
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA
| | | | - Andrew M. Evens
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA
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11
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Shu Y, Yue J, Li Y, Yin Y, Wang J, Li T, He X, Liang S, Zhang G, Liu Z, Wang Y. Development of human lactate dehydrogenase a inhibitors: high-throughput screening, molecular dynamics simulation and enzyme activity assay. J Comput Aided Mol Des 2024; 38:28. [PMID: 39123063 DOI: 10.1007/s10822-024-00568-y] [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: 03/04/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024]
Abstract
Lactate dehydrogenase A (LDHA) is highly expressed in many tumor cells and promotes the conversion of pyruvate to lactic acid in the glucose pathway, providing energy and synthetic precursors for rapid proliferation of tumor cells. Therefore, inhibition of LDHA has become a widely concerned tumor treatment strategy. However, the research and development of highly efficient and low toxic LDHA small molecule inhibitors still faces challenges. To discover potential inhibitors against LDHA, virtual screening based on molecular docking techniques was performed from Specs database of more than 260,000 compounds and Chemdiv-smart database of more than 1,000 compounds. Through molecular dynamics (MD) simulation studies, we identified 12 potential LDHA inhibitors, all of which can stably bind to human LDHA protein and form multiple interactions with its active central residues. In order to verify the inhibitory activities of these compounds, we established an enzyme activity assay system and measured their inhibitory effects on recombinant human LDHA. The results showed that Compound 6 could inhibit the catalytic effect of LDHA on pyruvate in a dose-dependent manner with an EC50 value of 14.54 ± 0.83 µM. Further in vitro experiments showed that Compound 6 could significantly inhibit the proliferation of various tumor cell lines such as pancreatic cancer cells and lung cancer cells, reduce intracellular lactic acid content and increase intracellular reactive oxygen species (ROS) level. In summary, through virtual screening and in vitro validation, we found that Compound 6 is a small molecule inhibitor for LDHA, providing a good lead compound for the research and development of LDHA related targeted anti-tumor drugs.
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Affiliation(s)
- Yuanyuan Shu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Jianda Yue
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Yaqi Li
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Yekui Yin
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Jiaxu Wang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Tingting Li
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Xiao He
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China
- New York University, East China Normal University Center for Computational Chemistry, New York University Shanghai, Shanghai, 200062, China
| | - Songping Liang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China
| | - Gaihua Zhang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China.
| | - Zhonghua Liu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China.
| | - Ying Wang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
- Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha, 410081, Hunan, China.
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12
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Masci D, Puxeddu M, Silvestri R, La Regina G. Metabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy. Molecules 2024; 29:2110. [PMID: 38731601 PMCID: PMC11085455 DOI: 10.3390/molecules29092110] [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: 03/15/2024] [Revised: 04/16/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Alterations in cellular metabolism, such as dysregulation in glycolysis, lipid metabolism, and glutaminolysis in response to hypoxic and low-nutrient conditions within the tumor microenvironment, are well-recognized hallmarks of cancer. Therefore, understanding the interplay between aerobic glycolysis, lipid metabolism, and glutaminolysis is crucial for developing effective metabolism-based therapies for cancer, particularly in the context of colorectal cancer (CRC). In this regard, the present review explores the complex field of metabolic reprogramming in tumorigenesis and progression, providing insights into the current landscape of small molecule inhibitors targeting tumorigenic metabolic pathways and their implications for CRC treatment.
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Affiliation(s)
- Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy;
| | - Michela Puxeddu
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
| | - Romano Silvestri
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
| | - Giuseppe La Regina
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (R.S.)
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13
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Yan F, Zhang L, Duan L, Li L, Liu X, Liu Y, Qiao T, Zeng Y, Fang H, Wu D, Wang X. Roles of glutamic pyruvate transaminase 2 in reprogramming of airway epithelial lipidomic and metabolomic profiles after smoking. Clin Transl Med 2024; 14:e1679. [PMID: 38706045 PMCID: PMC11070440 DOI: 10.1002/ctm2.1679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 05/07/2024] Open
Abstract
Metabolic abnormalities represent one of the pathological features of chronic obstructive pulmonary disease (COPD). Glutamic pyruvate transaminase 2 (GPT2) is involved in glutamate metabolism and lipid synthesis pathways, whilst the exact roles of GPT2 in the occurrence and development of COPD remains uncertain. This study aims at investigating how GPT2 and the associated genes modulate smoking-induced airway epithelial metabolism and damage by reprogramming lipid synthesis. The circulating or human airway epithelial metabolomic and lipidomic profiles of COPD patients or cell-lines explored with smoking were assessed to elucidate the pivotal roles of GPT2 in reprogramming processes. We found that GPT2 regulate the reprogramming of lipid metabolisms caused by smoking, especially phosphatidylcholine (PC) and triacylglycerol (TAG), along with changes in the expression of lipid metabolism-associated genes. GPT2 modulated cell sensitivities and survival in response to smoking by enhancing mitochondrial functions and maintaining lipid and energy homeostasis. Our findings provide evidence for the involvement of GPT2 in the reprogramming of airway epithelial lipids following smoking, as well as the molecular mechanisms underlying GPT2-mediated regulation, which may offer an alternative of therapeutic strategies for chronic lung diseases.
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Affiliation(s)
- Furong Yan
- Center for Tumor Diagnosis & TherapyJinshan HospitalFudan UniversityShanghaiChina
- Department of Pulmonary and Critical Care MedicineZhongshan HospitalFudan UniversityShanghaiChina
- Center of Molecular Diagnosis and TherapyThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouFujianChina
| | - Linlin Zhang
- Department of Pulmonary and Critical Care MedicineZhongshan HospitalFudan UniversityShanghaiChina
| | - Lian Duan
- Department of Pediatric SurgeryFaculty of Pediatricsthe Seventh Medical Center of PLA General HospitalBeijingChina
| | - Liyang Li
- Department of Pulmonary and Critical Care MedicineZhongshan HospitalFudan UniversityShanghaiChina
| | - Xuanqi Liu
- Department of Pulmonary and Critical Care MedicineZhongshan HospitalFudan UniversityShanghaiChina
| | - Yifei Liu
- Center of Molecular Diagnosis and TherapyThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouFujianChina
| | - Tiankui Qiao
- Center for Tumor Diagnosis & TherapyJinshan HospitalFudan UniversityShanghaiChina
| | - Yiming Zeng
- Center of Molecular Diagnosis and TherapyThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouFujianChina
| | - Hao Fang
- Department of AnesthesiologyShanghai Geriatic Medical CenterShanghaiChina
- Department of AnesthesiologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Duojiao Wu
- Center for Tumor Diagnosis & TherapyJinshan HospitalFudan UniversityShanghaiChina
| | - Xiangdong Wang
- Center for Tumor Diagnosis & TherapyJinshan HospitalFudan UniversityShanghaiChina
- Department of Pulmonary and Critical Care MedicineZhongshan HospitalFudan UniversityShanghaiChina
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14
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Blua F, Monge C, Gastaldi S, Clemente N, Pizzimenti S, Lazzarato L, Senetta R, Vittorio S, Gigliotti CL, Boggio E, Dianzani U, Vistoli G, Altomare AA, Aldini G, Dianzani C, Marini E, Bertinaria M. Discovery of a septin-4 covalent binder with antimetastatic activity in a mouse model of melanoma. Bioorg Chem 2024; 144:107164. [PMID: 38306824 DOI: 10.1016/j.bioorg.2024.107164] [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: 12/06/2023] [Revised: 01/23/2024] [Accepted: 01/28/2024] [Indexed: 02/04/2024]
Abstract
Cancer spreading through metastatic processes is one of the major causes of tumour-related mortality. Metastasis is a complex phenomenon which involves multiple pathways ranging from cell metabolic alterations to changes in the biophysical phenotype of cells and tissues. In the search for new effective anti-metastatic agents, we modulated the chemical structure of the lead compound AA6, in order to find the structural determinants of activity, and to identify the cellular target responsible of the downstream anti-metastatic effects observed. New compounds synthesized were able to inhibit in vitro B16-F10 melanoma cell invasiveness, and one selected compound, CM365, showed in vivo anti-metastatic effects in a lung metastasis mouse model of melanoma. Septin-4 was identified as the most likely molecular target responsible for these effects. This study showed that CM365 is a promising molecule for metastasis prevention, remarkably effective alone or co-administered with drugs normally used in cancer therapy, such as paclitaxel.
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Affiliation(s)
- Federica Blua
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Chiara Monge
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Simone Gastaldi
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Nausicaa Clemente
- Settore Centri di Ricerca e Infrastrutture di Ateneo e Laboratori - Polo di NO, University of Piemonte Orientale, Novara, Italy
| | - Stefania Pizzimenti
- Department of Clinical and Biological Science, University of Turin, Torino, Italy
| | - Loretta Lazzarato
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Rebecca Senetta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Serena Vittorio
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | | | - Elena Boggio
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Umberto Dianzani
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Giulio Vistoli
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | | | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Chiara Dianzani
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Elisabetta Marini
- Department of Drug Science and Technology, University of Turin, Turin, Italy.
| | - Massimo Bertinaria
- Department of Drug Science and Technology, University of Turin, Turin, Italy
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15
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Yao N, Hou Q, Liang Y, Cao X, Sun B, Wei L, Sun R, Cao J. Serum aspartate aminotransferase, a novel potential biomarker of prognosis in extranodal natural killer/T cell lymphoma, nasal type. Cancer Biomark 2024; 39:265-275. [PMID: 38108343 PMCID: PMC11191476 DOI: 10.3233/cbm-230068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 10/31/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND Aspartate aminotransferase (AST), an indicator of liver cell damage, was related to the prognosis of certain malignant tumors. OBJECTIVE This study examined the predictive value of AST in patients with extranodal natural killer/T cell lymphoma (ENKTL). METHODS We reviewed 183 cases diagnosed with ENKTL and selected 26 U/L as the optimum cut-off value of AST. We used the univariate and multivariate Cox regression to compare the different AST groups' overall survival (OS) and progression-free survival (PFS). RESULTS Prior to propensity score matching (PSM), Kaplan-Meier analysis showed that patients in the low AST subgroup had better OS and PFS than the high AST subgroup. Multivariate analysis revealed that AST was an independent indicator for prognosis. After PSM, the low AST subgroup maintained a significantly better OS and PFS than the high AST subgroup. CONCLUSION AST might represent a significant prognostic marker for ENKTL patients.
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Affiliation(s)
- Ningning Yao
- Department of Radiotherapy, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qing Hou
- Department of Radiotherapy, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yu Liang
- Department of Radiotherapy, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xin Cao
- Department of Radiotherapy, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Bochen Sun
- Department of Radiotherapy, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Lijuan Wei
- Department of Radiotherapy, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ruifang Sun
- Department of Tumor Biobank, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jianzhong Cao
- Department of Radiotherapy, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
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16
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Kim J, Lee HI, Kim IA, Lee JH, Cho J, Wee CW, Yoon HI. De Ritis ratio in elderly glioblastoma patients treated with chemoradiation: A comprehensive analysis of serum biomarkers. Neurooncol Adv 2024; 6:vdad173. [PMID: 38288092 PMCID: PMC10824161 DOI: 10.1093/noajnl/vdad173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND We aimed to comprehensively investigate the prognostic value of pretreatment laboratory parameters in elderly patients with glioblastoma treated with temozolomide (TMZ)-based chemoradiation. METHODS Patients aged ≥ 65 years from 4 institutions with newly diagnosed IDH-wild-type glioblastoma who received radiotherapy (RT) with concurrent TMZ between 2006 and 2021 were included. Patient factors (age, Karnofsky performance status (KPS), temporalis muscle thickness), molecular factors (MGMT promoter methylation, EGFR amplification, TERT promoter mutation, and TP53 mutation status), treatment factors (extent of resection, and RT dose), and pretreatment laboratory parameters (serum De Ritis ratio, glucose level, neutrophil-to-lymphocyte ratio, platelet count, and systemic immune-inflammation index) were included in the analysis. The primary endpoint was overall survival (OS). RESULTS In total, 490 patients were included in the analysis. The median follow-up period was 12.3 months (range, 1.6-149.9 months). Median OS was significantly prolonged in patients with De Ritis ratio < 1.2 (18.2 vs 15.3 months, P = .022) and in patients with glucose level < 150 mg/dL (18.7 vs 16.5 months, P = .034) per univariate analysis. In multivariate analysis, KPS ≥ 70, MGMT promoter methylation, extent of resection greater than partial resection, De Ritis ratio < 1.2, and glucose level < 150 mg/dL were significant prognostic factors for improved OS. CONCLUSIONS Along with well-known prognostic factors, pre-RT serum biomarkers, including the De Ritis ratio and glucose level, also had prognostic value in elderly patients with glioblastoma treated with TMZ-based chemoradiation.
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Affiliation(s)
- Jina Kim
- Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hye In Lee
- Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Department of Radiation Oncology, Asan Medical Center, Seoul, Korea
| | - In Ah Kim
- Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Joo Ho Lee
- Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jaeho Cho
- Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Chan Woo Wee
- Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Department of Radiation Oncology, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Hong In Yoon
- Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea
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17
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Wetz C, Ruhwedel T, Schatka I, Grabowski J, Jann H, Metzger G, Galler M, Amthauer H, Rogasch JMM. Plasma Markers for Therapy Response Monitoring in Patients with Neuroendocrine Tumors Undergoing Peptide Receptor Radionuclide Therapy. Cancers (Basel) 2023; 15:5717. [PMID: 38136263 PMCID: PMC10741556 DOI: 10.3390/cancers15245717] [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: 10/19/2023] [Revised: 12/03/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Pretherapeutic chromogranin A, alkaline phosphatase (ALP), or De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are prognostic factors in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). However, their value for intratherapeutic monitoring remains unclear. We evaluated if changes in plasma markers during PRRT can help identify patients with unfavorable outcomes. METHODS A monocentric retrospective analysis of 141 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC was conducted. Changes in laboratory parameters were calculated by dividing the values determined immediately before each cycle of PRRT by the pretherapeutic value. Patients with low vs. high PFS were compared with the Wilcoxon rank-sum test. RESULTS Progression, relapse, or death after PRRT was observed in 103/141 patients. Patients with low PFS showed a significant relative ALP increase before the third (p = 0.014) and fourth (p = 0.039) cycles of PRRT. Kaplan-Meier analysis revealed a median PFS of 24.3 months (95% CI, 20.7-27.8 months) in patients with decreasing ALP values (Δ > 10%) during treatment, 12.5 months (95% CI, 9.2-15.8 months) in patients with increasing ALP values (Δ > 10%), and 17.7 months (95% CI, 13.6-21.8 months) with stable ALP values (Δ ± 10%). CONCLUSIONS Based on these exploratory data, a rise in plasma ALP might indicate disease progression and should be interpreted cautiously during therapy.
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Affiliation(s)
- Christoph Wetz
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Tristan Ruhwedel
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Imke Schatka
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Jane Grabowski
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Henning Jann
- Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany;
| | - Giulia Metzger
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Markus Galler
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Holger Amthauer
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Julian M. M. Rogasch
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
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18
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Huyut Z, Uçar B, Altındağ F, Yıldızhan K, Huyut MT. Effect of curcumin on lipid profile, fibrosis, and apoptosis in liver tissue in abemaciclib-administered rats. Drug Chem Toxicol 2023; 46:1138-1146. [PMID: 36259448 DOI: 10.1080/01480545.2022.2135007] [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: 03/14/2022] [Revised: 08/18/2022] [Accepted: 09/13/2022] [Indexed: 11/03/2022]
Abstract
Abemaciclib (ABEM) is an important antitumor agent for breast cancer treatment. However, the side-effects of ABEM are unclear in the liver. This study investigated the protective effect of curcumin (CURC) on liver damage caused by ABEM. The rats were divided into five groups with eight animals in each group; Control, DMSO (150 µL for per rats), CURC, 30 mg/kg/day), ABE (26 mg/kg/day), and ABE + CURC (26 mg/kg/day ABE, 30 mg/kg/day) groups. Injections were administered daily for 28 days. The levels of AST, LDH, HDL, LDL, triglyceride, and total cholesterol in serum, and hepatic tissue fibrosis, caspase-3, Bax, and TNF-α expression were higher in the ABE group compared to the control group (p < 0.05). Also, these parameters in the ABEM + CURC group were lower than in the ABE group (p < 0.05). The results showed that ABE administration could cause liver damage and increase fibrosis in the liver. In addition, it was shown that co-administration of CURC with ABE could suppress the levels of AST, LDH, HDL, LDL, triglyceride, and total cholesterol in serum, and fibrosis, caspase-3, Bax, and TNF-α expressions in the liver. These data are the first in the literature. Therefore, the administration of CURC following ABE may be a therapeutic agent in preventing liver damage.
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Affiliation(s)
- Zübeyir Huyut
- Department of Biochemistry, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey
| | - Bünyamin Uçar
- Department of Biochemistry, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey
| | - Fikret Altındağ
- Department of Histology and Embryology, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey
| | - Kenan Yıldızhan
- Department of Biophysics, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey
| | - Mehmet Tahir Huyut
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey
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19
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Gaal S, Huang K, Rogasch JMM, Jochens HV, De Santis M, Erber B, Amthauer H. Prognostic Value of the De Ritis Ratio for Overall Survival in Patients with Metastatic Castration-Resistant Prostate Cancer Undergoing [ 177Lu]Lu-PSMA-617 Radioligand Therapy. Cancers (Basel) 2023; 15:4907. [PMID: 37894274 PMCID: PMC10605155 DOI: 10.3390/cancers15204907] [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: 08/18/2023] [Revised: 09/28/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
The De Ritis ratio (=aspartate transaminase/alanine transaminase) has shown prognostic value in different cancer types. This is the first such analysis in prostate cancer patients undergoing radioligand therapy (RLT) with [177Lu]Lu-PSMA-617. This retrospective monocentric analysis included 91 patients with a median of 3 RLT cycles (range 1-6) and median cumulative activity of 17.3 GBq. Univariable Cox regression regarding overall survival (OS) included age, different types of previous treatment, metastatic patterns and different laboratory parameters before RLT. Based on multivariable Cox regression, a prognostic score was derived. Seventy-two patients (79%) died (median follow-up in survivors: 19.8 months). A higher number of previous chemotherapy lines, the presence of liver metastases, brain metastases, a higher tumor load on PSMA-PET, a higher prostate-specific antigen (PSA) level, lower red blood cell count, lower hemoglobin, higher neutrophil-lymphocyte ratio and higher De Ritis ratio were associated with shorter OS (each p < 0.05). In multivariable Cox, a higher number of chemotherapy lines (range, 0-2; p = 0.036), brain metastases (p < 0.001), higher PSA (p = 0.004) and higher De Ritis ratio before RLT (hazard ratio, 1.27 per unit increase; p = 0.023) remained significant. This prognostic score separated five groups with a significantly different median OS ranging from 4.9 to 28.1 months (log-rank test, p < 0.001). If validated independently, the De Ritis ratio could enhance multifactorial models for OS after RLT.
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Affiliation(s)
- Sebastian Gaal
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Kai Huang
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Praxen für Diagnostische und Therapeutische Nuklearmedizin, Düppelstr. 30, 12163 Berlin, Germany
| | - Julian M M Rogasch
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Hans V Jochens
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Maria De Santis
- Department of Urology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
- Department of Urology, Medical University of Vienna, 1090 Vienna, Austria
| | - Barbara Erber
- Department of Urology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Holger Amthauer
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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20
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Wu YY, Law YY, Huang YW, Tran NB, Lin CY, Lai CY, Huang YL, Tsai CH, Ko CY, Chou MC, Huang WC, Cheng FJ, Fong YC, Tang CH. Glutamine metabolism controls amphiregulin-facilitated chemoresistance to cisplatin in human chondrosarcoma. Int J Biol Sci 2023; 19:5174-5186. [PMID: 37928274 PMCID: PMC10620823 DOI: 10.7150/ijbs.86116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 09/21/2023] [Indexed: 11/07/2023] Open
Abstract
Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting reactive oxygen species (ROS) accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.
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Affiliation(s)
- Yu-Ying Wu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Orthopedics, Chung Shan Medical University Hospital, Taichung, Taiwan
- Department of Orthopedics, Penghu Hospital, Ministry of Health and Welfare, Penghu, Taiwan
| | - Yat-Yin Law
- Department of Orthopedics, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yu-Wen Huang
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Nguyen Bao Tran
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Chih-Yang Lin
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Chao-Yang Lai
- Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan
| | - Yuan-Li Huang
- Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan
| | - Chun-Hao Tsai
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Chih-Yuan Ko
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Ming-Chih Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Wei-Chien Huang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Fang-Ju Cheng
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yi-Chin Fong
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan
| | - Chih-Hsin Tang
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, Taiwan
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21
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Xing W, Li X, Zhou Y, Li M, Zhu M. Lactate metabolic pathway regulates tumor cell metastasis and its use as a new therapeutic target. EXPLORATION OF MEDICINE 2023:541-559. [DOI: https:/doi.org/10.37349/emed.2023.00160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 04/17/2023] [Indexed: 09/04/2023] Open
Abstract
Abnormal energy metabolism is one of the ten hallmarks of tumors, and tumor cell metabolism provides energy and a suitable microenvironment for tumorigenesis and metastasis. Tumor cells can consume large amounts of glucose and produce large amounts of lactate through glycolysis even in the presence of oxygen, a process called aerobic glycolysis, also known as the Warburg effect. Lactate is the end product of the aerobic glycolysis. Lactate dehydrogenase A (LDHA), which is highly expressed in cancer cells, promotes lactate production and transports lactate to the tumor microenvironment and is taken up by surrounding stromal cells under the action of monocarboxylate transporter 1/4 (MCT1/4), which in turn influences the immune response and enhances the invasion and metastasis of cancer cells. Therapeutic strategies targeting lactate metabolism have been intensively investigated, focusing on its metastasis-promoting properties and various target inhibitors; AZD3965, an MCT1 inhibitor, has entered phase I clinical trials, and the LDHA inhibitor N-hydroxyindole (NHI) has shown cancer therapeutic activity in pre-clinical studies. Interventions targeting lactate metabolism are emerging as a promising option for cancer therapy, with chemotherapy or radiotherapy combined with lactate-metabolism-targeted drugs adding to the effectiveness of cancer treatment. Based on current research, this article outlines the role of lactate metabolism in tumor metastasis and the potential value of inhibitors targeting lactate metabolism in cancer therapy.
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Affiliation(s)
- Weimei Xing
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou 571199, Hainan, China
| | - Xiaowei Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou 571199, Hainan, China
| | - Yuli Zhou
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou 571199, Hainan, China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou 571199, Hainan, China; Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou 570311, Hainan, China; Institution of Tumour, First Affiliated Hospital, Hainan Medical University, Haikou 570102, Hainan, China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou 571199, Hainan, China
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22
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Cooper AJL, Dorai T, Pinto JT, Denton TT. Metabolic Heterogeneity, Plasticity, and Adaptation to "Glutamine Addiction" in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase-ω-Amidase (Glutaminase II)] Pathway. BIOLOGY 2023; 12:1131. [PMID: 37627015 PMCID: PMC10452834 DOI: 10.3390/biology12081131] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/06/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023]
Abstract
Many cancers utilize l-glutamine as a major energy source. Often cited in the literature as "l-glutamine addiction", this well-characterized pathway involves hydrolysis of l-glutamine by a glutaminase to l-glutamate, followed by oxidative deamination, or transamination, to α-ketoglutarate, which enters the tricarboxylic acid cycle. However, mammalian tissues/cancers possess a rarely mentioned, alternative pathway (the glutaminase II pathway): l-glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. The name glutaminase II may be confused with the glutaminase 2 (GLS2) isozyme. Thus, we recently renamed the glutaminase II pathway the "glutamine transaminase-ω-amidase (GTωA)" pathway. Herein, we summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway is that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia, diminishing cellular energy demands. We suggest that the ability to coordinate control of both pathways bestows a metabolic advantage to cancer cells. Finally, we discuss possible benefits of GTωA pathway inhibitors, not only as aids to studying the normal biological roles of the pathway but also as possible useful anticancer agents.
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Affiliation(s)
- Arthur J. L. Cooper
- Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA; (T.D.); (J.T.P.)
| | - Thambi Dorai
- Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA; (T.D.); (J.T.P.)
- Department of Urology, New York Medical College, Valhalla, NY 10595, USA
| | - John T. Pinto
- Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA; (T.D.); (J.T.P.)
| | - Travis T. Denton
- Department Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, Washington State University Health Sciences Spokane, Spokane, WA 99202, USA
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University Health Sciences Spokane, Spokane, WA 99164, USA
- Steve Gleason Institute for Neuroscience, Washington State University Health Sciences Spokane, Spokane, WA 99164, USA
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23
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Lynch A, Pearson P, Savinov SN, Li AY, Rich SM. Lactate Dehydrogenase Inhibitors Suppress Borrelia burgdorferi Growth In Vitro. Pathogens 2023; 12:962. [PMID: 37513809 PMCID: PMC10384987 DOI: 10.3390/pathogens12070962] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/15/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Borrelia burgdorferi, the causative agent of Lyme disease, has a highly reduced genome and relies heavily on glycolysis for carbon metabolism. As such, established inhibitors of lactate dehydrogenase (LDH) were evaluated in cultures to determine the extent of their impacts on B. burgdorferi growth. Both racemic and enantiopure (AT-101) gossypol, as well as oxamate, galloflavin, and stiripentol, caused the dose-dependent suppression of B. burgdorferi growth in vitro. Racemic gossypol and AT-101 were shown to fully inhibit spirochetal growth at concentrations of 70.5 and 187.5 μM, respectively. Differences between racemic gossypol and AT-101 efficacy may indicate that the dextrorotatory enantiomer of gossypol is a more effective inhibitor of B. burgdorferi growth than the levorotatory enantiomer. As a whole, LDH inhibition appears to be a promising mechanism for suppressing Borrelia growth, particularly with bulky LDH inhibitors like gossypol.
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Affiliation(s)
- Adam Lynch
- Department of Microbiology, University of Massachusetts, Amherst, MA 01003, USA
| | - Patrick Pearson
- Department of Microbiology, University of Massachusetts, Amherst, MA 01003, USA
| | - Sergey N Savinov
- Department of Biochemistry, University of Massachusetts, Amherst, MA 01003, USA
| | - Andrew Y Li
- Invasive Insect Biocontrol & Behavior Laboratory, USDA-ARS, Beltsville, MD 20705, USA
| | - Stephen M Rich
- Department of Microbiology, University of Massachusetts, Amherst, MA 01003, USA
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24
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Wang J, Ye J, Zhao X, Li X, Ma X. Prognostic value and model construction of preoperative inflammatory markers in patients with metastatic renal cell carcinoma. World J Surg Oncol 2023; 21:211. [PMID: 37480143 PMCID: PMC10360324 DOI: 10.1186/s12957-023-03110-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 07/12/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND Inflammation is considered to be one of the driving factors of cancer, and chronic inflammation plays a crucial role in tumor growth and metastasis. The aim of this study was to examine the predictive value of preoperative inflammatory biomarkers for overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC), including preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and aspartate aminotransferase-to-lymphocyte ratio (ALR), a novel inflammatory biomarker. METHOD This study included 198 patients with mRCC from a single center from 2006 to 2022. The optimal cut-off levels for the three biomarkers were derived using the receiver operating characteristic curve (ROC). Cox univariate and multivariate analyses were used to assess independent prognostic inflammatory biomarkers. Finally, independent prognostic inflammatory biomarkers were incorporated into the prognostic model to establish a nomogram to predict the postoperative survival of patients with mRCC. RESULT The area under the ROC curve for NLR, LMR, and ALR, respectively, is 0.71 (CI: 0.635-0.784), 0.68 (CI: 0.604-0.755), and 0.75 (CI: 0.680-0.819). The optimal LMR, NLR, and ALR cut-off levels as evaluated by the ROC curve were 3.836, 3.106, and 68.056, respectively. Patients with NLR and ALR higher than the cut-off level and LMR lower than the cut-off level had a significant relationship with OS. Multivariate analysis revealed that tumor necrosis, lower LMR, and higher ALR were independent risk factors for OS. In addition, a nomogram that includes independent prognostic inflammatory biomarkers can accurately predict the OS in patients with mRCC. CONCLUSION ALR and LMR are independent risk factors for the prognosis of individuals with mRCC. By monitoring ALR and LMR postoperatively, the prognosis of patients with mRCC can be better evaluated.
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Affiliation(s)
- Jichen Wang
- Senior Department of Urology, the Third Medical Center of PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Jiali Ye
- Senior Department of Urology, the Third Medical Center of PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Xupeng Zhao
- Senior Department of Urology, the Third Medical Center of PLA General Hospital, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Xiubin Li
- Senior Department of Urology, the Third Medical Center of PLA General Hospital, Beijing, China.
| | - Xin Ma
- Senior Department of Urology, the Third Medical Center of PLA General Hospital, Beijing, China.
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25
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Gondáš E, Kráľová Trančíková A, Šofranko J, Majerová P, Lučanský V, Dohál M, Kováč A, Murín R. The presence of pyruvate carboxylase in the human brain and its role in the survival of cultured human astrocytes. Physiol Res 2023; 72:403-414. [PMID: 37449752 PMCID: PMC10669001 DOI: 10.33549/physiolres.935026] [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: 10/11/2022] [Accepted: 02/28/2023] [Indexed: 08/26/2023] Open
Abstract
Pyruvate carboxylase (PC) is a mitochondrial, biotin-containing enzyme catalyzing the ATP-dependent synthesis of oxaloacetate from pyruvate and bicarbonate, with a critical anaplerotic role in sustaining the brain metabolism. Based on the studies performed on animal models, PC expression was assigned to be glia-specific. To study PC distribution among human neural cells, we probed the cultured human astrocytes and brain sections with antibodies against PC. Additionally, we tested the importance of PC for the viability of cultured human astrocytes by applying the PC inhibitor 3-chloropropane-1,2-diol (CPD). Our results establish the expression of PC in mitochondria of human astrocytes in culture and brain tissue and also into a subpopulation of the neurons in situ. CPD negatively affected the viability of astrocytes in culture, which could be partially reversed by supplementing media with malate, 2-oxoglutarate, citrate, or pyruvate. The provided data estimates PC expression in human astrocytes and neurons in human brain parenchyma. Furthermore, the enzymatic activity of PC is vital for sustaining the viability of cultured astrocytes.
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Affiliation(s)
- E Gondáš
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic.
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26
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Musicco C, Signorile A, Pesce V, Loguercio Polosa P, Cormio A. Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions. Int J Mol Sci 2023; 24:10420. [PMID: 37445598 DOI: 10.3390/ijms241310420] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 07/15/2023] Open
Abstract
Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy.
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Affiliation(s)
- Clara Musicco
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), CNR, 70126 Bari, Italy
| | - Anna Signorile
- Department of Translational Biomedicine and Neuroscience, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Vito Pesce
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", 70125 Bari, Italy
| | - Paola Loguercio Polosa
- Department of Biosciences, Biotechnologies and Environment, University of Bari "Aldo Moro", 70125 Bari, Italy
| | - Antonella Cormio
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "Aldo Moro", 70124 Bari, Italy
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27
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Potential strategies for the management of adenocarcinoma: a perspective. Future Med Chem 2023; 15:123-127. [PMID: 36802841 DOI: 10.4155/fmc-2023-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023] Open
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28
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Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers. Int J Mol Sci 2022; 23:ijms232416062. [PMID: 36555705 PMCID: PMC9785069 DOI: 10.3390/ijms232416062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/11/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Cell migration is an essential part of the complex and multistep process that is the development of cancer, a disease that is the second most common cause of death in humans. An important factor promoting the migration of cancer cells is TNF-α, a pro-inflammatory cytokine that, among its many biological functions, also plays a major role in mediating the expression of MMP9, one of the key regulators of cancer cell migration. It is also known that TNF-α is able to induce the Warburg effect in some cells by increasing glucose uptake and enhancing the expression and activity of lactate dehydrogenase subunit A (LDHA). Therefore, the aim of the present study was to investigate the interrelationship between the TNF-α-induced promigratory activity of cancer cells and their glucose metabolism status, using esophageal cancer cells as an example. By inhibiting LDHA activity with sodium oxamate (SO, also known as aminooxoacetic acid sodium salt or oxamic acid sodium salt) or siRNA-mediated gene silencing, we found using wound healing assay and gelatin zymography that LDHA downregulation impairs TNF-α-dependent tumor cell migration and significantly reduces TNF-α-induced MMP9 expression. These effects were associated with disturbances in the activation of the ERK1/2 signaling pathway, as we observed by Western blotting. We also reveal that in esophageal cancer cells, SO effectively reduces the production of lactic acid, which, as we have shown, synergizes the stimulating effect of TNF-α on MMP9 expression. In conclusion, our findings identified LDHA as a regulator of TNF-α-induced cell migration in esophageal cancer cells by the ERK1/2 signaling pathway, suggesting that LDHA inhibitors that limit the migration of cancer cells caused by the inflammatory process may be considered as an adjunct to standard therapy in esophageal cancer patients.
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29
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Vafaee R, Hamzeloo-Moghadam M, Razzaghi Z, Nikzamir M, Rostami Nejad M, Mansouri V. Introducing Protein Homeostasis and Glycogen Synthesis as Two Targets of Blue Light Radiation in Lentinula edodes. J Lasers Med Sci 2022; 13:e47. [PMID: 36743131 PMCID: PMC9841390 DOI: 10.34172/jlms.2022.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 08/15/2022] [Indexed: 01/27/2023]
Abstract
Introduction: There are documents about the biological effects of blue light radiation on different organisms. An understanding of the molecular mechanism of radiation effects on biological samples is an important event which has attracted researchers' attention. Determining the critical dysregulated proteins of Lentinula edodes following blue light radiation is the aim of this study. Methods: 22 differentially expressed proteins of L. edodes in response to 300 lux of blue light were extracted from the related literature. Experimental, text mining and co-expression connections between the queried proteins were assessed via the STRING database. The maps were compared and the critical proteins were identified. Results: Among the 21 queried proteins, six individuals including heat shock HSP70 protein, 20S proteasome subunit, 26S proteasome subunit P45, Aspartate aminotransferase, phosphopyruvate hydratase, and phosphoglucomutase were highlighted as the critical proteins in response to blue light radiation. Conclusion: The finding indicates that protein homeostasis and glycogen synthesis are affected by blue light radiation. Due to the critical roles of proteins as enzymes and structural elements in life maintenance and involvement of glycogen synthesis in energy consumption, blue light radiation can be considered as a life promotional agent in future investigations.
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Affiliation(s)
- Reza Vafaee
- Critical Care Quality Improvement Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Hamzeloo-Moghadam
- Traditional Medicine and Materia Medica Research Center and Department of Traditional Pharmacy, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Razzaghi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahfam Nikzamir
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami Nejad
- Research Institute for Gastroenterology and Liver Diseases, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Mansouri
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Correspondence to Vahid Mansouri,
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30
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Hatami N, Büttner C, Bock F, Simfors S, Musial G, Reis A, Cursiefen C, Clahsen T. Cystathionine β-synthase as novel endogenous regulator of lymphangiogenesis via modulating VEGF receptor 2 and 3. Commun Biol 2022; 5:950. [PMID: 36088423 PMCID: PMC9464209 DOI: 10.1038/s42003-022-03923-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 08/30/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractLymphangiogenesis is a key player in several diseases such as tumor metastasis, obesity, and graft rejection. Endogenous regulation of lymphangiogenesis is only partly understood. Here we use the normally avascular cornea as a model to identify endogenous regulators of lymphangiogenesis. Quantitative trait locus analysis of a large low-lymphangiogenic BALB/cN x high-lymphangiogenic C57BL/6 N intercross and prioritization by whole-transcriptome sequencing identify a novel gene responsible for differences in lymphatic vessel architecture on chromosome 17, the cystathionine β-synthase (Cbs). Inhibition of CBS in lymphatic endothelial cells results in reduce proliferation, migration, altered tube-formation, and decrease expression of vascular endothelial growth factor (VEGF) receptor 2 (VEGF-R2) and VEGF-R3, but not their ligands VEGF-C and VEGF-D. Also in vivo inflammation-induced lymphangiogenesis is significantly reduce in C57BL/6 N mice after pharmacological inhibition of CBS. The results confirm CBS as a novel endogenous regulator of lymphangiogenesis acting via VEGF receptor 2 and 3-regulation and open new treatment avenues in diseases associated with pathologic lymphangiogenesis.
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31
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Chen Q, Li M, Chen J, Huang Z, Chen X, Zhao H, Cai J. AST·MLR index and operation injury condition are novel prognostic predictor for the prediction of survival in patients with colorectal cancer liver metastases undergoing surgical resection. BMC Cancer 2022; 22:921. [PMID: 36008803 PMCID: PMC9414420 DOI: 10.1186/s12885-022-10009-4] [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: 06/30/2021] [Accepted: 08/16/2022] [Indexed: 11/23/2022] Open
Abstract
Background The prognostic values of preoperative aspartate aminotransferase (AST), monocyte-to-lymphocyte ratio (MLR), AST·MLR index (AMLRI) and operation injury condition in patients with colorectal cancer liver metastases (CRLM) remains unclear. This retrospective study assessed the relationship between these markers, progression-free survival (PFS), and overall survival (OS) in CRLM patients undergoing resection. Methods AMLRI was defined as AST × MLR. Operation injury condition was defined according to operation time and blood loss. Cox regression analyses were used to identify risk factors and to develop nomograms. C-indexes, time-dependent receiver operating characteristic (time-ROC) curves and calibration curves were used to assess the models. Results A total of 379 patients were enrolled. The optimal cut-off value of the AMLRI was 3.33. In the multivariable analysis, AMLRI > 3.33 (hazard ratio [HR] = 2.162, p = 0.002) and serious operation injury condition (HR = 1.539, p = 0.012) were predictive for unfavourable OS, and AMLRI > 3.33 (HR = 1.462, p = 0.021) was predictive for unfavourable PFS. The nomograms were superior to Fong’s Clinical Risk Score (CRS) according to the C-indexes (PFS: 0.682 vs. 0.600; OS: 0.730 vs. 0.586) and time-ROCs. Conclusions Preoperative AMLRI and operation injury condition are easily accessible predictors for prognosis. The nomograms performed better than CRS for the prediction of recurrence and survival. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10009-4.
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Affiliation(s)
- Qichen Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingxia Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinghua Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Chang MC, Mahar R, McLeod MA, Giacalone AG, Huang X, Boothman DA, Merritt ME. Synergistic Effect of β-Lapachone and Aminooxyacetic Acid on Central Metabolism in Breast Cancer. Nutrients 2022; 14:3020. [PMID: 35893874 PMCID: PMC9331106 DOI: 10.3390/nu14153020] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/19/2022] [Accepted: 07/19/2022] [Indexed: 11/20/2022] Open
Abstract
The compound β-lapachone, a naturally derived naphthoquinone, has been utilized as a potent medicinal nutrient to improve health. Over the last twelve years, numerous reports have demonstrated distinct associations of β-lapachone and NAD(P)H: quinone oxidoreductase 1 (NQO1) protein in the amelioration of various diseases. Comprehensive research of NQO1 bioactivity has clearly confirmed the tumoricidal effects of β-lapachone action through NAD+-keresis, in which severe DNA damage from reactive oxygen species (ROS) production triggers a poly-ADP-ribose polymerase-I (PARP1) hyperactivation cascade, culminating in NAD+/ATP depletion. Here, we report a novel combination strategy with aminooxyacetic acid (AOA), an aspartate aminotransferase inhibitor that blocks the malate-aspartate shuttle (MAS) and synergistically enhances the efficacy of β-lapachone metabolic perturbation in NQO1+ breast cancer. We evaluated metabolic turnover in MDA-MB-231 NQO1+, MDA-MB-231 NQO1-, MDA-MB-468, and T47D cancer cells by measuring the isotopic labeling of metabolites from a [U-13C]glucose tracer. We show that β-lapachone treatment significantly hampers lactate secretion by ~85% in NQO1+ cells. Our data demonstrate that combinatorial treatment decreases citrate, glutamate, and succinate enrichment by ~14%, ~50%, and ~65%, respectively. Differences in citrate, glutamate, and succinate fractional enrichments indicate synergistic effects on central metabolism based on the coefficient of drug interaction. Metabolic modeling suggests that increased glutamine anaplerosis is protective in the case of MAS inhibition.
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Affiliation(s)
- Mario C. Chang
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.C.C.); (R.M.); (M.A.M.); (A.G.G.)
| | - Rohit Mahar
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.C.C.); (R.M.); (M.A.M.); (A.G.G.)
| | - Marc A. McLeod
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.C.C.); (R.M.); (M.A.M.); (A.G.G.)
| | - Anthony G. Giacalone
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.C.C.); (R.M.); (M.A.M.); (A.G.G.)
| | - Xiumei Huang
- Department of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - David A. Boothman
- Department of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Matthew E. Merritt
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (M.C.C.); (R.M.); (M.A.M.); (A.G.G.)
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Di Magno L, Coluccia A, Bufano M, Ripa S, La Regina G, Nalli M, Di Pastena F, Canettieri G, Silvestri R, Frati L. Discovery of novel human lactate dehydrogenase inhibitors: Structure-based virtual screening studies and biological assessment. Eur J Med Chem 2022; 240:114605. [PMID: 35868126 DOI: 10.1016/j.ejmech.2022.114605] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/05/2022] [Accepted: 07/09/2022] [Indexed: 11/04/2022]
Abstract
Most cancer cells switch their metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis to generate ATP and precursors for the biosynthesis of key macromolecules. The aerobic conversion of pyruvate to lactate, coupled to oxidation of the nicotinamide cofactor, is a primary hallmark of cancer and is catalyzed by lactate dehydrogenase (LDH), a central effector of this pathological reprogrammed metabolism. Hence, inhibition of LDH is a potential new promising therapeutic approach for cancer. In the search for new LDH inhibitors, we carried out a structure-based virtual screening campaign. Here, we report the identification of a novel specific LDH inhibitor, the pyridazine derivative 18 (RS6212), that exhibits potent anticancer activity within the micromolar range in multiple cancer cell lines and synergizes with complex I inhibition in the suppression of tumor growth. Altogether, our data support the conclusion that compound 18 deserves to be further investigated as a starting point for the development of LDH inhibitors and for novel anticancer strategies based on the targeting of key metabolic steps.
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Affiliation(s)
- Laura Di Magno
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, I-00161, Rome, Italy.
| | - Antonio Coluccia
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Rome, Italy.
| | - Marianna Bufano
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Rome, Italy
| | - Silvia Ripa
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, I-00161, Rome, Italy
| | - Giuseppe La Regina
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Rome, Italy
| | - Marianna Nalli
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Rome, Italy
| | - Fiorella Di Pastena
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, I-00161, Rome, Italy
| | - Gianluca Canettieri
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, I-00161, Rome, Italy.
| | - Romano Silvestri
- Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Rome, Italy.
| | - Luigi Frati
- Institute Pasteur Italy - Cenci Bolognetti Foundation, Via Regina Elena 291, I-00161, Rome, Italy; IRCCS Neuromed S.p.A., Via Atinense 18, Pozzilli, Isernia, Italy.
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The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay. Bioorg Med Chem Lett 2022; 73:128883. [PMID: 35820623 DOI: 10.1016/j.bmcl.2022.128883] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/08/2022] [Accepted: 07/05/2022] [Indexed: 11/20/2022]
Abstract
Glutamate oxaloacetate transaminase 1 (GOT1) plays a key role in aberrant glutamine metabolism. GOT1 suppression can arrest tumor growth and prevent the development of cancer, indicating GOT1 as a potential anticancer target. Reported GOT1 inhibitors, on the other hand, are quite restricted. Here, we developed and optimized a coupling reaction-based high-throughput screening assay for the discovery of GOT1 inhibitors. By using this screening assay, we found that the cardiovascular drug hydralazine hydrochloride inhibited GOT1 catalytic activity, with an IC50 of 26.62 ± 7.45 μM, in a non-competitive and partial-reversible manner. In addition, we determined the binding affinity of hydralazine hydrochloride to GOT1, with a Kd of 16.54 ± 8.59 μM, using a microscale thermophoresis assay. According to structure-activity relationship analysis, the inhibitory activity of hydralazine hydrochloride is mainly derived from its hydrazine group. Furthermore, it inhibits the proliferation of cancer cells MCF-7 and MDA-MB-468 with a slight inhibitory effect compared to other tested cancer cells, highlighting GOT1 as a promising therapeutic target for the treatment of breast cancer.
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Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M. Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ 2022; 29:1304-1317. [PMID: 35831624 PMCID: PMC9287557 DOI: 10.1038/s41418-022-01022-y] [Citation(s) in RCA: 169] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 12/13/2022] Open
Abstract
During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy. ![]()
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Affiliation(s)
- Lourdes Sainero-Alcolado
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden
| | - Judit Liaño-Pons
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden
| | - María Victoria Ruiz-Pérez
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden
| | - Marie Arsenian-Henriksson
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, SE-171 65, Stockholm, Sweden.
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Bel’skaya LV, Sarf EA. Prognostic Value of Salivary Biochemical Indicators in Primary Resectable Breast Cancer. Metabolites 2022; 12:552. [PMID: 35736486 PMCID: PMC9227854 DOI: 10.3390/metabo12060552] [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: 05/20/2022] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 02/04/2023] Open
Abstract
Despite the fact that breast cancer was detected in the early stages, the prognosis was not always favorable. In this paper, we examined the impact of clinical and pathological characteristics of patients and the composition of saliva before treatment on overall survival and the risk of recurrence of primary resectable breast cancer. The study included 355 patients of the Omsk Clinical Oncology Center with a diagnosis of primary resectable breast cancer (T1-3N0-1M0). Saliva was analyzed for 42 biochemical indicators before the start of treatment. We have identified two biochemical indicators of saliva that can act as prognostic markers: alkaline phosphatase (ALP) and diene conjugates (DC). Favorable prognostic factors were ALP activity above 71.7 U/L and DC level above 3.93 c.u. Additional accounting for aspartate aminotransferase (AST) activity allows for forming a group with a favorable prognosis, for which the relative risk is reduced by more than 11 times (HR = 11.49, 95% CI 1.43-88.99, p = 0.01591). Salivary AST activity has no independent prognostic value. Multivariate analysis showed that tumor size, lymph nodes metastasis status, malignancy grade, tumor HER2 status, and salivary ALP activity were independent predictors. It was shown that the risk of recurrence decreased with menopause and increased with an increase in the size of the primary tumor and lymph node involvement. Significant risk factors for recurrence were salivary ALP activity below 71.7 U/L and DC levels below 3.93 c.u. before treatment. Thus, the assessment of biochemical indicators of saliva before treatment can provide prognostic information comparable in importance to the clinicopathological characteristics of the tumor and can be used to identify a risk group for recurrence in primary resectable breast cancer.
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Affiliation(s)
- Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 14 Tukhachevsky str, 644043 Omsk, Russia;
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FIRAT SN, TAŞKALDIRAN I, KUŞKONMAZ Ş, ÇULHA C. AST/ALT (De Ritis) Ratio in Early Stage Differentiated Thyroid Cancer. KOCAELI ÜNIVERSITESI SAĞLIK BILIMLERI DERGISI 2022. [DOI: 10.30934/kusbed.1009993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Objective: Differentiated thyroid cancers are the most common endocrine cancers and their frequency is increasing with the increase in imaging possibilities. In various malignancies; Even in the absence of liver metastases, it was determined that AST value increased compared to ALT due to increased metabolism, tissue damage and rapid tumor turnover. This rate is known as the De Ritis rate, and in our study, we planned to evaluate whether there is a relationship between histopathological subtype, multifocality, disease stage and risk group and AST/ALT (De Ritis) ratio in early stage thyroid cancers.
Method: A total of 154 patients diagnosed with differentiated thyroid cancer in our clinic between 2016 and 2019 were included in the study. The AST/ALT ratios of the patients in the preoperative period were recorded. Tumor staging of each patient was performed according to the American Joint Cancer Committee (AJCC) 8 by evaluating the postoperative pathology reports. The correlation between the patients' preoperative De Ritis rates and postoperative staging was evaluated.
Results: In our study, the mean De Ritis value of the patients was found to be 1.18. The rate of patients with De Ritis rate ≥1.5 was 15.9%. There was no statistically significant difference between preoperative De Ritis rate and histopathological subtype, vascular invasion, capsule invasion, tumor diameter, lymph node involvement and tumor stage.
Conclusion: In our study it was found that preoperative De Ritis ratio was not associated with disease stage and risk status in early stage differentiated thyroid cancers. Additional studies are needed for its importance in advanced differentiated thyroid cancers.
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Affiliation(s)
- Sevde Nur FIRAT
- Sağlık Bilimleri Üniversitesi, Ankara Eğitim ve Araştırma Hastanesi
| | | | - Şerife KUŞKONMAZ
- Sağlık Bilimleri Üniversitesi, Ankara Eğitim ve Araştırma Hastanesi
| | - Cavit ÇULHA
- Sağlık Bilimleri Üniversitesi, Ankara Eğitim ve Araştırma Hastanesi
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Oberkersch RE, Pontarin G, Astone M, Spizzotin M, Arslanbaeva L, Tosi G, Panieri E, Ricciardi S, Allega MF, Brossa A, Grumati P, Bussolati B, Biffo S, Tardito S, Santoro MM. Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis. Dev Cell 2022; 57:1241-1256.e8. [PMID: 35580611 DOI: 10.1016/j.devcel.2022.04.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 02/24/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022]
Abstract
Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive. We here shown in both human cell lines and mouse models that during developmental and pathological angiogenesis, endothelial cells (ECs) use glutaminolysis-derived glutamate to produce aspartate (Asp) via aspartate aminotransferase (AST/GOT). Asp leads to mTORC1 activation which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. Asp-dependent mTORC1 pathway activation also regulates de novo pyrimidine synthesis in angiogenic ECs. These findings identify glutaminolysis-derived Asp as a regulator of mTORC1-dependent endothelial translation and pyrimidine synthesis. Our studies may help overcome anti-VEGF therapy resistance by targeting endothelial growth factor receptor translation.
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Affiliation(s)
- Roxana E Oberkersch
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Giovanna Pontarin
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Matteo Astone
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Marianna Spizzotin
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Liaisan Arslanbaeva
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Giovanni Tosi
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Emiliano Panieri
- Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Sara Ricciardi
- National Institute of Molecular Genetics (INGM) and Department of Biosciences, University of Milan, Milan, Italy
| | - Maria Francesca Allega
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G611BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G611QH, UK
| | - Alessia Brossa
- Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Paolo Grumati
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | | | - Stefano Biffo
- National Institute of Molecular Genetics (INGM) and Department of Biosciences, University of Milan, Milan, Italy
| | - Saverio Tardito
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G611BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G611QH, UK
| | - Massimo M Santoro
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy.
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Development of Anticancer Peptides Using Artificial Intelligence and Combinational Therapy for Cancer Therapeutics. Pharmaceutics 2022; 14:pharmaceutics14050997. [PMID: 35631583 PMCID: PMC9147327 DOI: 10.3390/pharmaceutics14050997] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/28/2022] [Accepted: 05/04/2022] [Indexed: 01/27/2023] Open
Abstract
Cancer is a group of diseases causing abnormal cell growth, altering the genome, and invading or spreading to other parts of the body. Among therapeutic peptide drugs, anticancer peptides (ACPs) have been considered to target and kill cancer cells because cancer cells have unique characteristics such as a high negative charge and abundance of microvilli in the cell membrane when compared to a normal cell. ACPs have several advantages, such as high specificity, cost-effectiveness, low immunogenicity, minimal toxicity, and high tolerance under normal physiological conditions. However, the development and identification of ACPs are time-consuming and expensive in traditional wet-lab-based approaches. Thus, the application of artificial intelligence on the approaches can save time and reduce the cost to identify candidate ACPs. Recently, machine learning (ML), deep learning (DL), and hybrid learning (ML combined DL) have emerged into the development of ACPs without experimental analysis, owing to advances in computer power and big data from the power system. Additionally, we suggest that combination therapy with classical approaches and ACPs might be one of the impactful approaches to increase the efficiency of cancer therapy.
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Ascenção K, Szabo C. Emerging roles of cystathionine β-synthase in various forms of cancer. Redox Biol 2022; 53:102331. [PMID: 35618601 PMCID: PMC9168780 DOI: 10.1016/j.redox.2022.102331] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/29/2022] [Accepted: 05/04/2022] [Indexed: 12/12/2022] Open
Abstract
The expression of the reverse transsulfuration enzyme cystathionine-β-synthase (CBS) is markedly increased in many forms of cancer, including colorectal, ovarian, lung, breast and kidney, while in other cancers (liver cancer and glioma) it becomes downregulated. According to the clinical database data in high-CBS-expressor cancers (e.g. colon or ovarian cancer), high CBS expression typically predicts lower survival, while in the low-CBS-expressor cancers (e.g. liver cancer), low CBS expression is associated with lower survival. In the high-CBS expressing tumor cells, CBS, and its product hydrogen sulfide (H2S) serves as a bioenergetic, proliferative, cytoprotective and stemness factor; it also supports angiogenesis and epithelial-to-mesenchymal transition in the cancer microenvironment. The current article reviews the various tumor-cell-supporting roles of the CBS/H2S axis in high-CBS expressor cancers and overviews the anticancer effects of CBS silencing and pharmacological CBS inhibition in various cancer models in vitro and in vivo; it also outlines potential approaches for biomarker identification, to support future targeted cancer therapies based on pharmacological CBS inhibition.
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Galler M, Rogasch JMM, Huang K, Jann H, Plehm K, Wetz C, Amthauer H. Prognostic Value of the Largest Lesion Size for Progression-Free Survival in Patients with NET Undergoing Salvage PRRT with [177Lu]Lu-DOTATOC. Cancers (Basel) 2022; 14:cancers14071768. [PMID: 35406540 PMCID: PMC8996884 DOI: 10.3390/cancers14071768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Peptide receptor radionuclide therapy (PRRT) using radionuclide-labeled somatostatin analogues is based on the overexpression of somatostatin receptors on neuroendocrine tumors and is shown to have a good safety profile and efficacy in different types of metastatic neuroendocrine tumors. As this therapy is usually not curative, most patients experience disease progression after initial PRRT. In these cases, retreatment with PRRT, also called salvage PRRT, can be a treatment option, but little is known about the efficacy and possible risk factors. In this retrospective study that included 32 patients, we found that the size of the largest lesion is a significant predictor of disease progression after salvage PRRT. This risk factor is easy to obtain and can help identify patients who may benefit from intensified follow-up strategies. Abstract (1) Background: retreatment with radionuclide-labeled somatostatin analogues following disease progression after initial treatment cycles is often referred to as salvage peptide receptor radionuclide therapy (salvage PRRT). Salvage PRRT is shown to have a favorable safety profile in patients with metastatic neuroendocrine tumors (NETs), but numerous questions about the efficacy and prognostic or predictive factors remain to be answered. The purpose of this study was to evaluate two parameters that have shown prognostic significance in progression-free survival (PFS) in initial PRRT treatment, namely the size of the largest lesion (LLS) and the De Ritis ratio (aspartate aminotransferase (AST)/alanine aminotransferase (ALT)), as prognostic factors in the context of salvage PRRT. In addition, the PFS after initial PRRT was evaluated as a predictor of the PFS following salvage PRRT. (2) Methods: retrospective, monocentric analysis in 32 patients with NETs (gastroenteropancreatic, 23; unknown primary, 7; kidney, 1; lung, 1) and progression after initial PRRT undergoing retreatment with [177Lu]Lu-DOTATOC. The prognostic values of LLS, the De Ritis ratio, and PFS after initial treatment cycles regarding PFS following salvage PRRT were evaluated with univariable and multivariable Cox regression. PFS was defined as the time from treatment start until tumor progression according to RECIST 1.1 criteria, death from any cause or start of a new treatment due to progression of cancer-related symptoms (namely carcinoid syndrome). (3) Results: progression after salvage PRRT was observed in 29 of 32 patients with median PFS of 10.8 months (95% confidence interval (CI), 8.0–15.9 months). A higher LLS (hazard ratio (HR): 1.03; p = 0.002) and a higher De Ritis ratio (HR: 2.64; p = 0.047) were associated with shorter PFS after salvage PRRT in univariable Cox regression. PFS after initial PRRT was not associated with PFS following salvage PRRT. In multivariable Cox regression, only LLS remained a significant predictor. (4) Conclusions: the size of the largest lesion is easy to obtain and might help identify patients at risk of early disease progression after salvage PRRT. Validation is required.
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Affiliation(s)
- Markus Galler
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (J.M.M.R.); (K.H.); (C.W.); (H.A.)
- Correspondence:
| | - Julian M. M. Rogasch
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (J.M.M.R.); (K.H.); (C.W.); (H.A.)
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Kai Huang
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (J.M.M.R.); (K.H.); (C.W.); (H.A.)
| | - Henning Jann
- Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (H.J.); (K.P.)
| | - Kristina Plehm
- Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (H.J.); (K.P.)
| | - Christoph Wetz
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (J.M.M.R.); (K.H.); (C.W.); (H.A.)
| | - Holger Amthauer
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (J.M.M.R.); (K.H.); (C.W.); (H.A.)
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Song Z, Yang Y, Wu Y, Zheng M, Sun D, Li H, Chen L. Glutamic oxaloacetic transaminase 1 as a potential target in human cancer. Eur J Pharmacol 2022; 917:174754. [PMID: 35007521 DOI: 10.1016/j.ejphar.2022.174754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/08/2021] [Accepted: 01/06/2022] [Indexed: 12/31/2022]
Abstract
Glutamic Oxaloacetic Transaminase 1 (GOT1) is one distinct isoenzyme of glutamic oxaloacetic transaminase in eukaryotic cells, which is located in the cytoplasm. To date, several studies have shown that GOT1 plays a critical role in regulating cell proliferation by participating in amino acid metabolism, especially in glutamine metabolism. In addition, GOT1 is overexpressed in many cancer, so GOT1 has been identified as a potentially therapeutic target. Herein, this review summarizes the structure and function of GOT1 and the important roles of GOT1 in some tumor progress, as well as the characterization of GOT1 inhibitors. It may provide new insight into the discovery of small compounds as potential anti-GOT1 drugs for treatment of cancer.
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Affiliation(s)
- Zhuorui Song
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yueying Yang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yanli Wu
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mengzhu Zheng
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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Sharma S, Agnihotri N, Kumar S. Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis. Biochem Pharmacol 2022; 198:114943. [DOI: 10.1016/j.bcp.2022.114943] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
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Abstract
PURPOSE OF REVIEW Osteoblasts are responsible for bone matrix production during bone development and homeostasis. Much is known about the transcriptional regulation and signaling pathways governing osteoblast differentiation. However, less is known about how osteoblasts obtain or utilize nutrients to fulfill the energetic demands associated with osteoblast differentiation and bone matrix synthesis. The goal of this review is to highlight and discuss what is known about the role and regulation of bioenergetic metabolism in osteoblasts with a focus on more recent studies. RECENT FINDINGS Bioenergetic metabolism has emerged as an important regulatory node in osteoblasts. Recent studies have begun to identify the major nutrients and bioenergetic pathways favored by osteoblasts as well as their regulation during differentiation. Here, we highlight how osteoblasts obtain and metabolize glucose, amino acids, and fatty acids to provide energy and other metabolic intermediates. In addition, we highlight the signals that regulate nutrient uptake and metabolism and focus on how energetic metabolism promotes osteoblast differentiation. Bioenergetic metabolism provides energy and other metabolites that are critical for osteoblast differentiation and activity. This knowledge contributes to a more comprehensive understanding of osteoblast biology and may inform novel strategies to modulate osteoblast differentiation and bone anabolism in patients with bone disorders.
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Affiliation(s)
- Leyao Shen
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Guoli Hu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Courtney M Karner
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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Li J, Cao D, Peng L, Meng C, Xia Z, Li Y, Wei Q. Potential Clinical Value of Pretreatment De Ritis Ratio as a Prognostic Biomarker for Renal Cell Carcinoma. Front Oncol 2021; 11:780906. [PMID: 34993141 PMCID: PMC8724044 DOI: 10.3389/fonc.2021.780906] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/25/2021] [Indexed: 01/04/2023] Open
Abstract
Background We performed this study to explore the prognostic value of the pretreatment aspartate transaminase to alanine transaminase (De Ritis) ratio in patients with renal cell carcinoma (RCC). Methods PubMed, EMBASE, Web of Science, and Cochrane Library were searched to identify all studies. The hazard ratio (HR) with a 95% confidence interval (CI) for overall survival (OS) and cancer-specific survival (CSS) were extracted to evaluate their correlation. Results A total of 6,528 patients from 11 studies were included in the pooled analysis. Patients with a higher pretreatment De Ritis ratio had worse OS (HR = 1.41, p < 0.001) and CSS (HR = 1.59, p < 0.001). Subgroup analysis according to ethnicity, disease stage, cutoff value, and sample size revealed that the De Ritis ratio had a significant prognostic value for OS and CSS in all subgroups. Conclusions The present study suggests that an elevated pretreatment De Ritis ratio is significantly correlated with worse survival in patients with RCC. The pretreatment De Ritis ratio may serve as a potential prognostic biomarker in patients with RCC, but further studies are warranted to support these results.
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Affiliation(s)
- Jinze Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Dehong Cao
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Peng
- Department of Urology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Chunyang Meng
- Department of Urology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Zhongyou Xia
- Department of Urology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Yunxiang Li
- Department of Urology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
- *Correspondence: Yunxiang Li, ; Qiang Wei,
| | - Qiang Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Yunxiang Li, ; Qiang Wei,
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Ripoll C, Roldan M, Ruedas-Rama MJ, Orte A, Martin M. Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification. BIOLOGY 2021; 10:biology10121267. [PMID: 34943182 PMCID: PMC8698801 DOI: 10.3390/biology10121267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022]
Abstract
Simple Summary Recent studies on cancer cell metabolism have achieved notable breakthroughs that have led to a new scientific paradigm. How cancer cell metabolic reprogramming is orchestrated and the decisive role of this reprogramming in the oncogenic process and tumor adaptative evolution has been characterized at the molecular level. Despite this knowledge, it is essential to understand how cancer cells can metabolically respond as a living whole to ensure their survival and adaptation potential. In this work, we investigated whether different cancers and different subtypes display different metabolic phenotypes with a focus on breast cancer cell models representative of each clinical subtype. The potential results might have significant translational implications for diagnostic, prognostic and therapeutic applications. Abstract Metabolic reprogramming of cancer cells represents an orchestrated network of evolving molecular and functional adaptations during oncogenic progression. In particular, how metabolic reprogramming is orchestrated in breast cancer and its decisive role in the oncogenic process and tumor evolving adaptations are well consolidated at the molecular level. Nevertheless, potential correlations between functional metabolic features and breast cancer clinical classification still represent issues that have not been fully studied to date. Accordingly, we aimed to investigate whether breast cancer cell models representative of each clinical subtype might display different metabolic phenotypes that correlate with current clinical classifications. In the present work, functional metabolic profiling was performed for breast cancer cell models representative of each clinical subtype based on the combination of enzyme inhibitors for key metabolic pathways, and isotope-labeled tracing dynamic analysis. The results indicated the main metabolic phenotypes, so-called ‘metabophenotypes’, in terms of their dependency on glycolytic metabolism or their reliance on mitochondrial oxidative metabolism. The results showed that breast cancer cell subtypes display different metabophenotypes. Importantly, these metabophenotypes are clearly correlated with the current clinical classifications.
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Affiliation(s)
- Consuelo Ripoll
- Nanoscopy-UGR Laboratory, Departamento de Fisicoquimica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain; (C.R.); (M.J.R.-R.)
- GENYO, Pfizer-Universidad de Granada-Junta de Andalucia Centre for Genomics and Oncological Research, Avda Ilustracion 114, PTS, 18016 Granada, Spain;
| | - Mar Roldan
- GENYO, Pfizer-Universidad de Granada-Junta de Andalucia Centre for Genomics and Oncological Research, Avda Ilustracion 114, PTS, 18016 Granada, Spain;
- Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, Universidad de Granada, Avda. Fuentenueva, 18071 Granada, Spain
| | - Maria J. Ruedas-Rama
- Nanoscopy-UGR Laboratory, Departamento de Fisicoquimica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain; (C.R.); (M.J.R.-R.)
| | - Angel Orte
- Nanoscopy-UGR Laboratory, Departamento de Fisicoquimica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain; (C.R.); (M.J.R.-R.)
- Correspondence: (A.O.); (M.M.)
| | - Miguel Martin
- GENYO, Pfizer-Universidad de Granada-Junta de Andalucia Centre for Genomics and Oncological Research, Avda Ilustracion 114, PTS, 18016 Granada, Spain;
- Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, Universidad de Granada, Avda. Fuentenueva, 18071 Granada, Spain
- Correspondence: (A.O.); (M.M.)
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Mazzio E, Mack N, Badisa RB, Soliman KFA. Triple Isozyme Lactic Acid Dehydrogenase Inhibition in Fully Viable MDA-MB-231 Cells Induces Cytostatic Effects That Are Not Reversed by Exogenous Lactic Acid. Biomolecules 2021; 11:biom11121751. [PMID: 34944395 PMCID: PMC8698706 DOI: 10.3390/biom11121751] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/09/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
A number of aggressive human malignant tumors are characterized by an intensified glycolytic rate, over-expression of lactic acid dehydrogenase A (LDHA), and subsequent lactate accumulation, all of which contribute toward an acidic peri-cellular immunosuppressive tumor microenvironment (TME). While recent focus has been directed at how to inhibit LDHA, it is now becoming clear that multiple isozymes of LDH must be simultaneously inhibited in order to fully suppress lactic acid and halt glycolysis. In this work we explore the biochemical and genomic consequences of an applied triple LDH isozyme inhibitor (A, B, and C) (GNE-140) in MDA-MB-231 triple-negative breast cancer cells (TNBC) cells. The findings confirm that GNE-140 does in fact, fully block the production of lactic acid, which also results in a block of glucose utilization and severe impedance of the glycolytic pathway. Without a fully functional glycolytic pathway, breast cancer cells continue to thrive, sustain viability, produce ample energy, and maintain mitochondrial potential (ΔΨM). The only observable negative consequence of GNE-140 in this work, was the attenuation of cell division, evident in both 2D and 3D cultures and occurring in fully viable cells. Of important note, the cytostatic effects were not reversed by the addition of exogenous (+) lactic acid. While the effects of GNE-140 on the whole transcriptome were mild (12 up-regulated differential expressed genes (DEGs); 77 down-regulated DEGs) out of the 48,226 evaluated, the down-regulated DEGS collectively centered around a loss of genes related to mitosis, cell cycle, GO/G1–G1/S transition, and DNA replication. These data were also observed with digital florescence cytometry and flow cytometry, both corroborating a G0/G1 phase blockage. In conclusion, the findings in this work suggest there is an unknown element linking LDH enzyme activity to cell cycle progression, and this factor is completely independent of lactic acid. The data also establish that complete inhibition of LDH in cancer cells is not a detriment to cell viability or basic production of energy.
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Affiliation(s)
- Elizabeth Mazzio
- Institute of Public Health, College of Pharmacy & Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (E.M.); (N.M.); (R.B.B.)
| | - Nzinga Mack
- Institute of Public Health, College of Pharmacy & Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (E.M.); (N.M.); (R.B.B.)
- Institute of Computational Medicine, Johns Hopkins Whiting School of Engineering, Baltimore, MD 21218, USA
| | - Ramesh B. Badisa
- Institute of Public Health, College of Pharmacy & Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (E.M.); (N.M.); (R.B.B.)
| | - Karam F. A. Soliman
- Institute of Public Health, College of Pharmacy & Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (E.M.); (N.M.); (R.B.B.)
- Correspondence: ; Tel.: +1-850-599-3306; Fax: +1-850-599-3667
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Coronel-Hernández J, Pérez-Yépez EA, Delgado-Waldo I, Contreras-Romero C, Jacobo-Herrera N, Cantú-De León D, Pérez-Plasencia C. Aberrant Metabolism as Inductor of Epigenetic Changes in Breast Cancer: Therapeutic Opportunities. Front Oncol 2021; 11:676562. [PMID: 34692471 PMCID: PMC8531643 DOI: 10.3389/fonc.2021.676562] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 09/08/2021] [Indexed: 12/23/2022] Open
Abstract
Aberrant metabolism is arising interest in the scientific community not only because of the role it plays in the development and establishment of the tumor mass but also the possibility of drug poisoning of key enzymes overexpressed in tumor cells. Moreover, tumor metabolism provides key molecules to maintain the epigenetic changes that are also an undisputed characteristic of each tumor type. This metabolic change includes the Warburg effect and alterations in key pathways involved in glutaminolysis, pentose phosphate, and unsaturated fatty acid biosynthesis. Modifications in all these pathways have consequences that impact genetics and epigenetics processes such as DNA methylation patterns, histone post-translational modifications, triggering oncogenes activation, and loss in tumor suppressor gene expression to lead the tumor establishment. In this review, we describe the metabolic rearrangement and its association with epigenetic regulation in breast cancer, as well as its implication in biological processes involved in cancer progression. A better understanding of these processes could help to find new targets for the diagnosis, prognosis, and treatment of this human health problem.
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Affiliation(s)
| | - Eloy Andrés Pérez-Yépez
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City, Mexico.,Cátedra-CONACYT, Dirección de Cátedras, Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico City, Mexico
| | | | | | - Nadia Jacobo-Herrera
- Unidad de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City, Mexico
| | - David Cantú-De León
- Unidad de Investigación en Cáncer, Instituto Nacional de Cancerología , Mexico City, Mexico
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City, Mexico.,Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Li W, Cui X, Chen Z. Screening of lactate dehydrogenase inhibitor from bioactive compounds in natural products by electrophoretically mediated microanalysis. J Chromatogr A 2021; 1656:462554. [PMID: 34571279 DOI: 10.1016/j.chroma.2021.462554] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/26/2022]
Abstract
Lactate dehydrogenase (LDH) is a key enzyme in the glycolysis, which has been reported that the expression of LDH is elevated in a variety of cancer types and can promote tumor invasion and metastasis. Therefore, LDH has come to be an emerging therapeutic target for cancer. In this work, we described a new strategy for rapid screening of LDH inhibitors from natural products by integrating electrophoretically mediated microanalysis (EMMA), transverse diffusion of laminar flow profiles (TDLFP) and rapid pressure direction switching. LDH activity could be assayed by the quantification of the peak area of the produced β-Nicotinamide adenine dinucleotide hydrate (NAD+) and the inhibitory effect on LDH was reflected by the reduction of NAD+ peak area. Parameters affecting CE separation and enzymatic reaction were evaluated, including the pH of background electrolyte, incubation time, methanol percentage and enzyme concentration. The Michaelis-Menten constant (Km) determined on-line by EMMA method were 226.9 μM and 31.8 μM for substrates sodium pyruvate and NADH, respectively and the half-maximal inhibitory concentration (IC50) for the known positive inhibitor gossypol was determined to be 9.269 μM, which was comparable with the previous literature. Then the inhibitory activity of 12 bioactive compounds from natural products on LDH was investigated by employing the developed method. Three compounds including quercetin, luteolin, ursolic acid had potential inhibitory effect on LDH. Molecular docking study was implemented and well supported the experimental results. This study provides a potential tool for the preliminary screening of LDH inhibitors from bioactive compounds in natural products by capillary electrophoresis.
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Affiliation(s)
- Wen Li
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China; State Key Laboratory of Transducer Technology, Chinese Academy of Sciences, Beijing 10080, China
| | - Xinyue Cui
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China
| | - Zilin Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China; State Key Laboratory of Transducer Technology, Chinese Academy of Sciences, Beijing 10080, China.
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Structural and functional analysis of disease-associated mutations in GOT1 gene: An in silico study. Comput Biol Med 2021; 136:104695. [PMID: 34352456 DOI: 10.1016/j.compbiomed.2021.104695] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 07/23/2021] [Indexed: 11/20/2022]
Abstract
Disease-associated single nucleotide polymorphisms (SNPs) alter the natural functioning and the structure of proteins. Glutamic-oxaloacetic transaminase 1 (GOT1) is a gene associated with multiple cancers and neurodegenerative diseases which codes for aspartate aminotransferase. The present study involved a comprehensive in-silico analysis of the disease-associated SNPs of human GOT1. Four highly deleterious nsSNPs (L36R, Y159C, W162C and L345P) were identified through SNP screening using several sequence-based and structure-based tools. Conservation analysis and oncogenic analysis showed that most of the nsSNPs are at highly conserved residues, oncogenic in nature and cancer drivers. Molecular dynamics simulations (MDS) analysis was performed to understand the dynamic behaviour of native and mutant proteins. PTM analysis revealed that the nsSNP Y159C is at a PTM site and will mostly affect phosphorylation at that site. Based on the overall analyses carried out in this study, L36R is the most deleterious mutation amongst the aforementioned deleterious mutations of GOT1.
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