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1
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Li T, Yang C, Zhang L. Novel comprehensive perspective on Amadori compounds: preparation, multiple roles and interaction with other compounds. Crit Rev Food Sci Nutr 2025:1-24. [PMID: 40269616 DOI: 10.1080/10408398.2025.2494059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2025]
Abstract
Amadori compounds are pivotal intermediates in the Maillard reaction. Amadori compounds serve as flavor enhancers, browning precursors and bioactive components, so they are promising versatile food additives. Comprehensive reviews on multiple roles of Amadori compounds are scarce. Furthermore, there is a lack of reviews on green, efficient and commercially prospective preparation techniques of Amadori compounds and their interactions with other components. This paper reviewed preparation, multiple roles and interactions with other components in foods. Spray drying, microwave heating, natural deep eutectic solvents and vacuum dewatering were deemed as green, efficient and commercially prospective preparation techniques for Amadori compounds. Amadori compounds broadened the application field of Maillard reaction-obtained additives compared to final-products, enabling their uses not only in dark-colored foodstuffs but also in light-colored. Peptide-derived Amadori compounds showed greater potency for flavor generation compared to amino acid-derived. Amadori compounds presented eleven physiological activities. Amadori compounds exerted synergistic effect with essential nutrients (lipids, exogenous amino acids and carbohydrates), functional ingredients (polyphenols, carotenoids, glycosides) as well as several drugs. More preparation approaches of Amadori compounds and their synergistic effects with other ingredients await investigation. This review provided comprehensive theoretical guidance for industrial preparation and application of Amadori compounds as versatile additives.
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Affiliation(s)
- Tingting Li
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Cheng Yang
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Lianfu Zhang
- School of Food Science and Technology, Jiangnan University, Wuxi, China
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2
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Zhang N, Liu Q, Wang D, Wang X, Pan Z, Han B, He G. Multifaceted roles of Galectins: from carbohydrate binding to targeted cancer therapy. Biomark Res 2025; 13:49. [PMID: 40134029 PMCID: PMC11934519 DOI: 10.1186/s40364-025-00759-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/05/2025] [Indexed: 03/27/2025] Open
Abstract
Galectins play pivotal roles in cellular recognition and signaling processes by interacting with glycoconjugates. Extensive research has highlighted the significance of Galectins in the context of cancer, aiding in the identification of biomarkers for early detection, personalized therapy, and predicting treatment responses. This review offers a comprehensive overview of the structural characteristics, ligand-binding properties, and interacting proteins of Galectins. We delve into their biological functions and examine their roles across various cancer types. Galectins, characterized by a conserved carbohydrate recognition domain (CRD), are divided into prototype, tandem-repeat, and chimera types based on their structural configurations. Prototype Galectins contain a single CRD, tandem-repeat Galectins contain two distinct CRDs linked by a peptide, and the chimera-type Galectin-3 features a unique structural arrangement. The capacity of Galectins to engage in multivalent interactions allows them to regulate a variety of signaling pathways, thereby affecting cell fate and function. In cancer, Galectins contribute to tumor cell transformation, angiogenesis, immune evasion, and metastasis, making them critical targets for therapeutic intervention. This review discusses the multifaceted roles of Galectins in cancer progression and explores current advancements in the development of Galectin-targeted therapies. We also address the challenges and future directions for integrating Galectin research into clinical practice to enhance cancer treatment outcomes. In brief, understanding the complex functions of Galectins in cancer biology opens new avenues for therapeutic strategies. Continued research on Galectin interactions and their pathological roles is essential for developing effective carbohydrate-based treatments and improving clinical interventions for cancer patients.
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Affiliation(s)
- Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Qiao Liu
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Daihan Wang
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Xiaoyun Wang
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Zhaoping Pan
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Gu He
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, 116023, China.
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3
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Mossine VV, Mawhinney TP. 1-Amino-1-deoxy-d-fructose ("fructosamine") and its derivatives. Adv Carbohydr Chem Biochem 2023; 83:27-132. [PMID: 37968038 DOI: 10.1016/bs.accb.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2023]
Abstract
Fructosamine has long been considered as a key intermediate of the Maillard reaction, which to a large extent is responsible for specific aroma, taste, and color formation in thermally processed or dehydrated foods. Since the 1980s, however, as a product of the Amadori rearrangement reaction between glucose and biologically significant amines such as proteins, fructosamine has experienced a boom in biomedical research, mainly due to its relevance to pathologies in diabetes and aging. In this chapter, we assess the scope of the knowledge on and applications of fructosamine-related molecules in chemistry, food, and health sciences, as reflected mostly in publications within the past decade. Methods of fructosamine synthesis and analysis, its chemical, and biological properties, and degradation reactions, together with fructosamine-modifying and -recognizing proteins are surveyed.
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Affiliation(s)
- Valeri V Mossine
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
| | - Thomas P Mawhinney
- Department of Biochemistry, University of Missouri, Columbia, MO, United States.
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Cao J, Yang C, Zhang J, Zhang L, Tsao R. Amadori compounds: analysis, composition in food and potential health beneficial functions. Crit Rev Food Sci Nutr 2023; 65:406-428. [PMID: 39722481 DOI: 10.1080/10408398.2023.2274949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024]
Abstract
Amadori compounds (ACs) are key intermediates of the Maillard reaction, and found in various thermally processed foods. Simultaneous analysis of multiple ACs is challenging due to the complex amino acid and carbohydrate compositions, and the different food matrices. Most studies focus on the effects of ACs on food flavor and related sensory properties, but not their biological functions. However, increasing evidence shows that ACs possess various beneficial effects on human health, thus a comprehensive review on the various biological activities is warranted. In this review, we summarized the composition and content of ACs in different foods, their formation and degradation reactions, and discussed the latest advances in analytical methods of ACs and their biological functions related to human health. Limitations and research gaps were identified and future perspectives on ACs research were proposed. This review points to the needs of systematic and comprehensive in vitro and in vivo studies on human health related biological functions of ACs and their mechanisms of action, particularly the synergistic effects with other food components and drugs, and roles in intestinal health and metabolic syndrome.
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Affiliation(s)
- Jialing Cao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Cheng Yang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Jian Zhang
- College of Food, Shihezi University, Shihezi, China
| | - Lianfu Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- College of Food, Shihezi University, Shihezi, China
| | - Rong Tsao
- Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, Canada
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5
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Laderach DJ, Compagno D. Inhibition of galectins in cancer: Biological challenges for their clinical application. Front Immunol 2023; 13:1104625. [PMID: 36703969 PMCID: PMC9872792 DOI: 10.3389/fimmu.2022.1104625] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Abstract
Galectins play relevant roles in tumor development, progression and metastasis. Accordingly, galectins are certainly enticing targets for medical intervention in cancer. To date, however, clinical trials based on galectin inhibitors reported inconclusive results. This review summarizes the galectin inhibitors currently being evaluated and discusses some of the biological challenges that need to be addressed to improve these strategies for the benefit of cancer patients.
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Affiliation(s)
- Diego José Laderach
- Molecular and Functional Glyco-Oncology Laboratory, Instituto de Química Biológica de la Facutad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Buenos Aires, Argentina,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina,Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina,*Correspondence: Diego José Laderach,
| | - Daniel Compagno
- Molecular and Functional Glyco-Oncology Laboratory, Instituto de Química Biológica de la Facutad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Buenos Aires, Argentina,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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6
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The Diagnostic and Therapeutic Potential of Galectin-3 in Cardiovascular Diseases. Biomolecules 2021; 12:biom12010046. [PMID: 35053194 PMCID: PMC8774137 DOI: 10.3390/biom12010046] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/25/2021] [Accepted: 12/27/2021] [Indexed: 12/25/2022] Open
Abstract
Galectin-3 plays a prominent role in chronic inflammation and has been implicated in the development of many disease conditions, including heart disease. Galectin-3, a regulatory protein, is elevated in both acute and chronic heart failure and is involved in the inflammatory pathway after injury leading to myocardial tissue remodelling. We discussed the potential utility of galectin-3 as a diagnostic and disease severity/prognostic biomarker in different cardio/cerebrovascular diseases, such as acute ischemic stroke, acute coronary syndromes, heart failure and arrhythmogenic cardiomyopathy. Over the last decade there has been a marked increase in the understanding the role of galectin-3 in myocardial fibrosis and inflammation and as a therapeutic target for the treatment of heart failure and myocardial infarction.
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Patel V, Szász I, Koroknai V, Kiss T, Balázs M. Molecular Alterations Associated with Acquired Drug Resistance during Combined Treatment with Encorafenib and Binimetinib in Melanoma Cell Lines. Cancers (Basel) 2021; 13:cancers13236058. [PMID: 34885166 PMCID: PMC8656772 DOI: 10.3390/cancers13236058] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 12/21/2022] Open
Abstract
Combination treatment using BRAF/MEK inhibitors is a promising therapy for patients with advanced BRAFV600E/K mutant melanoma. However, acquired resistance largely limits the clinical efficacy of this drug combination. Identifying resistance mechanisms is essential to reach long-term, durable responses. During this study, we developed six melanoma cell lines with acquired resistance for BRAFi/MEKi treatment and defined the molecular alterations associated with drug resistance. We observed that the invasion of three resistant cell lines increased significantly compared to the sensitive cells. RNA-sequencing analysis revealed differentially expressed genes that were functionally linked to a variety of biological functions including epithelial-mesenchymal transition, the ROS pathway, and KRAS-signalling. Using proteome profiler array, several differentially expressed proteins were detected, which clustered into a unique pattern. Galectin showed increased expression in four resistant cell lines, being the highest in the WM1617E+BRes cells. We also observed that the resistant cells behaved differently after the withdrawal of the inhibitors, five were not drug addicted at all and did not exhibit significantly increased lethality; however, the viability of one resistant cell line (WM1617E+BRes) decreased significantly. We have selected three resistant cell lines to investigate the protein expression changes after drug withdrawal. The expression patterns of CapG, Enolase 2, and osteopontin were similar in the resistant cells after ten days of "drug holiday", but the Snail protein was only expressed in the WM1617E+BRes cells, which showed a drug-dependent phenotype, and this might be associated with drug addiction. Our results highlight that melanoma cells use several types of resistance mechanisms involving the altered expression of different proteins to bypass drug treatment.
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Affiliation(s)
- Vikas Patel
- Doctoral School of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary;
| | - István Szász
- MTA-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Viktória Koroknai
- MTA-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Tímea Kiss
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Margit Balázs
- MTA-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
- Correspondence:
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8
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Kumar V, Xin X, Ma J, Tan C, Osna N, Mahato RI. Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis. Adv Drug Deliv Rev 2021; 176:113888. [PMID: 34314787 PMCID: PMC8440458 DOI: 10.1016/j.addr.2021.113888] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/12/2021] [Accepted: 07/18/2021] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM) associated non-alcoholic fatty liver disease (NAFLD) is the fourth-leading cause of death. Hyperglycemia induces various complications, including nephropathy, cirrhosis and eventually hepatocellular carcinoma (HCC). There are several etiological factors leading to liver disease development, which involve insulin resistance and oxidative stress. Free fatty acid (FFA) accumulation in the liver exerts oxidative and endoplasmic reticulum (ER) stresses. Hepatocyte injury induces release of inflammatory cytokines from Kupffer cells (KCs), which are responsible for activating hepatic stellate cells (HSCs). In this review, we will discuss various molecular targets for treating chronic liver diseases, including homeostasis of FFA, lipid metabolism, and decrease in hepatocyte apoptosis, role of growth factors, and regulation of epithelial-to-mesenchymal transition (EMT) and HSC activation. This review will also critically assess different strategies to enhance drug delivery to different cell types. Targeting nanocarriers to specific liver cell types have the potential to increase efficacy and suppress off-target effects.
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Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Xiaofei Xin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jingyi Ma
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chalet Tan
- Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
| | - Natalia Osna
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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9
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Sindrewicz P, Yates EA, Turnbull JE, Lian LY, Yu LG. Interaction with the heparin-derived binding inhibitors destabilizes galectin-3 protein structure. Biochem Biophys Res Commun 2019; 523:336-341. [PMID: 31866013 DOI: 10.1016/j.bbrc.2019.12.054] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 12/11/2019] [Indexed: 12/22/2022]
Abstract
The β-galactoside-binding protein, galectin-3, is extensively involved in cancer development, progression and metastasis through multiple mechanisms. Inhibition of the galectin-3-mediated actions is increasingly considered as a promising therapeutic approach for cancer treatment. Our early studies have identified several novel galectin-3 binding inhibitors from chemical modification of the anticoagulant drug heparin. These heparin-derived galectin-3 binding inhibitors, which show no anticoagulant activity and bind to the galectin-3 canonical carbohydrate-binding site, induce galectin-3 conformational changes and inhibit galectin-3-mediated cancer cell adhesion, invasion and angiogenesis in vitro and reduce metastasis in mice. In this study, we determined the binding affinities of these heparin-derived ligands to galectin-3 using an isothermal titration calorimetry (ITC) ligand displacement approach. Such ITC experiments showed that the 2-de-O-sulphated, N-acetylated (compound E) and 6-de-O-sulphated, N-acetylated (F) heparin-derived ligands and their ultra-low molecular weight sub-fractions (E3 and F3) bind to galectin-3 with KD ranging from 0.96 to 1.32 mM.Differential scanning fluorimetry analysis revealed that, in contrast to the disaccharide ligand, N-acetyl-lactosamine, which binds to the fully folded form of galectin-3 and promotes galectin-3 thermal stability, the heparin-derived ligands preferentially bind to the unfolded state of galectin-3 and cause destabilization of the galectin-3 protein structure. These results provide molecular insights into the interaction of galectin-3 with the heparin-derived ligands and explain the previously demonstrated in vitro and in vivo effects of these binding inhibitors on galectin-3-mediated cancer cell behaviours.
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Affiliation(s)
- Paulina Sindrewicz
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GE, UK
| | - Edwin A Yates
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
| | - Jeremy E Turnbull
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
| | - Lu-Yun Lian
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK.
| | - Lu-Gang Yu
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GE, UK.
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10
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Vuong L, Kouverianou E, Rooney CM, McHugh BJ, Howie SEM, Gregory CD, Forbes SJ, Henderson NC, Zetterberg FR, Nilsson UJ, Leffler H, Ford P, Pedersen A, Gravelle L, Tantawi S, Schambye H, Sethi T, MacKinnon AC. An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade. Cancer Res 2019; 79:1480-1492. [PMID: 30674531 DOI: 10.1158/0008-5472.can-18-2244] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 11/16/2018] [Accepted: 01/17/2019] [Indexed: 11/16/2022]
Abstract
A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8+ T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. SIGNIFICANCE: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg.
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Affiliation(s)
- Lynda Vuong
- Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London, United Kingdom
| | - Eleni Kouverianou
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom
| | - Claire M Rooney
- Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London, United Kingdom
| | - Brian J McHugh
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom
| | - Sarah E M Howie
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom
| | - Christopher D Gregory
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom
| | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom
| | - Neil C Henderson
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom
| | | | - Ulf J Nilsson
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, Lund, Sweden
| | - Hakon Leffler
- Department of Laboratory Medicine, Section MIG, Lund University, Lund, Sweden
| | - Paul Ford
- Galecto Biotech, Copenhagen, Denmark
| | | | | | | | | | - Tariq Sethi
- Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London, United Kingdom
| | - Alison C MacKinnon
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom.
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11
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Di Carlo C, Brandi J, Cecconi D. Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma. World J Stem Cells 2018; 10:172-182. [PMID: 30631392 PMCID: PMC6325076 DOI: 10.4252/wjsc.v10.i11.172] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/10/2018] [Accepted: 10/17/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a five-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells (PCSCs) contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are reviewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic targets are also discussed with a focus on selected specific inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specific drug delivery are highlighted, and their limitations considered.
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Affiliation(s)
- Claudia Di Carlo
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
| | - Jessica Brandi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy.
| | - Daniela Cecconi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
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12
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Peterson K, Kumar R, Stenström O, Verma P, Verma PR, Håkansson M, Kahl-Knutsson B, Zetterberg F, Leffler H, Akke M, Logan DT, Nilsson UJ. Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity. J Med Chem 2018; 61:1164-1175. [PMID: 29284090 DOI: 10.1021/acs.jmedchem.7b01626] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (Kd down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (Kd 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.
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Affiliation(s)
- Kristoffer Peterson
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University , Box 124, SE-221 00 Lund, Sweden
| | - Rohit Kumar
- Biochemistry and Structural Biology, Center for Molecular Protein Science, Department of Chemistry, Lund University , Box 124, SE-221 00 Lund, Sweden
| | - Olof Stenström
- Biophysical Chemistry, Center for Molecular Protein Science, Department of Chemistry, Lund University , Box 124, SE-221 00 Lund, Sweden
| | - Priya Verma
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University , Box 124, SE-221 00 Lund, Sweden
| | - Prashant R Verma
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University , Box 124, SE-221 00 Lund, Sweden
| | - Maria Håkansson
- SARomics Biostructures AB , Medicon Village, SE-223 63 Lund, Sweden
| | - Barbro Kahl-Knutsson
- Department of Laboratory Medicine, Section MIG, Lund University BMC-C1228b , Klinikgatan 28, 221 84 Lund, Sweden
| | - Fredrik Zetterberg
- Galecto Biotech AB , Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Gothenburg, Sweden
| | - Hakon Leffler
- Department of Laboratory Medicine, Section MIG, Lund University BMC-C1228b , Klinikgatan 28, 221 84 Lund, Sweden
| | - Mikael Akke
- Biophysical Chemistry, Center for Molecular Protein Science, Department of Chemistry, Lund University , Box 124, SE-221 00 Lund, Sweden
| | - Derek T Logan
- Biochemistry and Structural Biology, Center for Molecular Protein Science, Department of Chemistry, Lund University , Box 124, SE-221 00 Lund, Sweden.,SARomics Biostructures AB , Medicon Village, SE-223 63 Lund, Sweden
| | - Ulf J Nilsson
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University , Box 124, SE-221 00 Lund, Sweden
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Dion J, Advedissian T, Storozhylova N, Dahbi S, Lambert A, Deshayes F, Viguier M, Tellier C, Poirier F, Téletchéa S, Dussouy C, Tateno H, Hirabayashi J, Grandjean C. Development of a Sensitive Microarray Platform for the Ranking of Galectin Inhibitors: Identification of a Selective Galectin-3 Inhibitor. Chembiochem 2017; 18:2428-2440. [DOI: 10.1002/cbic.201700544] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Indexed: 12/31/2022]
Affiliation(s)
- Johann Dion
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2, chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Tamara Advedissian
- Université Paris Diderot-Paris 7 Sorbonne Paris Cité; Institut Jacques Monod; UMR CNRS 7592; 15 rue Hélène Brion 75205 Paris Cedex 13 France
| | - Nataliya Storozhylova
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2, chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Samir Dahbi
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2, chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Annie Lambert
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2, chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Frédérique Deshayes
- Université Paris Diderot-Paris 7 Sorbonne Paris Cité; Institut Jacques Monod; UMR CNRS 7592; 15 rue Hélène Brion 75205 Paris Cedex 13 France
| | - Mireille Viguier
- Université Paris Diderot-Paris 7 Sorbonne Paris Cité; Institut Jacques Monod; UMR CNRS 7592; 15 rue Hélène Brion 75205 Paris Cedex 13 France
| | - Charles Tellier
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2, chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Françoise Poirier
- Université Paris Diderot-Paris 7 Sorbonne Paris Cité; Institut Jacques Monod; UMR CNRS 7592; 15 rue Hélène Brion 75205 Paris Cedex 13 France
| | - Stéphane Téletchéa
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2, chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Christophe Dussouy
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2, chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
| | - Hiroaki Tateno
- Biotechnology Research Institute for Drug Discovery; Cellular Glycome-Targeted Technology Group; National Institute of Advanced Industrial Science and Technology (AIST); Central 2 1-1-1 Umezuno Tsukuba Ibaraki 305-8568 Japan
| | - Jun Hirabayashi
- Biotechnology Research Institute for Drug Discovery; Cellular Glycome-Targeted Technology Group; National Institute of Advanced Industrial Science and Technology (AIST); Central 2 1-1-1 Umezuno Tsukuba Ibaraki 305-8568 Japan
| | - Cyrille Grandjean
- Faculté des Sciences et des Techniques; Unité Fonctionnalité et Ingénierie des Protéines (UFIP); Université de Nantes; UMR CNRS 6286; 2, chemin de la Houssinière B. P. 92208 44322 Nantes Cedex 3 France
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14
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Methyl 2,3,6-tri-O-Benzoyl-4-O-(tert-butyldimethylsilyl)-β-d-galactopyranoside. MOLBANK 2017. [DOI: 10.3390/m935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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15
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Hidden IgG Antibodies to the Tumor-Associated Thomsen-Friedenreich Antigen in Gastric Cancer Patients: Lectin Reactivity, Avidity, and Clinical Relevance. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6097647. [PMID: 28316982 PMCID: PMC5339540 DOI: 10.1155/2017/6097647] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 01/04/2017] [Indexed: 11/17/2022]
Abstract
Natural antibodies to the tumor-associated Thomsen-Friedenreich antigen (TF) are related to tumor immunosurveillance and cancer patients' survival. Hidden IgG antibodies (HAbs) to TF, their lectin reactivity, avidity, and clinical relevance were studied. HAbs were present in cancer patients and controls. A decreased level of IgG HAbs was detected in cancer. The HAbs level positively correlated with the sialospecific SNA lectin binding in purified total IgG (tIgG) in donors and cancer patients, indicating that HAbs are higher sialylated. The avidity of anti-TF IgG in tIgG samples was lower in cancer patients (P = 0.025) while no difference in the avidity of free anti-TF IgG was established. A negative correlation between the avidity of anti-TF IgG in tIgG and SNA binding in both groups was observed (P < 0.0001). The HAbs level negatively correlated with the anti-TF IgG avidity in tIgG only in donors (P = 0.003). Changes in the level of HAbs and Abs avidity showed a rather good stage- and gender-dependent diagnostic accuracy. Cancer patients with a lower anti-TF IgG avidity in tIgG showed a benefit in survival. Thus the TF-specific HAbs represent a particular subset of anti-TF IgG that differ from free serum anti-TF IgG in SNA reactivity, avidity, diagnostic potential, and relation to survival.
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16
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Ilmer M, Mazurek N, Gilcrease MZ, Byrd JC, Woodward WA, Buchholz TA, Acklin K, Ramirez K, Hafley M, Alt E, Vykoukal J, Bresalier RS. Low expression of galectin-3 is associated with poor survival in node-positive breast cancers and mesenchymal phenotype in breast cancer stem cells. Breast Cancer Res 2016; 18:97. [PMID: 27687248 PMCID: PMC5043623 DOI: 10.1186/s13058-016-0757-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 09/14/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Galectin-3 (Gal3) plays diverse roles in cancer initiation, progression, and drug resistance depending on tumor type characteristics that are also associated with cancer stem cells (CSCs). Recurrence of breast carcinomas may be attributed to the presence of breast CSCs (BCSCs). BCSCs exist in mesenchymal-like or epithelial-like states and the transition between these states endows BCSCs with the capacity for tumor progression. The discovery of a feedback loop with galectins during epithelial-to-mesenchymal transition (EMT) prompted us to investigate its role in breast cancer stemness. METHOD To elucidate the role of Gal3 in BCSCs, we performed various in vitro and in vivo studies such as sphere-formation assays, Western blotting, flow cytometric apoptosis assays, and limited dilution xenotransplant models. Histological staining for Gal3 in tissue microarrays of breast cancer patients was performed to analyze the relationship of clinical outcome and Gal3 expression. RESULTS Here, we show in a cohort of 87 node-positive breast cancer patients treated with doxorubicin-based chemotherapy that low Gal3 was associated with increased lymphovascular invasion and reduced overall survival. Analysis of in vitro BCSC models demonstrated that Gal3 knockdown by small hairpin RNA (shRNA) interference in epithelial-like mammary spheres leads to EMT, increased sphere-formation ability, drug-resistance, and heightened aldefluor activity. Furthermore, Gal3negative BCSCs were associated with enhanced tumorigenicity in orthotopic mouse models. CONCLUSIONS Thus, in at least some breast cancers, loss of Gal3 might be associated with EMT and cancer stemness-associated traits, predicts poor response to chemotherapy, and poor prognosis.
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Affiliation(s)
- Matthias Ilmer
- Current address: Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich (LMU), Munich, Germany
| | - Nachman Mazurek
- Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Michael Z Gilcrease
- Department of Pathology, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - James C Byrd
- Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wendy A Woodward
- Department of Breast Radiation Oncology, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Thomas A Buchholz
- Department of Breast Radiation Oncology, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Kim Acklin
- Department of Stem Cell Transplantation and Cellular Therapies, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Karen Ramirez
- Department of Stem Cell Transplantation and Cellular Therapies, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Margarete Hafley
- Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Eckhard Alt
- Department of Medicine, Tulane University Health Science Center, New Orleans, LA, USA
| | - Jody Vykoukal
- Department of Translational Molecular Pathology, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Robert S Bresalier
- Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
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17
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Delaine T, Collins P, MacKinnon A, Sharma G, Stegmayr J, Rajput VK, Mandal S, Cumpstey I, Larumbe A, Salameh BA, Kahl-Knutsson B, van Hattum H, van Scherpenzeel M, Pieters RJ, Sethi T, Schambye H, Oredsson S, Leffler H, Blanchard H, Nilsson UJ. Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition. Chembiochem 2016; 17:1759-70. [PMID: 27356186 DOI: 10.1002/cbic.201600285] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Indexed: 11/12/2022]
Abstract
Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3'-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin-carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.
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Affiliation(s)
- Tamara Delaine
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden
| | - Patrick Collins
- Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia
| | - Alison MacKinnon
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - G Sharma
- Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden
| | - John Stegmayr
- Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden
| | - Vishal K Rajput
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden
| | - Santanu Mandal
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden
| | - Ian Cumpstey
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden
| | - Amaia Larumbe
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden
| | - Bader A Salameh
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.,Chemistry Department, The Hashemite University, P. O. Box 150459, Zarka, 13115, Jordan
| | - Barbro Kahl-Knutsson
- Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden
| | - Hilde van Hattum
- Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB, Utrecht, Netherlands
| | - Monique van Scherpenzeel
- Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB, Utrecht, Netherlands.,Translational Metabolic Laboratory, 51 Radboud University Medical Center, P. O. Box 9101, 6500 HB, Nijmegen, Netherlands
| | - Roland J Pieters
- Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB, Utrecht, Netherlands
| | - Tariq Sethi
- Department of Respiratory Medicine and Allergy, Kings College, 41 Denmark Hill Campus, Bessemer Road, London, SE5 9RJ, UK
| | - Hans Schambye
- Galecto Biotech ApS, COBIS, Ole Maaloes vej 3, Copenhagen N, 2200, Denmark
| | - Stina Oredsson
- Department of Biology, Lund University, P. O. Box 118, 221 00, Lund, Sweden
| | - Hakon Leffler
- Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden
| | - Helen Blanchard
- Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia.
| | - Ulf J Nilsson
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.
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18
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Cagnoni AJ, Pérez Sáez JM, Rabinovich GA, Mariño KV. Turning-Off Signaling by Siglecs, Selectins, and Galectins: Chemical Inhibition of Glycan-Dependent Interactions in Cancer. Front Oncol 2016; 6:109. [PMID: 27242953 PMCID: PMC4865499 DOI: 10.3389/fonc.2016.00109] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/18/2016] [Indexed: 12/25/2022] Open
Abstract
Aberrant glycosylation, a common feature associated with malignancy, has been implicated in important events during cancer progression. Our understanding of the role of glycans in cancer has grown exponentially in the last few years, concurrent with important advances in glycomics and glycoproteomic technologies, paving the way for the validation of a number of glycan structures as potential glycobiomarkers. However, the molecular bases underlying cancer-associated glycan modifications are still far from understood. Glycans exhibit a natural heterogeneity, crucial for their diverse functional roles as specific carriers of biologically relevant information. This information is decoded by families of proteins named lectins, including sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), C-type lectin receptors (CLRs), and galectins. Siglecs are primarily expressed on the surface of immune cells and differentially control innate and adaptive immune responses. Among CLRs, selectins are a family of cell adhesion molecules that mediate interactions between cancer cells and platelets, leukocytes, and endothelial cells, thus facilitating tumor cell invasion and metastasis. Galectins, a family of soluble proteins that bind β-galactoside-containing glycans, have been implicated in diverse events associated with cancer biology such as apoptosis, homotypic cell aggregation, angiogenesis, cell migration, and tumor-immune escape. Consequently, individual members of these lectin families have become promising targets for the design of novel anticancer therapies. During the past decade, a number of inhibitors of lectin–glycan interactions have been developed including small-molecule inhibitors, multivalent saccharide ligands, and more recently peptides and peptidomimetics have offered alternatives for tackling tumor progression. In this article, we review the current status of the discovery and development of chemical lectin inhibitors and discuss novel strategies to limit cancer progression by targeting lectin–glycan interactions.
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Affiliation(s)
- Alejandro J Cagnoni
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Juan M Pérez Sáez
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) , Buenos Aires , Argentina
| | - Gabriel A Rabinovich
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Karina V Mariño
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) , Buenos Aires , Argentina
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Blanchard H, Bum-Erdene K, Bohari MH, Yu X. Galectin-1 inhibitors and their potential therapeutic applications: a patent review. Expert Opin Ther Pat 2016; 26:537-54. [PMID: 26950805 DOI: 10.1517/13543776.2016.1163338] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Galectins have affinity for β-galactosides. Human galectin-1 is ubiquitously expressed in the body and its expression level can be a marker in disease. Targeted inhibition of galectin-1 gives potential for treatment of inflammatory disorders and anti-cancer therapeutics. AREAS COVERED This review discusses progress in galectin-1 inhibitor discovery and development. Patent applications pertaining to galectin-1 inhibitors are categorised as monovalent- and multivalent-carbohydrate-based inhibitors, peptides- and peptidomimetics. Furthermore, the potential of galectin-1 protein as a therapeutic is discussed along with consideration of the unique challenges that galectin-1 presents, including its monomer-dimer equilibrium and oxidized and reduced forms, with regard to delivering an intact protein to a pathologically relevant site. EXPERT OPINION Significant evidence implicates galectin-1's involvement in cancer progression, inflammation, and host-pathogen interactions. Conserved sequence similarity of the carbohydrate-binding sites of different galectins makes design of specific antagonists (blocking agents/inhibitors of function) difficult. Key challenges pertaining to the therapeutic use of galectin-1 are its monomer-dimer equilibrium, its redox state, and delivery of intact galectin-1 to the desired site. Developing modified forms of galectin-1 has resulted in increased stability and functional potency. Gene and protein therapy approaches that deliver the protein toward the target are under exploration as is exploitation of different inhibitor scaffolds.
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Affiliation(s)
- Helen Blanchard
- a Institute for Glycomics , Griffith University , Gold Coast Campus , Queensland , Australia
| | - Khuchtumur Bum-Erdene
- a Institute for Glycomics , Griffith University , Gold Coast Campus , Queensland , Australia
| | | | - Xing Yu
- a Institute for Glycomics , Griffith University , Gold Coast Campus , Queensland , Australia
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20
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Duckworth CA, Guimond SE, Sindrewicz P, Hughes AJ, French NS, Lian LY, Yates EA, Pritchard DM, Rhodes JM, Turnbull JE, Yu LG. Chemically modified, non-anticoagulant heparin derivatives are potent galectin-3 binding inhibitors and inhibit circulating galectin-3-promoted metastasis. Oncotarget 2015; 6:23671-87. [PMID: 26160844 PMCID: PMC4695144 DOI: 10.18632/oncotarget.4409] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 06/12/2015] [Indexed: 12/26/2022] Open
Abstract
Concentrations of circulating galectin-3, a metastasis promoter, are greatly increased in cancer patients. Here we show that 2- or 6-de-O-sulfated, N-acetylated heparin derivatives are galectin-3 binding inhibitors. These chemically modified heparin derivatives inhibited galectin-3-ligand binding and abolished galectin-3-mediated cancer cell-endothelial adhesion and angiogenesis. Unlike standard heparin, these modified heparin derivatives and their ultra-low molecular weight sub-fractions had neither anticoagulant activity nor effects on E-, L- or P-selectin binding to their ligands nor detectable cytotoxicity. Intravenous injection of such heparin derivatives (with cancer cells pre-treated with galectin-3 followed by 3 subcutaneous injections of the derivatives) abolished the circulating galectin-3-mediated increase in lung metastasis of human melanoma and colon cancer cells in nude mice. Structural analysis using nuclear magnetic resonance and synchrotron radiation circular dichroism spectroscopies showed that the modified heparin derivatives bind to the galectin-3 carbohydrate-recognition domain. Thus, these chemically modified, non-anticoagulant, low-sulfated heparin derivatives are potent galectin-3 binding inhibitors with substantial potential as anti-metastasis/cancer drugs.
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Affiliation(s)
- Carrie A. Duckworth
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Scott E. Guimond
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Paulina Sindrewicz
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Ashley J. Hughes
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Diamond Light Source Ltd, Harwell Innovation Campus, Didcot, UK
| | - Neil S. French
- Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Lu-Yun Lian
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Edwin A. Yates
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - D. Mark Pritchard
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Jonathan M. Rhodes
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Jeremy E. Turnbull
- Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Lu-Gang Yu
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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21
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Ochieng J, Nangami GN, Ogunkua O, Miousse IR, Koturbash I, Odero-Marah V, McCawley L, Nangia-Makker P, Ahmed N, Luqmani Y, Chen Z, Papagerakis S, Wolf GT, Dong C, Zhou BP, Brown DG, Colacci A, Hamid RA, Mondello C, Raju J, Ryan EP, Woodrick J, Scovassi I, Singh N, Vaccari M, Roy R, Forte S, Memeo L, Salem HK, Amedei A, Al-Temaimi R, Al-Mulla F, Bisson WH, Eltom SE. The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis. Carcinogenesis 2015; 36 Suppl 1:S128-S159. [PMID: 26106135 PMCID: PMC4565611 DOI: 10.1093/carcin/bgv034] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 11/14/2014] [Accepted: 11/19/2014] [Indexed: 12/12/2022] Open
Abstract
The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis.
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Affiliation(s)
- Josiah Ochieng
- *To whom correspondence should be addressed. Tel: +1 615 327 6119; Fax: +1 615 327 6442;
| | - Gladys N. Nangami
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Olugbemiga Ogunkua
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Isabelle R. Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Valerie Odero-Marah
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Lisa McCawley
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
| | | | - Nuzhat Ahmed
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
| | - Yunus Luqmani
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - Zhenbang Chen
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Silvana Papagerakis
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
| | - Gregory T. Wolf
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
| | - Chenfang Dong
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Binhua P. Zhou
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Dustin G. Brown
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Roslida A. Hamid
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
| | - Chiara Mondello
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
| | - Jayadev Raju
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Elizabeth P. Ryan
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Jordan Woodrick
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Ivana Scovassi
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
| | - Neetu Singh
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Stefano Forte
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Lorenzo Memeo
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Hosni K. Salem
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
| | - Rabeah Al-Temaimi
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - Fahd Al-Mulla
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Sakina E. Eltom
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA
- Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia
- Faculty of Pharmacy, Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Otolaryngology, University of Michigan Medical College, Ann Arbor, MI 48109, USA
- Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Faculty of Medicine and Health Sciences, University Putra, Serdang, Selangor 43400, Malaysia
- Istituto di Genetica Molecolare, CNR, via Abbiategrasso 207, 27100 Pavia, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy and
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
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22
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Early microlesion of viral encephalitis confirmed by galectin-3 expression after a virus inoculation. Neurosci Lett 2015; 592:107-12. [DOI: 10.1016/j.neulet.2015.02.061] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 02/27/2015] [Indexed: 12/29/2022]
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Biswas S, Medina SH, Barchi JJ. Synthesis and cell-selective antitumor properties of amino acid conjugated tumor-associated carbohydrate antigen-coated gold nanoparticles. Carbohydr Res 2015; 405:93-101. [PMID: 25556664 PMCID: PMC4354769 DOI: 10.1016/j.carres.2014.11.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 11/04/2014] [Accepted: 11/05/2014] [Indexed: 11/26/2022]
Abstract
The Thomsen Friedenreich antigen (TFag) disaccharide is a tumor-associated carbohydrate antigen (TACA) found primarily on carcinoma cells and rarely expressed in normal tissue. The TFag has been shown to interact with Galectin-3 (Gal-3), one in a family of β-galactoside binding proteins. Galectins have a variety of cellular functions, and Gal-3 has been shown to be the sole galectin with anti-apoptotic activity. We have previously prepared gold nanoparticles (AuNP) coated with the TFag in various presentations as potential anti-adhesive therapeutic tools or antitumor vaccine platforms. Here we describe the synthesis of TFag-glycoamino acid conjugates attached to gold nanoparticles through a combined alkane/PEG linker, where the TFag was attached to either a serine or threonine amino acid. Particles were fully characterized by a host of biophysical techniques, and along with a control particle carrying hydroxyl-terminated linker units, were evaluated in both Gal-3 positive and negative cell lines. We show that the particles bearing the saccharides selectively inhibited tumor cell growth of the Gal-3 positive cells significantly more than the Gal-3 negative cells. In addition, the threonine-attached TF particles were more potent than the serine-attached constructs. These results support the use of AuNP as antitumor therapeutic platforms, targeted against cell lines that express specific lectins that interact with TFag.
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Affiliation(s)
- Souvik Biswas
- Chemical Biology Laboratory, The Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, United States
| | - Scott H Medina
- Chemical Biology Laboratory, The Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, United States
| | - Joseph J Barchi
- Chemical Biology Laboratory, The Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, United States.
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24
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Su J, Zhang T, Wang P, Liu F, Tai G, Zhou Y. The water network in galectin-3 ligand binding site guides inhibitor design. Acta Biochim Biophys Sin (Shanghai) 2015; 47:192-8. [PMID: 25662390 DOI: 10.1093/abbs/gmu132] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Galectin-3 (Gal-3) which shows affinity of β-galactosides is a cancer-related protein. Thus, it is important to understand its ligand binding mechanism and then design its specific inhibitor. It was suggested that the positions of water molecules in Gal-3 ligand-binding site could be replaced by appropriate chemical groups of ideal inhibitors. However, the reported structures of Gal-3 carbohydrate recognition domain (CRD) complexed with lactose showed that the number of water molecules are different and the water positions are inconsistent in the ligand-binding site. This study reported four high-resolution (1.24-1.19 Å) structures of Gal-3 CRD complexed with lactose, and accurately located 12 conserved water molecules in the water network of Gal-3 CRD ligand-binding site by merging these structures. These water molecules either directly stabilize the binding of Gal-3 CRD and lactose, or hold the former water molecules at the right place. In particular, water molecule 4 (W4) which only coordinates with water molecule 5 (W5) and water molecule 6 (W6) plays a key role in stabilizing galactose residue. In addition, by three-dimensional alignment of the positions of all residues, 14 flexible parts of Gal-3 CRD were found to dynamically fluctuate in the crystalline environment.
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Affiliation(s)
- Jiyong Su
- School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Tao Zhang
- School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Peiqi Wang
- School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Fengjian Liu
- School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Guihua Tai
- School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Yifa Zhou
- School of Life Sciences, Northeast Normal University, Changchun 130024, China
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25
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Glinskii OV, Li F, Wilson LS, Barnes S, Rittenhouse-Olson K, Barchi JJ, Pienta KJ, Glinsky VV. Endothelial integrin α3β1 stabilizes carbohydrate-mediated tumor/endothelial cell adhesion and induces macromolecular signaling complex formation at the endothelial cell membrane. Oncotarget 2015; 5:1382-9. [PMID: 24675526 PMCID: PMC4012737 DOI: 10.18632/oncotarget.1837] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Blood borne metastatic tumor cell adhesion to endothelial cells constitutes a critical rate-limiting step in hematogenous cancer metastasis. Interactions between cancer associated carbohydrate Thomsen-Friedenreich antigen (TF-Ag) and endothelium-expressed galectin-3 (Gal-3) have been identified as the leading molecular mechanism initiating tumor/endothelial cell adhesion in several types of cancer. However, it is unknown how these rather weak and transient carbohydrate/lectin mediated interactions are stabilized. Here, using Western blot and LC tandem mass spectrometry analyses of pull-downs utilizing TF-Ag loaded gold nanoparticles, we identified Gal-3, endothelial integrin α3β1, Src kinase, as well as 5 additional molecules mapping onto focal adhesion pathway as parts of the macromolecular complexes formed at the endothelial cell membranes downstream of TF-Ag/Gal-3 interactions. In a modified parallel flow chamber assay, inhibiting α3β1 integrin greatly reduced the strength of tumor/endothelial cell interactions without affecting the initial cancer cell adhesion. Further, the macromolecular complex induced by TF-Ag/Gal-3/α3β1 interactions activates Src kinase, p38, and ERK1/2, pathways in endothelial cells in a time- and α3β1-dependent manner. We conclude that, following the initial metastatic cell attachment to endothelial cells mediated by TF-Ag/Gal-3 interactions, endothelial integrin α3β1 stabilizes tumor/endothelial cell adhesion and induces the formation of macromolecular signaling complex activating several major signaling pathways in endothelial cells.
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Affiliation(s)
- Olga V Glinskii
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO
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26
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Hossein G, Keshavarz M, Ahmadi S, Naderi N. Synergistic effects of PectaSol-C modified citrus pectin an inhibitor of Galectin-3 and paclitaxel on apoptosis of human SKOV-3 ovarian cancer cells. Asian Pac J Cancer Prev 2014; 14:7561-8. [PMID: 24460334 DOI: 10.7314/apjcp.2013.14.12.7561] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Galectin-3 (Gal-3) is a carbohydrate-binding protein which is thought to be involved in cancer progression but its contribution to epithelial ovarian cancer (EOC) remains unclear. The present study sought to determine the role of Gal-3 in chemoresistance of the human SKOV-3 ovarian cancer cell line to paclitaxel (PTX) using recombinant human Gal-3 (rhGal-3) and PectaSol-C modified citrus pectin (Pect-MCP) as a specific Gal-3 competitive inhibitor. Our results showed 41% increased cell proliferation, 36% decreased caspase-3 activity and 33.6% increased substrate-dependent adhesion in the presence of rhGal-3 compared to the control case (p<0.001). Treatment of cells with a non-effective dose of PTX (100nM) and 0.1% Pect-MCP in combination revealed synergistic cytotoxic effects with 75% reduced cell viability and subsequent 3.9-fold increase in caspase-3 activity. Moreover, there was 39% decrease in substrate-dependent adhesion compared to control (p<0.001). These results suggest that inhibition of Gal-3 could be a useful therapeutic tool for combination therapy of ovarian cancer.
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Affiliation(s)
- Ghamartaj Hossein
- Department of Animal Physiology, Developmental Biology Laboratory, School of Biology, University College of Science, University of Tehran, Tehran, Iran E-mail :
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27
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Rachel H, Chang-Chun L. Recent advances toward the development of inhibitors to attenuate tumor metastasis via the interruption of lectin-ligand interactions. Adv Carbohydr Chem Biochem 2014; 69:125-207. [PMID: 24274369 DOI: 10.1016/b978-0-12-408093-5.00005-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aberrant glycosylation is a well-recognized phenomenon that occurs on the surface of tumor cells, and the overexpression of a number of ligands (such as TF, sialyl Tn, and sialyl Lewis X) has been correlated to a worse prognosis for the patient. These unique carbohydrate structures play an integral role in cell-cell communication and have also been associated with more metastatic cancer phenotypes, which can result from binding to lectins present on cell surfaces. The most well studied metastasis-associated lectins are the galectins and selectins, which have been correlated to adhesion, neoangiogenesis, and immune-cell evasion processes. In order to slow the rate of metastatic lesion formation, a number of approaches have been successfully developed which involve interfering with the tumor lectin-substrate binding event. Through the generation of inhibitors, or by attenuating lectin and/or carbohydrate expression, promising results have been observed both in vitro and in vivo. This article briefly summarizes the involvement of lectins in the metastatic process and also describes different approaches used to prevent these undesirable carbohydrate-lectin binding events, which should ultimately lead to improvement in current cancer therapies.
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Affiliation(s)
- Hevey Rachel
- Alberta Glycomics Centre, Department of Chemistry, University of Calgary, Calgary, Alberta, Canada
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28
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Compagno D, Gentilini LD, Jaworski FM, Pérez IG, Contrufo G, Laderach DJ. Glycans and galectins in prostate cancer biology, angiogenesis and metastasis. Glycobiology 2014; 24:899-906. [PMID: 24939371 DOI: 10.1093/glycob/cwu055] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide. While localized prostate cancer can be cured, advanced and metastatic prostate cancer remains a significant therapeutic challenge. Malignant transformation is associated with important modifications of the cellular glycosylation profile, and it is postulated that these changes have a considerable relevance for tumor biology. Metastasis is a multiphasic process that encompasses angiogenesis, the spread of tumor cells and their growth at distant sites from the primary tumor location. Recognition of glycoconjugates by galectins, among other lectins, plays a fundamental role in the metastatic spread, tumor immune escape and the neovascularization process. Particularly in prostate cancer, both carbohydrates and galectins have been implicated in many cellular processes such as proliferation, apoptosis, migration and invasion. However, a limited number of studies assessed their potential implications in the induction of metastasis in prostate cancer patients or in animal models. Moreover, the role of galectin-glycan interactions in vivo still remains poorly understood; concerted effort should thus be made in order to shed some light on this question. This review summarizes current evidence on both the expression and role of glycans and galectins in prostate cancer, particularly turning our attention to the angiogenic and metastatic processes.
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Affiliation(s)
- Daniel Compagno
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Lucas D Gentilini
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Felipe M Jaworski
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ignacio González Pérez
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Geraldine Contrufo
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego J Laderach
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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29
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Guha P, Bandyopadhyaya G, Polumuri SK, Chumsri S, Gade P, Kalvakolanu DV, Ahmed H. Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, α9 nicotinic acetylcholine receptor and STAT3. Breast Cancer Res Treat 2014; 145:5-22. [PMID: 24668500 DOI: 10.1007/s10549-014-2912-z] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 03/13/2014] [Indexed: 10/25/2022]
Abstract
Nicotine, a main addictive compound in tobacco smoke, has been linked to promotion and progression of lung, head and neck, pancreatic, and breast cancers, but the detailed mechanisms of cancer progression remain elusive. Here, we show that nicotine induces the expression of galectin-3 (an anti-apoptotic β-galactoside-binding lectin) in breast cancer cell line and in primary tumors from breast cancer patients. Nicotine-induced up regulation of galectin-3 is due to an increased expression of α9 isoform of nicotinic acetylcholine receptor (α9nAChR), which activates transcription factor STAT3 that in turn, physically binds to galectin-3 (LGALS3) promoter and induces transcription of galectin-3. Intracellular galectin-3 increased mitochondrial integrity and suppressed chemotherapeutic-induced apoptosis of breast cancer cell. Moreover, nicotine-induced enrichment of side population cells with cancer stem cell-like properties was modulated by galectin-3 expression and could be significantly reduced by transient knock down of LGALS3 and its upstream signaling molecules STAT3 and α9nAChR. Thus, galectin-3 or its upstream signaling molecule STAT3 or α9nAChR could be a potential target to prevent nicotine-induced chemoresistance in breast cancer.
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Affiliation(s)
- Prasun Guha
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
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30
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Blanchard H, Bum-Erdene K, Hugo MW. Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics. Aust J Chem 2014. [DOI: 10.1071/ch14362] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Galectins are a family of galactoside-specific lectins that are involved in a myriad of metabolic and disease processes. Due to roles in cancer and inflammatory and heart diseases, galectins are attractive targets for drug development. Over the last two decades, various strategies have been used to inhibit galectins, including polysaccharide-based therapeutics, multivalent display of saccharides, peptides, peptidomimetics, and saccharide-modifications. Primarily due to galectin carbohydrate binding sites having high sequence identities, the design and development of selective inhibitors targeting particular galectins, thereby addressing specific disease states, is challenging. Furthermore, the use of different inhibition assays by research groups has hindered systematic assessment of the relative selectivity and affinity of inhibitors. This review summarises the status of current inhibitors, strategies, and novel scaffolds that exploit subtle differences in galectin structures that, in conjunction with increasing available data on multiple galectins, is enabling the feasible design of effective and specific inhibitors of galectins.
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31
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Leclere L, Cutsem PV, Michiels C. Anti-cancer activities of pH- or heat-modified pectin. Front Pharmacol 2013; 4:128. [PMID: 24115933 PMCID: PMC3792700 DOI: 10.3389/fphar.2013.00128] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 09/14/2013] [Indexed: 02/01/2023] Open
Abstract
Despite enormous efforts that have been made in the search for novel drugs and treatments, cancer continues to be a major public health problem. Moreover, the emergence of resistance to cancer chemotherapy often prevents complete remission. Researchers have thus turned to natural products mainly from plant origin to circumvent resistance. Pectin and pH- or heat-modified pectin have demonstrated chemopreventive and antitumoral activities against some aggressive and recurrent cancers. The focus of this review is to describe how pectin and modified pectin display these activities and what are the possible underlying mechanisms. The failure of conventional chemotherapy to reduce mortality as well as serious side effects make natural products, such as pectin-derived products, ideal candidates for exerting synergism in combination with conventional anticancer drugs.
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Affiliation(s)
- Lionel Leclere
- Unité de Recherche en Biologie Cellulaire, Namur Research Institute for Life Sciences, University of Namur Namur, Belgium
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32
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Bum-Erdene K, Gagarinov IA, Collins PM, Winger M, Pearson AG, Wilson JC, Leffler H, Nilsson UJ, Grice ID, Blanchard H. Investigation into the Feasibility of Thioditaloside as a Novel Scaffold for Galectin-3-Specific Inhibitors. Chembiochem 2013; 14:1331-42. [DOI: 10.1002/cbic.201300245] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2013] [Indexed: 01/02/2023]
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33
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Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death. Blood 2012; 120:4635-44. [PMID: 23065155 DOI: 10.1182/blood-2012-06-438234] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and an aggressive malignancy. Galectin-3 (gal-3), the only antiapoptotic member of the galectin family, is overexpressed in DLBCL. While gal-3 can localize to intracellular sites, gal-3 is secreted by DLBCL cells and binds back to the cell surface in a carbohydrate-dependent manner. The major counterreceptor for gal-3 on DLBCL cells was identified as the transmembrane tyrosine phosphatase CD45. Removal of cell-surface gal-3 from CD45 with the polyvalent glycan inhibitor GCS-100 rendered DLBCL cells susceptible to chemotherapeutic agents. Binding of gal-3 to CD45 modulated tyrosine phosphatase activity; removal of endogenous cell-surface gal-3 from CD45 with GCS-100 increased phosphatase activity, while addition of exogenous gal-3 reduced phosphatase activity. Moreover, the increased susceptibility of DLBCL cells to chemotherapeutic agents after removal of gal-3 by GCS-100 required CD45 phosphatase activity. Gal-3 binding to a subset of highly glycosylated CD45 glycoforms was regulated by the C2GnT-1 glycosyltransferase, indicating that specific glycosylation of CD45 is important for regulation of gal-3-mediated signaling. These data identify a novel role for cell-surface gal-3 and CD45 in DLBCL survival and suggest novel therapeutic targets to sensitize DLBCL cells to death.
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Braeuer RR, Shoshan E, Kamiya T, Bar-Eli M. The sweet and bitter sides of galectins in melanoma progression. Pigment Cell Melanoma Res 2012; 25:592-601. [DOI: 10.1111/j.1755-148x.2012.01026.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Baskar AA, Al Numair KS, Alsaif MA, Ignacimuthu S. In vitro antioxidant and antiproliferative potential of medicinal plants used in traditional Indian medicine to treat cancer. Redox Rep 2012; 17:145-56. [PMID: 22776996 DOI: 10.1179/1351000212y.0000000017] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
OBJECTIVE The goal of this study was to evaluate the antioxidant and antiproliferative activities of 10 traditional medicinal plants, Asclepias curassavica, Ophiorrhiza mungos Linn., Cynodon dactylon (L.) Pers, Costus speciosus (J. Koenig.) Smith Costaceae, Achyranthes aspera L., Amaranthus tristis Roxb., Blepharis maderaspatensis L., Merremia emerginata Hall.f., Aegle marmelos Corr., and Tabernaemontana heyneana Wall., used in the traditional Indian system of medicine as a cure for cancer. The present study focuses on the anticancer potential of traditional medicinal plants to induce apoptosis in cancer cell lines. METHODS Plants were sequentially extracted with hexane, ethyl acetate, and methanol. The extract was concentrated to yield the crude extract, which was tested for antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl, nitric oxide and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays on four cancer cell lines and a normal cell line. The anticancer potential of cytotoxic extracts was determined by the Annexin-fluorescein isothiocyanate-conjugated assay in human colon adenocarcinoma cell lines (COLO 320 DM). RESULTS All the tested extracts showed significant antioxidant and antiproliferative activities in a concentration- and time-dependant manner in the following descending order: A. curassavica > C. dactylon > C. speciosus root > A. tristis > M. emarginata > O. mungos > T. Heyneana > B. maderaspatensis > A. marmelos > A. aspera. CONCLUSION The results of the present study support the need of further studies to isolate potential anticancer drug with cancer cell-specific cytotoxicity. Additionally, the study supports the anticancer property of medicinal plants used in the traditional Indian medicine system and further evaluation of the selected medicinal plants for an effective anticancer drug with minimal side effects.
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Affiliation(s)
- Arul-Albert Baskar
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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Inhibition of prostate cancer bone metastasis by synthetic TF antigen mimic/galectin-3 inhibitor lactulose-L-leucine. Neoplasia 2012; 14:65-73. [PMID: 22355275 DOI: 10.1593/neo.111544] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 12/19/2011] [Accepted: 12/19/2011] [Indexed: 11/18/2022] Open
Abstract
Currently incurable, prostate cancer metastasis has a remarkable ability to spread to the skeleton. Previous studies demonstrated that interactions mediated by the cancer-associated Thomsen-Friedenreich glycoantigen (TF-Ag) and the carbohydrate-binding protein galectin-3 play an important role in several rate-limiting steps of cancer metastasis such as metastatic cell adhesion to bone marrow endothelium, homotypic tumor cell aggregation, and clonogenic survival and growth. This study investigated the ability of a synthetic small-molecular-weight nontoxic carbohydrate-based TF-Ag mimic lactulose-L-leucine (Lac-L-Leu) to inhibit these processes in vitro and, ultimately, prostate cancer bone metastasis in vivo. Using an in vivo mouse model, based on intracardiac injection of human PC-3 prostate carcinoma cells stably expressing luciferase, we investigated the ability of Lac-L-Leu to impede the establishment and growth of bone metastasis. Parallel-flow chamber assay, homotypic aggregation assay, modified Boyden chamber assay, and clonogenic growth assay were used to assess the effects of Lac-L-Leu on tumor cell adhesion to the endothelium, homotypic tumor cell aggregation, transendothelial migration, and clonogenic survival and growth, respectively. We report that daily intraperitoneal administration of Lac-L-Leu resulted in a three-fold (P < .05) decrease in metastatic tumor burden compared with the untreated control. Mechanistically, the effect of Lac-L-Leu, which binds and inhibits galectins by mimicking essential structural features of the TF-Ag, was associated with a dose-dependent inhibition of prostate cancer cell adhesion to bone marrow endothelium, homotypic aggregation, transendothelial migration, and clonogenic growth. We conclude that small-molecular-weight carbohydrate-based compounds targeting β-galactoside-mediated interactions could provide valuable means for controlling and preventing metastatic prostate cancer spread to the skeleton.
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Gao X, Zhi Y, Zhang T, Xue H, Wang X, Foday AD, Tai G, Zhou Y. Analysis of the neutral polysaccharide fraction of MCP and its inhibitory activity on galectin-3. Glycoconj J 2012; 29:159-65. [PMID: 22562786 DOI: 10.1007/s10719-012-9382-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Revised: 04/05/2012] [Accepted: 04/17/2012] [Indexed: 12/01/2022]
Abstract
The pH-modified citrus pectin (MCP) has been demonstrated to inhibit galectin-3 in cancer progression. The components and structures of MCP related to this inhibition remained unknown. In this paper, we fractionated MCP on DEAE-cellulose column into a homogenous neutral fraction MCP-N (about 20 kDa) and a pectin mixture fraction MCP-A (wide molecular distribution on Sepharose CL-6B chromatography). Both MCP-N and MCP-A inhibited hemagglutination mediated by galectin-3 with minimum inhibition concentration (MIC) 625 and 0.5 μg/ml, respectively. MCP-N was identified to be a type I arabinogalactan (AG-I) with a main chain of β-1→4-galactan. MCP-N was digested by α-L-arabinofuranosidase to give its main chain structure fraction (M-galactan, around 18 kDa), which was more active than the original molecule, MIC 50 μg/ml. The acidic degradation of M-galactan increased the inhibitory activity, MIC about 5 times lower than M-galactan. These results above showed that the functional motif of the β-1→4-galactan fragment might lie in the terminal residues rather than in the internal region of the chain. Therefore, MCP-N and its degraded products might be developed to new potential galectin-3 inhibitors. This is the first report concerning the fractionation of MCP and its components on galectin-3 inhibition. The information provided in this paper is valuable for screening more active galectin-3 inhibitors from natural polysaccharides.
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Affiliation(s)
- Xiaoge Gao
- School of Life Sciences, Northeast Normal University, 5268 Renmin Street, Changchun, 130024, People's Republic of China
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Abalsamo L, Spadaro F, Bozzuto G, Paris L, Cecchetti S, Lugini L, Iorio E, Molinari A, Ramoni C, Podo F. Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells. Breast Cancer Res 2012; 14:R50. [PMID: 22429397 PMCID: PMC3446384 DOI: 10.1186/bcr3151] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Revised: 03/01/2012] [Accepted: 03/19/2012] [Indexed: 02/06/2023] Open
Abstract
Introduction Acquisition of mesenchymal characteristics confers to breast cancer (BC) cells the capability of invading tissues different from primary tumor site, allowing cell migration and metastasis. Regulators of the mesenchymal-epithelial transition (MET) may represent targets for anticancer agents. Accruing evidence supports functional implications of choline phospholipid metabolism in oncogene-activated cell signaling and differentiation. We investigated the effects of D609, a xanthate inhibiting phosphatidylcholine-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS), as a candidate regulator of cell differentiation and MET in the highly metastatic BC cell line MDA-MB-231. Methods PC-PLC expression and activity were investigated using confocal laser scanning microscopy (CLSM), immunoblotting and enzymatic assay on human MDA-MB-231 compared with MCF-7 and SKBr3 BC cells and a nontumoral immortalized counterpart (MCF-10A). The effects of D609 on PC-PLC and SMS activity, loss of mesenchymal markers and changes in migration and invasion potential were monitored in MDA-MB-231 cells by enzymatic assays, CLSM, immunoblotting and transwell chamber invasion combined with scanning electron microscopy examinations. Cell proliferation, formation and composition of lipid bodies and cell morphology were investigated in D609-treated BC cells by cell count, CLSM, flow-cytometry of BODIPY-stained cells, nuclear magnetic resonance and thin-layer chromatography. Results PC-PLC (but not phospholipase D) showed 2- to 6-fold activation in BC compared with nontumoral cells, the highest activity (up to 0.4 pmol/μg protein/min) being detected in the poorly-differentiated MDA-MB-231 cells. Exposure of the latter cells to D609 (50 μg/mL, 24-72 h) resulted into 60-80% PC-PLC inhibition, while SMS was transiently inhibited by a maximum of 21%. These features were associated with progressive decreases of mesenchymal traits such as vimentin and N-cadherin expression, reduced galectin-3 and milk fat globule EGF-factor 8 levels, β-casein formation and decreased in vitro cell migration and invasion. Moreover, proliferation arrest, changes in cell morphology and formation of cytosolic lipid bodies typical of cell differentiation were induced by D609 in all investigated BC cells. Conclusions These results support a critical involvement of PC-PLC in controlling molecular pathways responsible for maintaining a mesenchymal-like phenotype in metastatic BC cells and suggests PC-PLC deactivation as a means to promote BC cell differentiation and possibly enhance the effectiveness of antitumor treatments.
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Affiliation(s)
- Laura Abalsamo
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Roma, 00161, Italy
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The interconnectedness of cancer cell signaling. Neoplasia 2012; 13:1183-93. [PMID: 22241964 DOI: 10.1593/neo.111746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Revised: 12/14/2011] [Accepted: 12/14/2011] [Indexed: 11/18/2022] Open
Abstract
The elegance of fundamental and applied research activities have begun to reveal a myriad of spatial and temporal alterations in downstream signaling networks affected by cell surface receptor stimulation including G protein-coupled receptors and receptor tyrosine kinases. Interconnected biochemical pathways serve to integrate and distribute the signaling information throughout the cell by orchestration of complex biochemical circuits consisting of protein interactions and covalent modification processes. It is clear that scientific literature summarizing results from both fundamental and applied scientific research activities has served to provide a broad foundational biologic database that has been instrumental in advancing our continued understanding of underlying cancer biology. This article reflects on historical advances and the role of innovation in the competitive world of grant-sponsored research.
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Mayo KH. From Carbohydrate to Peptidomimetic Inhibitors of Galectins. ACS SYMPOSIUM SERIES 2012. [DOI: 10.1021/bk-2012-1115.ch003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Affiliation(s)
- Kevin H. Mayo
- Department of Biochemistry, Molecular Biology & Biophysics, 6-155 Jackson Hall, University of Minnesota, 321 Church Street, Minneapolis, Minnesota 55455
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Darrow AL, Shohet RV, Maresh JG. Transcriptional analysis of the endothelial response to diabetes reveals a role for galectin-3. Physiol Genomics 2011; 43:1144-52. [PMID: 21791638 PMCID: PMC3217326 DOI: 10.1152/physiolgenomics.00035.2011] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 07/25/2011] [Indexed: 02/07/2023] Open
Abstract
To characterize the endothelial dysfunction associated with Type II diabetes, we surveyed transcriptional responses in the vascular endothelia of mice receiving a diabetogenic, high-fat diet. Tie2-GFP mice were fed a diet containing 60% fat calories (HFD); controls were littermates fed normal chow. Following 4, 6, and 8 wk, aortic and leg muscle tissues were enzymatically dispersed, and endothelial cells were obtained by fluorescence-activated cell sorting. Relative mRNA abundance in HFD vs. control endothelia was measured with long-oligo microarrays; highly dysregulated genes were confirmed by real-time PCR and protein quantification. HFD mice were hyperglycemic by 2 wk and displayed vascular insulin resistance and decreased glucose tolerance by 5 and 6 wk, respectively. Endothelial transcripts upregulated by HFD included galectin-3 (Lgals3), 5-lipoxygenase-activating protein, and chemokine ligands 8 and 9. Increased LGALS3 protein was detected in muscle endothelium by immunohistology accompanied by elevated LGALS3 in the serum of HFD mice. Our comprehensive analysis of the endothelial transcriptional response in a model of Type II diabetes reveals novel regulation of transcripts with roles in inflammation, insulin sensitivity, oxidative stress, and atherosclerosis. Increased endothelial expression and elevated humoral levels of LGALS3 supports a role for this molecule in the vascular response to diabetes, and its potential as a direct biomarker for the inflammatory state in diabetes.
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Affiliation(s)
- April L Darrow
- Center for Cardiovascular Research, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii 96813, USA
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Idikio HA. Galectin-3 and Beclin1/Atg6 genes in human cancers: using cDNA tissue panel, qRT-PCR, and logistic regression model to identify cancer cell biomarkers. PLoS One 2011; 6:e26150. [PMID: 22039439 PMCID: PMC3198435 DOI: 10.1371/journal.pone.0026150] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Accepted: 09/20/2011] [Indexed: 01/31/2023] Open
Abstract
Background Cancer biomarkers are sought to support cancer diagnosis, predict cancer patient response to treatment and survival. Identifying reliable biomarkers for predicting cancer treatment response needs understanding of all aspects of cancer cell death and survival. Galectin-3 and Beclin1 are involved in two coordinated pathways of programmed cell death, apoptosis and autophagy and are linked to necroptosis/necrosis. The aim of the study was to quantify galectin-3 and Beclin1 mRNA in human cancer tissue cDNA panels and determine their utility as biomarkers of cancer cell survival. Methods and Results A panel of 96 cDNAs from eight (8) different normal and cancer tissue types were used for quantitative real-time polymerase chain reaction (qRT-PCR) using ABI7900HT. Miner2.0, a web-based 4- and 3- parameter logistic regression software was used to derive individual well polymerase chain reaction efficiencies (E) and cycle threshold (Ct) values. Miner software derived formula was used to calculate mRNA levels and then fold changes. The ratios of cancer to normal tissue levels of galectin-3 and Beclin1 were calculated (using the mean for each tissue type). Relative mRNA expressions for galectin-3 were higher than for Beclin1 in all tissue (normal and cancer) types. In cancer tissues, breast, kidney, thyroid and prostate had the highest galectin-3 mRNA levels compared to normal tissues. High levels of Beclin1 mRNA levels were in liver and prostate cancers when compared to normal tissues. Breast, kidney and thyroid cancers had high galectin-3 levels and low Beclin1 levels. Conclusion Galectin-3 expression patterns in normal and cancer tissues support its reported roles in human cancer. Beclin1 expression pattern supports its roles in cancer cell survival and in treatment response. qRT-PCR analysis method used may enable high throughput studies to generate molecular biomarker sets for diagnosis and predicting cancer treatment response.
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Affiliation(s)
- Halliday A Idikio
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
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Wang O, Liu S, Zou J, Lu L, Chen L, Qiu S, Li H, Lu X. Anticancer activity of 2α, 3α, 19β, 23β-Tetrahydroxyurs-12-en-28-oic acid (THA), a novel triterpenoid isolated from Sinojackia sarcocarpa. PLoS One 2011; 6:e21130. [PMID: 21695177 PMCID: PMC3112233 DOI: 10.1371/journal.pone.0021130] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Accepted: 05/20/2011] [Indexed: 01/28/2023] Open
Abstract
Background Natural products represent an important source for agents of cancer prevention and cancer treatment. More than 60% of conventional anticancer drugs are derived from natural sources, particularly from plant-derived materials. In this study, 2α, 3α, 19β, 23β-tetrahydroxyurs-12-en-28-oic acid (THA), a novel triterpenoid from the leaves of Sinojackia sarcocarpa, was isolated, and its anticancer activity was investigated both in vitro and in vivo. Principal Findings THA possessed potent tumor selected toxicity in vitro. It exhibited significantly higher cytotoxicity to the cancer cell lines A2780 and HepG2 than to IOSE144 and QSG7701, two noncancerous cell lines derived from ovary epithelium and liver, respectively. Moreover, THA showed a dose-dependent inhibitory effect on A2780 ovary tumor growth in vivo in nude mice. THA induced a dose-dependent apoptosis and G2/M cell cycle arrest in A2780 and HepG2 cells. The THA-induced cell cycle arrest was accompanied by a downregulation of Cdc2. The apoptosis induced by THA was evident by induction of DNA fragmentation, release of cytoplasmic Cytochrome c from mitochondria, activation of caspases, downregulation of Bcl-2 and upregulation of Bax. Conclusion The primary data indicated that THA exhibit a high toxicity toward two cancer cells than their respective non-cancerous counterparts and has a significant anticancer activity both in vitro and in vivo. Thus, THA and/or its derivatives may have great potential in the prevention and treatment of human ovary tumors and other malignancies.
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Affiliation(s)
- Ouchen Wang
- Institute of Genomic Medicine, Wenzhou Medical College, Wenzhou, China
- First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
| | - Sujun Liu
- Leshan Normal University, Leshan, China
| | - Jiawei Zou
- Institute of Genomic Medicine, Wenzhou Medical College, Wenzhou, China
| | - Liting Lu
- Institute of Genomic Medicine, Wenzhou Medical College, Wenzhou, China
| | - Lin Chen
- Institute of Genomic Medicine, Wenzhou Medical College, Wenzhou, China
| | - Sunquan Qiu
- Institute of Genomic Medicine, Wenzhou Medical College, Wenzhou, China
| | - He Li
- First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
| | - Xincheng Lu
- Institute of Genomic Medicine, Wenzhou Medical College, Wenzhou, China
- * E-mail:
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Dinosaurs and ancient civilizations: reflections on the treatment of cancer. Neoplasia 2011; 12:957-68. [PMID: 21170260 DOI: 10.1593/neo.101588] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Revised: 11/15/2010] [Accepted: 11/15/2010] [Indexed: 12/14/2022] Open
Abstract
Research efforts in the area of palaeopathology have been seen as an avenue to improve our understanding of the pathogenesis of cancer. Answers to questions of whether dinosaurs had cancer, or if cancer plagued ancient civilizations, have captured the imagination as well as the popular media. Evidence for dinosaurian cancer may indicate that cancer may have been with us from the dawn of time. Ancient recorded history suggests that past civilizations attempted to fight cancer with a variety of interventions. When contemplating the issue why a generalized cure for cancer has not been found, it might prove useful to reflect on the relatively limited time that this issue has been an agenda item of governmental attention as well as continued introduction of an every evolving myriad of manmade carcinogens relative to the total time cancer has been present on planet Earth. This article reflects on the history of cancer and the progress made following the initiation of the "era of cancer chemotherapy."
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Kim MK, Sung CO, Do IG, Jeon HK, Song TJ, Park HS, Lee YY, Kim BG, Lee JW, Bae DS. Overexpression of Galectin-3 and its clinical significance in ovarian carcinoma. Int J Clin Oncol 2011; 16:352-8. [PMID: 21327452 DOI: 10.1007/s10147-011-0190-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2010] [Accepted: 01/13/2011] [Indexed: 12/20/2022]
Abstract
BACKGROUND Galectin-3 (Gal-3) is a β-galactoside-binding lectin involved in regulating cell growth, angiogenesis, and tumor progression. We investigated the clinical significance of Gal-3 expression including its possible use as a prognostic marker or therapeutic target in epithelial ovarian carcinoma (EOC). METHODS Gal-3 expression was evaluated by immunohistochemistry in 71 patients with 54 serous, 13 endometrioid, and 4 mucinous ovarian carcinomas. We assessed the correlation of Gal-3 expression with clinical characteristics including histology, optimal debulking, chemosensitivity, and survival. In vitro, Gal-3 was inhibited using siRNA to evaluate its role in cell growth and sensitivity to chemotherapeutic agents in ovarian carcinoma cell lines. RESULTS Gal-3 protein, which was mainly cytoplasmic in location, was observed in a majority (63/71, 88.7%) of the EOCs but not in normal ovarian tissues (P < 0.001). High Gal-3 expression in EOCs correlated with shorter progression-free survival (PFS) of patients (P = 0.039; 43.1 and 49.5 months, respectively). Moreover, cotreatment with Gal-3 siRNA and paclitaxel showed an enhanced cytotoxic effect compared with control siRNA in SKOV3 cells. CONCLUSION These findings suggest that Gal-3 expression can be a prognostic factor for PFS and may be involved in regulating the response to paclitaxel-based chemotherapy in the treatment of EOC.
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Affiliation(s)
- Min Kyu Kim
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, Korea
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Demotte N, Wieërs G, Van Der Smissen P, Moser M, Schmidt C, Thielemans K, Squifflet JL, Weynand B, Carrasco J, Lurquin C, Courtoy PJ, van der Bruggen P. A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Res 2010; 70:7476-88. [PMID: 20719885 DOI: 10.1158/0008-5472.can-10-0761] [Citation(s) in RCA: 126] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Human CD8(+) tumor-infiltrating T lymphocytes (TIL), in contrast with CD8(+) blood cells, show impaired IFN-γ secretion on ex vivo restimulation. We have attributed the impaired IFN-γ secretion to a decreased mobility of T-cell receptors on trapping in a lattice of glycoproteins clustered by extracellular galectin-3. Indeed, we have previously shown that treatment with N-acetyllactosamine, a galectin ligand, restored this secretion. We strengthened this hypothesis here by showing that CD8(+) TIL treated with an anti-galectin-3 antibody had an increased IFN-γ secretion. Moreover, we found that GCS-100, a polysaccharide in clinical development, detached galectin-3 from TIL and boosted cytotoxicity and secretion of different cytokines. Importantly, we observed that not only CD8(+) TIL but also CD4(+) TIL treated with GCS-100 secreted more IFN-γ on ex vivo restimulation. In tumor-bearing mice vaccinated with a tumor antigen, injections of GCS-100 led to tumor rejection in half of the mice, whereas all control mice died. In nonvaccinated mice, GCS-100 had no effect by itself. These results suggest that a combination of galectin-3 ligands and therapeutic vaccination may induce more tumor regressions in cancer patients than vaccination alone.
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Affiliation(s)
- Nathalie Demotte
- Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels, Belgium
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The War on Cancer rages on. Neoplasia 2010; 11:1252-63. [PMID: 20019833 DOI: 10.1593/neo.91866] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2009] [Revised: 11/03/2009] [Accepted: 11/03/2009] [Indexed: 02/08/2023] Open
Abstract
In 1971, the "War on Cancer" was launched by the US government to cure cancer by the 200-year anniversary of the founding of the United States of America, 1976. This article briefly looks back at the progress that has been made in cancer research and compares progress made in other areas of human affliction. While progress has indeed been made, the battle continues to rage on.
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Diaz JA, Ramacciotti E, Wakefield TW. Do galectins play a role in venous thrombosis? a review. Thromb Res 2009; 125:373-6. [PMID: 19959209 DOI: 10.1016/j.thromres.2009.11.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2009] [Revised: 11/04/2009] [Accepted: 11/07/2009] [Indexed: 01/13/2023]
Abstract
Galectins are a family of carbohydrate-binding proteins that have a high affinity to galactosides on cell surfaces and extra cellular glycoproteins. They are involved in a variety of biological functions, including modulation of cell apoptosis, cell activation and inflammation. Our laboratory has recently identified galectin-3 binding protein (Gal-3BP) as being up-regulated in a microparticle proteomics analysis for deep venous thrombosis (DVT) patients compared to negative controls. P-selectin, another glycoprotein involved in thrombus propagation, has proven a promising target for DVT management and has been widely studied by our group. Galectins are involved in P-selectin expression and can potentially be implicated in the venous thrombogenesis process. The function of galectins, their role in inflammation and thrombosis as well as their potential implications as a new pharmacological target for DVT management are reviewed in this manuscript.
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Affiliation(s)
- Jose A Diaz
- Department of Surgery, University of Michigan, Jobst Vascular Research Laboratories, Section of Vascular Surgery, Cardiovascular Center, Ann Arbor, MI, USA.
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