chondroitin-sulfates and Neoplasms

Fucosylated chondroitin sulfates (FCS) are a sulfated polysaccharide exclusively existing in the body wall of sea cucumber. FCS possesses a mammalian chondroitin sulfate like backbone, namely repeating disaccharides units composed of GlcA and GalNAc, with fucosyl branches linked to GlcA and/or GalNAc residues. It is found that FCS can prevent unhealthy dietary pattern-induced metabolic syndromes, including insulin resistance and β-cell function improvement, anti-inflammation, anti-hyperlipidemia, and anti-adipogenesis. Further studies show that those activities of FCS might be achieved through positively modulating gut microbiota composition. Besides, FCS also show therapeutic efficacy in cancer, HIV infection, and side effects of cyclophosphamide. Furthermore, bioactivities of FCS are closely affected by their molecular weights, sulfation pattern of the fucosyl branches, and chain conformations. This review summarizes the recent 20 years studies to provide references for the future studies and applications of FCS in functional foods or drugs.

Topics: Animals; Chondroitin Sulfates; Disaccharides; Gastrointestinal Microbiome; HIV Infections; Humans; Immunomodulation; Metabolic Syndrome; Mice; Molecular Weight; Neoplasms; Polysaccharides; Sea Cucumbers; Structure-Activity Relationship; Sulfates; Virus Diseases

The polysaccharide-based biomaterials hyaluronic acid (HA) and chondroitin sulfate (CS) have aroused great interest for use in drug delivery systems for tumor therapy, as they have outstanding biocompatibility and great targeting ability for cluster determinant 44 (CD44). In addition, modified HA and CS can self-assemble into micelles or micellar nanoparticles (NPs) for targeted drug delivery. This review discusses the formation of HA- and CS-based NPs, and various types of CS-based NPs including CS-drug conjugates, CS-polymer NPs, CS-small molecule NPs, polyelectrolyte nanocomplexes (PECs), CS-metal NPs, and nanogels. We then focus on the applications of HA- and CS-based NPs in tumor chemotherapy, gene therapy, photothermal therapy (PTT), photodynamic therapy (PDT), sonodynamic therapy (SDT), and immunotherapy. Finally, this review is expected to provide guidelines for the development of various HA- and CS-based NPs used in multiple cancer therapies.

Topics: Animals; Chondroitin Sulfates; Clinical Trials as Topic; Doxorubicin; Drug Delivery Systems; Glycosaminoglycans; Humans; Hyaluronan Receptors; Hyaluronic Acid; Molecular Targeted Therapy; Nanoparticles; Neoplasms; Topoisomerase II Inhibitors

The standard chemotherapy is facing the challenges of lack of cancer selectivity and development of drug resistance. Currently, with the application of nanotechnology, the rationally designed nanocarriers of chondroitin sulfate (CS) have been fabricated and their unique features of low toxicity, biocompatibility, and active and passive targeting made them drug delivery vehicles of the choice for cancer therapy. The hydrophilic and anionic CS could be incorporated as a building block into- or decorated on the surface of nanoformulations. Micellar nanoparticles (NPs) self-assembled from amphiphilic CS-drug conjugates and CS-polymer conjugates, polyelectrolyte complexes (PECs) and nanogels of CS have been widely implicated in cancer directed therapy. The surface modulation of organic, inorganic, lipid and metallic NPs with CS promotes the receptor-mediated internalization of NPs to the tumor cells. The potential contribution of CS and CS-proteoglycans (CSPGs) in the pathogenesis of various cancer types, and CS nanocarriers in immunotherapy, radiotherapy, sonodynamic therapy (SDT) and photodynamic therapy (PDT) of cancer are summarized in this review paper.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chondroitin Sulfates; Drug Carriers; Humans; Nanoparticles; Neoplasms; Theranostic Nanomedicine

Solid tumors remain a major challenge for targeted therapeutic intervention strategies such as antibody-drug conjugates and immunotherapy. At a minimum, clear and actionable solid tumor targets have to comply with the key biological requirement of being differentially over-expressed in solid tumors and metastasis, in contrast to healthy organs. Oncofetal chondroitin sulfate is a cancer-specific secondary glycosaminoglycan modification to proteoglycans expressed in a variety of solid tumors and metastasis. Normally, this modification is found to be exclusively expressed in the placenta, where it is thought to facilitate normal placental implantation during pregnancy. Informed by this biology, oncofetal chondroitin sulfate is currently under investigation as a broad and specific target in solid tumors. Here, we discuss oncofetal chondroitin sulfate as a potential therapeutic target in childhood solid tumors in the context of current knowhow obtained over the past five years in adult cancers.

Topics: Adult; Child; Chondroitin Sulfates; Female; Fetus; Humans; Molecular Targeted Therapy; Neoplasms; Placenta; Pregnancy

Malaria research has led to the discovery of oncofetal chondroitin sulfate, which appears to be shared between placental trophoblasts and cancer cells and can be detected by the evolutionary refined malaria protein VAR2CSA. Interestingly, using recombinant VAR2CSA to target oncofetal chondroitin sulfate shows promise for novel cancer diagnostics and therapeutics.

Topics: Antigens, Neoplasm; Antigens, Protozoan; Chondroitin Sulfates; Neoplasms; Plasmodium; Recombinant Proteins

The remarkable structural heterogeneity of chondroitin sulfate (CS) and dermatan sulfate (DS) generates biological information that can be unique to each of these glycosaminoglycans (GAGs), and changes in their composition are translated into alterations in the binding profiles of these molecules. CS/DS can bind to various cytokines and growth factors, cell surface receptors, adhesion molecules, enzymes and fibrillar glycoproteins of the extracellular matrix, thereby influencing both cell behavior and the biomechanical and biochemical properties of the matrix. In this review, we summarize the current knowledge concerning CS/DS metabolism in the human cancer stroma. The remodeling of the GAG profile in the tumor niche is manifested as a substantial increase in the CS content and a gradual decrease in the proportion between DS and CS. Furthermore, the composition of CS and DS is also affected, which results in a substantial increase in the 6-O-sulfated and/or unsulfated disaccharide content, which is concomitant with a decrease in the 4-O-sulfation level. Here, we discuss the possible impact of alterations in the CS/DS sulfation pattern on the binding capacity and specificity of these GAGs. Moreover, we propose potential consequences of the stromal accumulation of chondroitin-6-sulfate for the progression and metastasis of cancer.

Topics: Animals; Chondroitin Sulfates; Dermatan Sulfate; Humans; Inflammation; Neoplasms; Stromal Cells; Tumor Microenvironment

Aberrant cell signaling in response to secreted growth factors has been linked to the development of multiple diseases, including cancer. As such, understanding mechanisms that control growth factor availability and receptor-growth factor interaction is vital. Dually modified transmembrane proteoglycans (DMTPs), which are classified as cell surface macromolecules composed of a core protein decorated with covalently linked heparan sulfated (HS) and/or chondroitin sulfated (CS) glycosaminoglycan (GAG) chains, provide one type of regulatory mechanism. Specifically, DMTPs betaglycan and syndecan-1 (SDC1) play crucial roles in modulating key cell signaling pathways, such as Wnt, transforming growth factor-β and fibroblast growth factor signaling, to affect epithelial cell biology and cancer progression. This review outlines current and potential functions for betaglycan and SDC1, with an emphasis on comparing individual roles for HS and CS modified DMTPs. We highlight the mutual dependence of DMTPs' GAG chains and core proteins and provide comprehensive knowledge on how these DMTPs, through regulation of ligand availability and receptor internalization, control cell signaling pathways involved in development and disease.

Topics: Animals; Chondroitin Sulfates; Epithelial Cells; Glycosaminoglycans; Heparitin Sulfate; Humans; Intercellular Signaling Peptides and Proteins; Mice; Neoplasms; Proteoglycans; Receptors, Transforming Growth Factor beta; Signal Transduction; Syndecan-1; Transforming Growth Factor beta; Wnt Proteins

Finding adequate carriers for protein and peptide delivery has become an urgent need, owing to the growing number of macromolecules identified as having therapeutic potential. Nanoparticles have emerged in the field as very promising vehicles and much work has been directed to testing the capacity of different materials to compose the matrix of these carriers. Natural materials and, specifically, polysaccharides have been taking the forefront of the challenge, because of several favoring properties that include the higher propensity to exhibit biodegradability and biocompatibility, and also the high structural flexibility. The majority of works found in the literature regarding polysaccharide nanoparticles uses very popular materials like chitosan or hyaluronic acid. This review is aimed at describing and exploring the potential of polysaccharides that are not so well known or that are less explored. For those, the main properties will be described, together with an overview of the reported applications as nanoparticle matrix materials.

Topics: Antineoplastic Agents; Caco-2 Cells; Chondroitin Sulfates; Drug Delivery Systems; Glucans; Humans; Hydrophobic and Hydrophilic Interactions; Insulin; Molecular Targeted Therapy; Nanoparticles; Neoplasms; Serum Albumin; Starch; Static Electricity

Recent functional studies on chondroitin sulfate-dermatan sulfate (CS-DS) demonstrated its indispensable roles in various biological events including brain development and cancer. CS-DS proteoglycans exert their physiological activity through interactions with specific proteins including growth factors, cell surface receptors, and matrix proteins. The characterization of these interactions is essential for regulating the biological functions of CS-DS proteoglycans. Although amino acid sequences on the bioactive proteins required for these interactions have already been elucidated, the specific saccharide sequences involved in the binding of CS-DS to target proteins have not yet been sufficiently identified. In this review, recent findings are described on the interaction between CS-DS and some proteins which are especially involved in the central nervous system and cancer development/metastasis.

Topics: Animals; Chondroitin Sulfates; Dermatan Sulfate; Extracellular Matrix Proteins; Humans; Intercellular Signaling Peptides and Proteins; Neoplasm Metastasis; Neoplasms; Neuronal Plasticity; Neurons; Protein Binding; Receptor for Advanced Glycation End Products; Receptors, Cell Surface; Wnt Signaling Pathway

Glycosylation is a multi-step post-translational enzymatic process which enhances the functional diversity of secreted or membrane proteins and is implicated in physiological and pathological conditions. Chondroitin sulfate (CS) chains are glycosaminoglycan chains, consisting of disaccharide units of glucuronic acid and N-acetylgalactosamine, attached to proteins as part of proteoglycans.. The existing knowledge on glycosylation by CS (CS glycanation) of cell membrane proteins and receptors, such as syndecans, chondroitin sulfate proteoglycan 4, betaglycan, neuropilin-1, integrins and receptor protein tyrosine phosphatase β/ζ, is summarized and the importance of CS glycanation in growth factor-induced migration, angiogenesis and tumor growth and invasion is described.. Identification of glycosylation so far used to be a means of further characterizing and categorizing proteins and receptors. Although there is a significant amount of information regarding the interaction of growth factors with CS chains, very little information exists on the core proteins involved. It is now evident that there is more than meets the eye regarding the addition of glycans.. Future effort should focus on characterizing CS glycanation of membrane proteins and receptors of interest in an attempt to elucidate its contribution in fine-tuning growth factor-induced signaling. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Topics: Animals; Blood Vessels; Cell Membrane; Cell Movement; Chondroitin Sulfates; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms

Glycosaminoglycans are natural heteropolysaccharides that are present in every mammalian tissue. They are composed of repeating disaccharide units that consist of either sulfated or non-sulfated monosaccharides. Their molecular size and the sulfation type vary depending on the tissue, and their state either as part of proteoglycan or as free chains. In this regard, glycosaminoglycans play important roles in physiological and pathological conditions. During recent years, cell biology studies have revealed that glycosaminoglycans are among the key macromolecules that affect cell properties and functions, acting directly on cell receptors or via interactions with growth factors. The accumulated knowledge regarding the altered structure of glycosaminoglycans in several diseases indicates their importance as biomarkers for disease diagnosis and progression, as well as pharmacological targets. This review summarizes how the fine structural characteristics of glycosaminoglycans, and enzymes involved in their biosynthesis and degradation, are involved in cell signaling, cell function and cancer progression. Prospects for glycosaminoglycan-based therapeutic targeting in cancer are also discussed.

Topics: Chondroitin Sulfates; Disease Progression; Glycosaminoglycans; Humans; Hyaluronic Acid; Intercellular Signaling Peptides and Proteins; Neoplasms; Signal Transduction

Chondroitin sulfate (CS) dermatan sulfate (DS), and CS/DS hybrid chains are biologically active like heparan sulfate, and structurally the most complex species of the glycosaminoglycan family along with heparan sulfate. They exist at the cell surface and extracellular matrix in the form of proteoglycans. They function as regulators of functional proteins such as growth factors, cytokines, chemokines, adhesion molecules, and lipoproteins through interactions with the ligands of these proteins via specific saccharide domains. Structural alterations have been often implicated in pathological conditions, such as cancer and atherosclerosis. Recent microsequencing of CS/DS oligosaccharides that bind growth factors, such as pleiotrophin, and various monoclonal antibodies against CS/DS, have revealed a considerable number of unique oligosaccharide sequences. This review focuses on recent advances in the study of the structure-function relation of CS, DS and their hybrid chains in physiological and pathological conditions.

Topics: Animals; Antibodies, Monoclonal; Carbohydrate Sequence; Chondroitin Sulfates; Dermatan Sulfate; Epitopes; Humans; Joint Diseases; Molecular Sequence Data; Neoplasms; Neurons; Oligosaccharides; Signal Transduction

Glycosaminoglycans (GAGs) are complex polysaccharides, which play important roles in cell growth, differentiation, morphogenesis, cell migration, and bacterial/viral infections. Major GAGs include heparin (Hep)/heparan sulfate, and chondroitin sulfate (CS)/dermatan sulfate (DS). Hep has been used for the treatment of thromboembolic disorders for more than 75 years, and has an established position in therapy today. CS/DS has attracted less attention and its clinical use is limited. However, CS/DS also have intriguing biological activities, which in turn should help in the development of CS/DS-based therapeutics. In this review, the following potential applications of CS/DS chains are discussed. (1) Sugar drugs for parasitic and viral infections. Particular CS variants appear to be involved in infections of various microbes, suggesting that CS/DS oligosaccharide sequences specifically interacting with microbes will lead to the development of inhibitory drugs for these infections. (2) Regenerative medicine. Biological activities of CS/DS chains possibly involve various growth factors, also known as Hep-binding growth factors. Specific CS/DS chains recruit growth/neurotrophic factors and/or potentiate their activities, suggesting that minute amounts of functional CS/DS chains can be utilized for tissue regeneration instead of signaling proteins. (3) Anti-tumor drugs. Specific saccharide structures in CS/DS chains appear to be involved in tumor cell proliferation and metastasis. The detection and identification of such CS/DS saccharide sequences would be an important contribution to cancer therapy.

Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Chondroitin Sulfates; Dermatan Sulfate; Drug Discovery; Glycosaminoglycans; Humans; Infections; Liver Regeneration; Neoplasms; Neurodegenerative Diseases; Osteoarthritis

Topics: Amino Acid Sequence; Animals; Chondroitin Sulfates; Cytokines; Heparitin Sulfate; Humans; Inflammation; Midkine; Molecular Sequence Data; Neoplasms; Nerve Growth Factor; Protein Binding; Protein Conformation; Protein Structure, Tertiary

Topics: Animals; Blood Coagulation; Cartilage; Chondroitin Lyases; Chondroitin Sulfates; Dermatan Sulfate; Humans; Neoplasms; Osteoarthritis; Polysaccharides; Signal Transduction

Topics: Animals; Antineoplastic Agents; Aorta; Atherosclerosis; Biomechanical Phenomena; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Cytokines; Disease Progression; Epidermal Growth Factor; Extracellular Matrix; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Lipoproteins, LDL; Neoplasms; Signal Transduction; Versicans

CD44 is a major cell surface receptor for the glycosaminoglycan, hyaluronan (HA). CD44 binds HA specifically, although certain chondroitin-sulfate containing proteoglycans may also be recognized. CD44 binding of HA is regulated by the cells in which it is expressed. Thus, CD44 expression alone does not correlate with HA binding activity. CD44 is subject to a wide array of post-translational carbohydrate modifications, including N-linked, O-linked and glycosaminoglycan side chain additions. These modifications, which differ in different cell types and cell activation states, can have profound effects on HA binding function and are the main mechanism of regulating CD44 function that has been described to date. Some glycosaminoglycan modifications also affect ligand binding specificity, allowing CD44 to interact with proteins of the extracellular matrix, such as fibronectin and collagen, and to sequester heparin binding growth factors. It is not yet established whether the HA binding function of CD44 is responsible for its proposed involvement in inflammation. It has been shown, however, that CD44/HA interactions can mediate leukocyte rolling on endothelial and tissue substrates and that CD44-mediated recognition of HA can contribute to leukocyte activation. Changes in CD44 expression (mainly up-regulation, occasionally down-regulation, and frequently alteration in the pattern of isoforms expressed) are associated with a wide variety of cancers and the degree to which they spread; however, in other cancers, the CD44 pattern remains unchanged. Increased expression of CD44 is associated with increased binding to HA and increased metastatic potential in some experimental tumor systems; however, in other systems increased HA binding and metastatic potential are not correlated. CD44 may contribute to malignancy through changes in the regulation of HA recognition, the recognition of new ligands and/or other new biological functions of CD44 that remain to be discovered.

Topics: Animals; Antigens, CD; Chondroitin Sulfates; Genetic Variation; Humans; Hyaluronan Receptors; Hyaluronic Acid; Inflammation; Neoplasm Metastasis; Neoplasms; Proteoglycans

In this review, evidence that proteoglycans are involved in cell adhesion and related behavior is considered, together with their putative role(s) during tumorigenesis. Proteoglycans are large, carboxylated and/or sulfated structures that interact with specific binding sites on cell surfaces. Their distribution and synthesis in tissues alter with the onset of tumorigenesis so that hyaluronic acid is generally increased and heparan sulfate decreased in the developing tumor and surrounding tissue. However, the precise role of proteoglycans during the tumorigenic process is far from clarified. Data suggest any putative roles will be related to the adhesive properties that these molecules confer to cells. Hyaluronic acid and chondroitin sulfate appear to be weakly adhesive molecules that may promote 'transformed' characteristics when they occur on cells in large amounts. These characteristics include reduced cell spreading, increased cell motility, as well as reduced contact inhibition. Consistent with such properties, neither hyaluronic acid nor chondroitin sulfate are localized in specialized adhesion sites such as focal or close contacts. In contrast, heparan sulfate is associated with increased cell-substratum adhesion and is involved in the spreading of cells onto fibronectin and other substrata. Its presence is generally associated with reduced motility and with a well-spread morphology. Unlike hyaluronate and chondroitin sulfate, heparan sulfate is found in specialized contacts. These adhesive properties of proteoglycans predict an instructive role in tumor development, and recent experiments have defined an involvement of these molecules in metastatic arrest. Additional studies utilizing invasive and metastatic tumor variants including tumor cells that employ different mechanisms to invade are required to clarify the role of proteoglycans in tumor progression.

Topics: Animals; Carrier Proteins; Cell Adhesion; Cell Movement; Chemical Phenomena; Chemistry; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Hyaluronan Receptors; Hyaluronic Acid; Neoplasms; Proteoglycans; Receptors, Cell Surface

Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism.. Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial.. One university and 2 regional teaching hospitals.. 188 patients treated with heparin or danaparoid for acute venous thromboembolism.. The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively.. Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders.. A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Topics: Acenocoumarol; Acute Disease; Adult; Aged; Body Surface Area; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Combinations; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Neoplasms; Odds Ratio; Prospective Studies; Risk Factors; Single-Blind Method; Thromboembolism; Thrombolytic Therapy

The potential antithrombotic effect of a new low molecular weight heparinoid, Org 10172, was examined in a randomized, double-blind, placebo-controlled, dose-ranging pilot study of the prevention of deep venous thrombosis (DVT) in 45 high-risk patients having major thoracic or abdominal surgery for cancer. Org 10172 was given in doses of 500, 750 or 1000 U bd subcutaneously. DVT occurred in 9 of 14 patients given placebo and in 4 of 11 patients given 500 U bd but in none of the 20 patients given 750 or 1000 U bd. Operative blood loss and post-operative bleeding were not significantly different between the groups but one patient given 1000 U bd had major post-operative bleeding. Average mid-interval and trough plasma anti-Xa levels reached 0.26 and 0.20 U/ml respectively following the highest dose. It is concluded that Org 10172 is a potentially useful antithrombotic agent and that the effective and safe dose appears to be between 500 and 1000 U bd for prevention of DVT in high-risk patients.

Topics: Aged; Aged, 80 and over; Chondroitin Sulfates; Dermatan Sulfate; Factor X; Factor Xa; Female; Glycosaminoglycans; Hemorrhage; Heparitin Sulfate; Humans; Injections, Subcutaneous; Male; Middle Aged; Neoplasms; Pilot Projects; Research Design; Thoracic Surgery; Thrombophlebitis

Various biomarkers targeting cell-free DNA (cfDNA) and circulating proteins have been tested for pan-cancer detection. Oncofetal chondroitin sulfate (ofCS), which distinctively modifies proteoglycans (PGs) of most cancer cells and binds specifically to the recombinant Plasmodium falciparum VAR2CSA proteins (rVAR2), is explored for its potential as a plasma biomarker in pan-cancer detection. To quantitate the plasma ofCS/ofCSPGs, we optimized an ELISA using different capture/detection pairs (rVAR2/anti-CD44, -SDC1, and -CSPG4) in a case-control study with six cancer types. We show that the plasma levels of ofCS/ofCSPGs are significantly higher in cancer patients (P values, 1.2 × 10

Topics: Case-Control Studies; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Humans; Neoplasms; Proteoglycans; Sulfates

Although nanoparticle-based chemotherapeutic strategies have gained in popularity, the efficacy of such therapies is still limited in part due to the different nanoparticle sizes needed to best accommodate different parts of the drug delivery pathway. Herein, we describe a nanogel-based nanoassembly based on the entrapment of ultrasmall starch nanoparticles (size 10-40 nm) within disulfide-crosslinked chondroitin sulfate-based nanogels (size 150-250 nm) to address this challenge. Upon exposure of the nanoassembly to the reductive tumor microenvironment, the chondroitin sulfate-based nanogel can degrade to release the doxorubicin-loaded starch nanoparticles in the tumor to facilitate improved intratumoral penetration. CT26 colon carcinoma spheroids could be efficiently penetrated by the nanoassembly (resulting in 1 order of magnitude higher DOX-derived fluorescence inside the spheroid relative to free DOX), while

Topics: Chondroitin Sulfates; Disulfides; Doxorubicin; Drug Carriers; Drug Liberation; Humans; Nanogels; Neoplasms; Tumor Microenvironment

To make preliminary exploration into the Golgi apparatus targeting of chondroitin sulfate-modified micelles (CSmicelles) co-loaded with pirarubicin (THP) and vinorelbine (VRL) in tumor cells, as well as their. It was found that CSmicelles could significantly increase cellular uptake of drugs. CSmicelles were internalized into cells through clathrin-mediated and caveolin-mediated endocytosis, which was energy-dependent active transport and exhibited substantial ability of targeting Golgi apparatus in tumor cells. THP+VTL-CSmicelles could break down the structure of Golgi apparatus and significantly inhibit the migration and invasion of tumor cells.. THP+VTL-CSmicelles demonstrate high affinity towards Golgi apparatus in tumor cells, exert targeted effects and inhibit tumor cell metastasis, which provides a novel idea and method for the treatment of cancer metastasis.

Topics: Animals; Chondroitin Sulfates; Golgi Apparatus; Mice; Micelles; Neoplasms

The high heterogeneity and mutation rate of cancer cells often lead to the failure of targeted therapy, and therefore, new targets for multitarget therapy of tumors are urgently needed. Aberrantly expressed glycosaminoglycans (GAGs) have been shown to be involved in tumorigenesis and are promising new targets. Recently, the GAG-binding domain rVAR2 of the Plasmodium falciparum VAR2CSA protein was identified as a probe targeting cancer-associated chondroitin sulfate A-like epitopes. In this study, we found that rVAR2 could also bind to heparin (Hep) and chondroitin sulfate E. Therefore, we used rVAR2 as a model to establish a method based on random mutagenesis of the GAG-binding protein and phage display to identify and optimize probes targeting tumor GAGs. We identified a new probe, VAR2HP, which selectively recognized Hep by interacting with unique epitopes consisting of a decasaccharide structure that contains at least three HexA2S(1-4)GlcNS6S disaccharides. Moreover, we found that these Hep-like epitopes were overexpressed in various cancer cells. Most importantly, our in vivo experiments showed that VAR2HP had good biocompatibility and preferentially localizes to tumors, which indicates that VAR2HP has great application potential in tumor diagnosis and targeted therapy. In conclusion, this study provides a strategy for the discovery of novel tumor-associated GAG epitopes and their specific probes.

Topics: Chondroitin Sulfates; Epitopes; Glycosaminoglycans; Heparin; Humans; Neoplasms

The study was to construct reduction-responsive chondroitin sulfate A (CSA)-conjugated TOS (CST) micelles with disulfide bond linkage, which was used for controlled doxorubicin (DOX) release and improved drug efficacy in vivo.. CST and non-responsive CSA-conjugated TOS (CAT) were synthesized, and the chemical structure was confirmed by Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, fluorescence spectrophotometer and dynamic light scattering. Antitumour drug DOX was physically encapsulated into CST and CSA by dialysis method. Cell uptake of DOX-based formulations was investigated by confocal laser scanning microscopy. In vitro cytotoxicity was studied in A549 and AGS cells. Furthermore, antitumour activity was evaluated in A549-bearing mice.. CST and CAT can form self-assembled micelles, and have low value of critical micelle concentration. Notably, DOX-containing CST (D-CST) micelles demonstrated reduction-triggered drug release in glutathione-containing media. Further, reduction-responsive uptake of D-CST was observed in A549 cells. In addition, D-CST induced stronger cytotoxicity (P < 0.05) than DOX-loaded CAT (D-CAT) against A549 and AGS cells. Moreover, D-CST exhibited significantly stronger antitumour activity in A549-bearing nude mice than doxorubicin hydrochloride and D-CAT.. The reduction-responsive CST micelles enhanced the DOX effect at tumour site and controlled drug release.

Topics: A549 Cells; alpha-Tocopherol; Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Chondroitin Sulfates; Delayed-Action Preparations; Disulfides; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Micelles; Neoplasms; Polymers; Stomach Neoplasms; Xenograft Model Antitumor Assays

Pingyangmycin is a clinically used anticancer drug and induces lung fibrosis in certain cancer patients. We previously reported that the negatively charged cell surface glycosaminoglycans are involved in the cellular uptake of the positively charged pingyangmycin. However, it is unknown if pingyangmycin affects glycosaminoglycan structures. Seven cell lines and a Lewis lung carcinoma-injected C57BL/6 mouse model were used to understand the cytotoxicity of pingyangmycin and its effect on glycosaminoglycan biosynthesis. Stable isotope labelling coupled with LC/MS method was used to quantify glycosaminoglycan disaccharide compositions from pingyangmycin-treated and untreated cell and tumour samples. Pingyangmycin reduced both chondroitin sulphate and heparan sulphate sulphation in cancer cells and in tumours. The effect was persistent at different pingyangmycin concentrations and at different exposure times. Moreover, the cytotoxicity of pingyangmycin was decreased in the presence of soluble glycosaminoglycans, in the glycosaminoglycan-deficient cell line CHO745, and in the presence of chlorate. A flow cytometry-based cell surface FGF/FGFR/glycosaminoglycan binding assay also showed that pingyangmycin changed cell surface glycosaminoglycan structures. Changes in the structures of glycosaminoglycans may be related to fibrosis induced by pingyangmycin in certain cancer patients.

Topics: A549 Cells; Animals; Antibiotics, Antineoplastic; Bleomycin; Cell Line, Tumor; CHO Cells; Chondroitin Sulfates; Cricetulus; Glycosaminoglycans; HCT116 Cells; Heparitin Sulfate; HT29 Cells; Humans; Mass Spectrometry; Mice; Mice, Inbred C57BL; Neoplasms; Pulmonary Fibrosis

The glycocalyx is thought to perform a potent, but not yet defined function in cellular adhesion and signaling. Since 95% of cancer cells have altered glycocalyx structure, this role can be especially important in cancer development and metastasis. The glycocalyx layer of cancer cells directly influences cancer progression, involving the complicated kinetic process of cellular adhesion at various levels. In the present work, we investigated the effect of enzymatic digestion of specific glycocalyx components on cancer cell adhesion to RGD (arginine-glycine-aspartic acid) peptide motif displaying surfaces. High resolution kinetic data of cell adhesion was recorded by the surface sensitive label-free resonant waveguide grating (RWG) biosensor, supported by fluorescent staining of the cells and cell surface charge measurements. We found that intense removal of chondroitin sulfate (CS) and dermatan sulfate chains by chondroitinase ABC reduced the speed and decreased the strength of adhesion of HeLa cells. In contrast, mild digestion of glycocalyx resulted in faster and stronger adhesion. Control experiments on a healthy and another cancer cell line were also conducted, and the discrepancies were analysed. We developed a biophysical model which was fitted to the kinetic data of HeLa cells. Our analysis suggests that the rate of integrin receptor transport to the adhesion zone and integrin-RGD binding is strongly influenced by the presence of glycocalyx components, but the integrin-RGD dissociation is not. Moreover, based on the kinetic data we calculated the dependence of the dissociation constant of integrin-RGD binding on the enzyme concentration. We also determined the dissociation constant using a 2D receptor binding model based on saturation level static data recorded at surfaces with tuned RGD densities. We analyzed the discrepancies of the kinetic and static dissociation constants, further illuminating the role of cancer cell glycocalyx during the adhesion process. Altogether, our experimental results and modelling demonstrated that the chondroitin sulfate and dermatan sulfate chains of glycocalyx have an important regulatory function during the cellular adhesion process, mainly controlling the kinetics of integrin transport and integrin assembly into mature adhesion sites. Our results potentially open the way for novel type of cancer treatments affecting these regulatory mechanisms of cellular glycocalyx.

Topics: Biophysical Phenomena; Biosensing Techniques; Cell Adhesion; Chondroitin ABC Lyase; Chondroitin Sulfates; Dermatan Sulfate; Focal Adhesions; Glycocalyx; HeLa Cells; Humans; Integrins; Kinetics; Models, Biological; Neoplasms; Oligopeptides

The maximally tolerated dose (MTD) approach in conventional chemotherapy accompanies adverse effects, primarily due to high drug concentrations in the blood after intravenous administration and non-specific damages to highly proliferating cells, including immune cells. This causes the immune system to dysfunction. To rather boost intrinsic tumor-fighting immune capacity, we demonstrate a new oral route treatment regimen of docetaxel (DTX) without apparent toxicity. The DTX-loaded cationic solid lipid nanoparticles (DSLN-CSG) were coated with an anionic polymer conjugated with glycocholic acid. The resulting nanoparticles (DSLN-CSG, ~120 nm in diameter) were actively absorbed in the distal ileum mediated by interactions with the apical sodium bile acid transporter. The plasma DTX profile was sustained up to 24 h after a single oral dose and did not impair the functions of the immune system. In mouse models, daily oral DSLN-CSG administration inhibited the growth of existing tumors and tumor formation by medication prior to cancer cell inoculation. The extent of effects depended on the cancer cell lines of melanoma, colorectal adenocarcinoma, and breast carcinoma. It was most effective for melanoma in growth inhibition and in preventing tumor formation in mice. During the medication, the cytotoxic T cell population increased while the populations of tumor-associated macrophage and regulatory T cell declined. The low dose daily oral treatment may help patients with intermittent maintenance therapy between MTD cycles and prevent tumor recurrence after completing remission for certain tumors.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chondroitin Sulfates; Docetaxel; Drug Liberation; Glycocholic Acid; Humans; Ileum; Lymphatic Vessels; Macrophages; Male; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Rats, Sprague-Dawley; T-Lymphocytes, Cytotoxic

Programmable drug delivery systems hold great promise to enhance cancer treatment. Herein, a programmable drug delivery system using a chondroitin sulfate (CS)-based composite nanoparticle was developed for enhancing and sensitizing chemotherapy to drug-resistant cancer. The nanoparticle was composed of a cross-linked CS hydrogel shell and hydrophobic cores containing both free drugs and CS-linked prodrugs. Interestingly, the nanoparticle could mediate tumor-specific CD44 targeting. After specific cellular uptake, the payloads were suddenly released because of the decomposition of the CS shell, and the free drug molecules with synergistic effects induced tumor-specific cytotoxicity rapidly. Subsequently, the inner cores of the nanoparticles sustainedly release their cargos in drug-resistant tumor cells to keep the effective drug concentration against the drug efflux mediated by P-glycoprotein. CS dissociated from the outer shell and sensitized cancer cells to the antitumor drugs through downregulation of Bcl-XL, an antiapoptosis protein. Such a programmable drug delivery system with specific tumor-targeting and sensitized therapy is promising for rational drug delivery and provides more versatility for controlled release in biomedical applications.

Topics: Animals; Antineoplastic Agents; bcl-X Protein; Cell Line, Tumor; Cell Survival; Chondroitin Sulfates; Down-Regulation; Drug Carriers; Drug Resistance, Neoplasm; Humans; Hyaluronan Receptors; Hydrogels; Hydrophobic and Hydrophilic Interactions; Mice; Microscopy, Fluorescence; Nanoparticles; Neoplasms; Paclitaxel; Sunitinib; Transplantation, Heterologous

In this study, reduction-sensitive self-assembled polymer nanoparticles based on poly (lactic-co-glycolic acid) (PLGA) and chondroitin sulfate A (CSA) were developed and characterized. PLGA was conjugated with CSA via a disulfide linkage (PLGA-ss-CSA). The critical micelle concentration (CMC) of PLGA-ss-CSA conjugate is 3.5 µg/mL. The anticancer drug doxorubicin (DOX) was chosen as a model drug, and was effectively encapsulated into the nanoparticles (PLGA-ss-CSA/DOX) with high loading efficiency of 15.1%. The cumulative release of DOX from reduction-sensitive nanoparticles was only 34.8% over 96 h in phosphate buffered saline (PBS, pH 7.4). However, in the presence of 20 mM glutathione-containing PBS environment, DOX release was notably accelerated and almost complete from the reduction-sensitive nanoparticles up to 96 h. Moreover, efficient intracellular DOX release of PLGA-ss-CSA/DOX nanoparticles was confirmed by CLSM assay in A549 cells. In vitro cytotoxicity study showed that the half inhibitory concentrations of PLGA-ss-CSA/DOX nanoparticles and free DOX against A549 cells were 1.141 and 1.825 µg/mL, respectively. Therefore, PLGA-ss-CSA/DOX nanoparticles enhanced the cytotoxicity of DOX in vitro. These results suggested that PLGA-ss-CSA nanoparticles could be a promising carrier for drug delivery.

Topics: A549 Cells; Antibiotics, Antineoplastic; Chondroitin Sulfates; Doxorubicin; Drug Carriers; Drug Liberation; Humans; Nanoparticles; Neoplasms; Polylactic Acid-Polyglycolic Acid Copolymer

Induction of cancer-specific cytotoxic T lymphocytes is crucially important to complement therapeutic effects of immune checkpoint inhibitors and to achieve efficient cancer immunotherapy. To induce cancer-specific cytotoxic T lymphocytes, cancer antigen carriers must have multiple functions to deliver cancer antigens to antigen presenting cells, release antigens into cytosol, and promote the maturation of these cells. We earlier achieved cytosolic delivery of antigens and induction of antigen-specific cytotoxic T lymphocytes using carboxylated polyglycidol or polysaccharide derivative-modified liposomes that can induce membrane fusion with endosomes in response to weakly acidic pH. Furthermore, pH-sensitivity and adjuvant properties of these polymers were enhanced strongly by introduction of hydrophobic carboxylated units to dextran. Against our expectations, these polymer-modified liposomes only slightly induce cancer immunity, probably because of the high hydrophobicity of spacer units. This study used a polysaccharide with charged groups (chondroitin sulfate) instead of dextran as a backbone to reduce hydrophobicity. Chondroitin sulfate derivative-modified liposomes showed almost equal pH-sensitivity to that of dextran derivative-modified liposomes and achieved selective delivery to dendritic cells, whereas dextran derivative-modified liposomes were highly taken up by both dendritic cells and fibroblasts. Chondroitin sulfate derivative-modified liposomes delivered model antigenic proteins into cytosol of dendritic cells and promoted cytokine production from the cells, leading to tumor regression on tumor-bearing mice after subcutaneous administration. Results demonstrate that charged groups having polysaccharide as a backbone can be used in an effective strategy to balance strong hydrophobicity of spacer units with their utilization for immunity-inducing systems.

Topics: Animals; Antigens; Chondroitin Sulfates; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Liposomes; Mice; Neoplasms; Polymers

In the past few years, significant progress has been made in inhibiting neovascularization at the tumor site, cutting off the nutrient supply of the tumor, and inhibiting tumor growth and metastasis. However, many proteins/peptides have the disadvantage of poor stability, short half-life, and uncertain targeting ability. Chemical modification can be used to overcome these disadvantages; many polyethylene glycol-modified proteins/peptides have been approved by US FDA. The purpose of this study was to obtain a novel anti-angiogenic chondroitin sulfate (CS)-peptide nanoparticle conjugate with efficient anti-neovascularization and tumor targeting ability and an acceptable half-life.. The CS-ES2-AF nanoparticle conjugate was synthesized and characterized using. The CS-ES2-AF could self-assemble into stable nanoparticles in aqueous solution, which significantly enhances its anti-neovascularization activity, tumor targeting more explicit, and prolongs its half-life.. CS is an effective protein/peptide modifier, and CS-ES2-AF displayed good potential in tumor targeting therapy.

Topics: Angiogenesis Inhibitors; Animals; Cell Movement; Chondroitin Sulfates; Chorioallantoic Membrane; Humans; Hyaluronan Receptors; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Neovascularization, Pathologic; Particle Size; Peptides; Proton Magnetic Resonance Spectroscopy; Time Factors; Xenograft Model Antitumor Assays

Metastasis is a multistep biological process regulated by multiple signaling pathways. The integrity of the Golgi apparatus plays an important role in these signaling pathways. Inspired by the mechanism and our previous finding about accumulation of chondroitin sulfate in Golgi apparatus in hepatic stellate cells, we developed a Golgi apparatus-targeting prodrug nanoparticle system by synthesizing retinoic acid (RA)-conjugated chondroitin sulfate (CS) (CS-RA). The prodrug nanoparticles appeared to accumulate in the Golgi apparatus in cancer cells and realized RA release under an acidic environment. We confirmed that CS-RA exhibited successful inhibition of multiple metastasis-associated proteins expression

Topics: Cell Line, Tumor; Chondroitin Sulfates; Drug Delivery Systems; Golgi Apparatus; Humans; Nanoparticles; Neoplasm Metastasis; Neoplasms; Paclitaxel; Prodrugs

To develop a reactive oxygen species (ROS) sensitive drug carrier, a chondroitin sulfate (CS)-anthocyanin (ATC) based nanocomplex was developed. Doxorubicin hydrochloride (DOX) was loaded in the CS-ATC nanocomplex (CS-ATC-DOX) via intermolecular stacking interaction. The nanocomplex was fabricated by a simple mixing method in the aqueous phase. The morphology and size of CS-ATC-DOX were determined by ATC content. In the group with 1.5mg/ml of ATC loaded CS-ATC-DOX (CS-ATC2-DOX), the drug content and loading efficiency were 8.5% and 99.1%, respectively. The ROS sensitive drug release of CS-ATC2-DOX was confirmed under in vitro physiological conditions. The results demonstrated that 1.67 times higher DOX release occurred in CS-ATC2-DOX for 48h compared to CS-DOX (ATC absent sample). Drug release and nanocomplex destruction were induced by ROS mediated ATC degradation. We determined that 66.7% of ROS was scavenged by CS-ATC2-DOX. Additionally, an HCT-116 tumor bearing animal model was used to confirm ROS sensitive therapeutic effects of CS-ATC2-DOX. The results indicate that DOX was released from the intravenously injected CS-ATC2-DOX in the tumor tissue. Thus, nuclei shrinkage and dead cells were observed in H&E staining and TUNEL assay, respectively. These data suggest that the tumor growth was effectively inhibited. This study means that CS-ATC2-DOX has potential in improving tumor therapy.

Topics: Animals; Anthocyanins; Antineoplastic Agents; Chondroitin Sulfates; Doxorubicin; Drug Liberation; HCT116 Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Reactive Oxygen Species; Tumor Burden

Of all live births with congenital anomalies, approximately one-third exhibit deformities of the head and face. Most craniofacial disorders are associated with defects in a migratory stem and progenitor cell population, which is designated the neural crest (NC). Musculocontractural Ehlers-Danlos syndrome (MCEDS) is a heritable connective tissue disorder with distinct craniofacial features; this syndrome comprises multiple congenital malformations that are caused by dysfunction of dermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE). Studies in mice have extended our understanding of DS-epi1 in connective tissue maintenance; however, its role in fetal development is not understood. We demonstrate that DS-epi1 is important for the generation of isolated iduronic acid residues in chondroitin sulfate (CS)/DS proteoglycans in early Xenopus embryos. The knockdown of DS-epi1 does not affect the formation of early NC progenitors; however, it impairs the correct activation of transcription factors involved in the epithelial-mesenchymal transition (EMT) and reduces the extent of NC cell migration, which leads to a decrease in NC-derived craniofacial skeleton, melanocytes and dorsal fin structures. Transplantation experiments demonstrate a tissue-autonomous role for DS-epi1 in cranial NC cell migration in vivo Cranial NC explant and single-cell cultures indicate a requirement of DS-epi1 in cell adhesion, spreading and extension of polarized cell processes on fibronectin. Thus, our work indicates a functional link between DS and NC cell migration. We conclude that NC defects in the EMT and cell migration might account for the craniofacial anomalies and other congenital malformations in MCEDS, which might facilitate the diagnosis and development of therapies for this distressing condition. Moreover, the presented correlations between human DS-epi1 expression and gene sets of mesenchymal character, invasion and metastasis in neuroblastoma and malignant melanoma suggest an association between DS and NC-derived cancers.

Topics: Animals; Base Sequence; Biomarkers; Cell Adhesion; Cell Movement; Cell Polarity; Chondroitin Sulfates; Dermatan Sulfate; Ehlers-Danlos Syndrome; Embryo, Nonmammalian; Feedback, Physiological; Fibronectins; Gene Expression Regulation, Developmental; Iduronic Acid; Models, Biological; Muscles; Neoplasms; Neural Crest; Neural Plate; Racemases and Epimerases; Xenopus laevis; Xenopus Proteins

Tumor metastasis with resistance to anticancer therapies is the main cause of death in cancer patients. It is necessary to develop reliable tumor metastasis models that can closely recapitulate the pathophysiological features of the native tumor tissue. In this study, chondroitin sulfate (CS)-modified alginate hydrogel beads (ALG-CS) are developed to mimic the in vivo tumor microenvironment with an abnormally increased expression of CS for the promotion of tumor cell metastasis. The modification mechanism of CS on alginate hydrogel is due to the cross-linking between CS and alginate molecules via coordination of calcium ions, which enables ALG-CS to possess significantly different physical characteristics than the traditional alginate beads (ALG). And quantum chemistry calculations show that in addition to the traditional egg-box structure, novel asymmetric egg-box-like structures based on the interaction between these two kinds of polymers are also formed within ALG-CS. Moreover, tumor cell metastasis is significantly enhanced in ALG-CS compared with that in ALG, as confirmed by the increased expression of MMP genes and proteins and greater in vitro invasion ability. Therefore, ALG-CS could be a convenient and effective 3D biomimetic scaffold that would be used to construct standardized tumor metastasis models for tumor research and anticancer drug screening.

Topics: Alginates; Biomimetics; Calcium; Cell Line, Tumor; Chondroitin Sulfates; Drug Screening Assays, Antitumor; Glucuronic Acid; Hexuronic Acids; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment

We hypothesize that a plasma glycosaminoglycan, chondroitin sulfate, may be responsible for the biological and clinical effects attributed to the Gc protein-derived Macrophage Activating Factor (GcMAF), a protein that is extracted from human blood. Thus, Gc protein binds chondroitin sulfate on the cell surface and such an interaction may occur also in blood, colostrum and milk. This interpretation would solve the inconsistencies encountered in explaining the effects of GcMAF in vitro and in vivo. According to our model, the Gc protein or the GcMAF bind to chondroitin sulfate both on the cell surface and in bodily fluids, and the resulting multimolecular complexes, under the form of oligomers trigger a transmembrane signal or, alternatively, are internalized and convey the signal directly to the nucleus thus eliciting the diverse biological effects observed for both GcMAF and chondroitin sulfate.

Topics: Animals; Antineoplastic Agents; Cell Membrane; Cell Proliferation; Cholecalciferol; Chondroitin Sulfates; Glycosylation; Humans; Immunosuppression Therapy; Immunotherapy; Macrophage-Activating Factors; Macrophages; Models, Theoretical; Neoplasms; Neovascularization, Pathologic; Oleic Acid; Peptides; Signal Transduction; Threonine; Vitamin D-Binding Protein

Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target.. The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy. Mol Cancer Res; 14(12); 1288-99. ©2016 AACR.

Topics: Animals; Antigens, Protozoan; Carcinoma, Lewis Lung; Cell Line, Tumor; Chondroitin Sulfates; Humans; Integrins; Melanoma, Experimental; Mice; Neoplasm Metastasis; Neoplasms; Pancreatic Neoplasms; Signal Transduction

A new cationic polymer eprosartan-graft-PEI (ESP) containing eprosartan (ES) and polyethylenimine 1.8K was successfully developed and employed as a safe gene vector to assemble a drug (ES) and gene co-delivery complex (ESP/pDNA). Chondroitin sulfate (CS) was then used as a coating polymer to shield the surface charge of ESP/pDNA complexes, as well as a tumor targeting entity to ensure specific delivery of CS/ESP/pDNA complexes. The CS/ESP/pDNA complexes with desirable particle size and zeta potential, exhibited amidase-responsive drug release and CS-mediated endocytosis in vitro. As compared with ESP/pDNA complexes, in vivo imaging results demonstrated decreased reticuloendothelial system uptake and remarkably increased tumor accumulation of CS/ESP/pDNA complexes. All these findings indicated the potential of CS/ESP/pDNA as a promising tumor-targeted drug and gene co-delivery system.

Topics: Acrylates; Chondroitin Sulfates; Drug Delivery Systems; Endocytosis; Gene Transfer Techniques; Hep G2 Cells; Humans; Imidazoles; Neoplasms; Plasmids; Polyethyleneimine; Thiophenes

Cationic antimicrobial peptides (CAPs) with antitumor activity have potential for use as novel antitumor agents because of their lower risk for induction of resistance. Of these peptides, magainin II (MG2) exhibited cytotoxicity in tumor cells only at high concentrations, likely due to the inefficiency of MG2 in cell membrane binding and cell entry. Conjugation to a cell-penetrating peptide (CPP) might enhance the cytotoxicity of MG2 in tumor cells. Here, we constructed a fusion peptide MG2A by conjugating MG2 to the N-terminus of the CPP penetratin (Antp). It was found that the fusion peptide MG2A is more potent than unconjugated MG2 at tumor cell killing. The IC50s of MG2A for the tumor cells tested were at least 30 times lower than the IC50s of unconjugated MG2. These data indicate that conjugation to Antp significantly enhanced the cytotoxicity of MG2 in tumor cells. Moreover, the IC50s of MG2A for tumor cells are within 2 to 3 μM, which are about three to five times lower than the IC50 for normal cells. Furthermore, chondroitin sulfate (CS) was found to be overexpressed on the surface of the tested tumor cells, and the cytotoxicity of MG2A could be inhibited by the addition of exogenous CS. These results suggest that binding of Antp to CS on tumor cells might be one important cause for the selective cytotoxicity of MG2A in tumor cells. Taken together, conjugation of MG2 to Antp can significantly enhance its antitumor activity, and the fusion of CAP to Antp might be an alternative for cancer-targeted therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Carrier Proteins; Caspases; Cell Survival; Cell-Penetrating Peptides; Central Nervous System Neoplasms; Chlorocebus aethiops; Chondroitin Sulfates; Drug Carriers; Glioma; HeLa Cells; Humans; Inhibitory Concentration 50; Kidney Tubules, Proximal; Lung Neoplasms; Magainins; Melanoma; Molecular Targeted Therapy; Neoplasms; Rats; Skin Neoplasms; Vero Cells; Xenopus Proteins

Soft tissue deficits associated with exposed tendon and absent paratenon pose difficult reconstructive problems due to tendon adhesions, poor range of motion, poor cosmesis, and donor site morbidity. Integra Bilayer Matrix Wound Dressing (Integra Lifesciences Corp Plainsboro, NJ) is a skin substitute widely used in reconstructive surgery, including the incidental coverage of tendons. However, Integra's post-operative functionality of the tendons has not been well documented. We report the results of using Integra for soft tissue reconstruction overlying tendons with loss of paratenon in upper and lower extremity soft tissue defects.. Forty-two patients (35 men and 7 women) with exposed tendons due to trauma (37), cancer excision (2) or chronic wounds (3) were reconstructed using Integra. Results were compiled in a prospective manner, including age, gender, wound location, wound size, time to final closure, operative time, follow-up length, split-thickness skin graft percentage take and active post-operative range of motion. Likewise using Medline, a literature search of current surgical techniques for the treatment of exposed tendons and the results from the literature were compared with these study results.. All patients healed with an average split-thickness skin graft take rate of 92.5% ± 6.1 (range, 80-100%). The thirty-two patients not lost to follow-up achieved an average range of motion of 91.2% ± 6.5 (range, 80-100%).. Integra offers a convenient, efficient operative procedure with minimal morbidity, demonstrating good cosmesis and tendon function. Thus, Integra may offer an alternative option for immediate tendon coverage in both the upper and lower extremities.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Chondroitin Sulfates; Collagen; Debridement; Electrocoagulation; Female; Humans; Length of Stay; Male; Middle Aged; Neoplasms; Plastic Surgery Procedures; Postoperative Complications; Range of Motion, Articular; Retrospective Studies; Soft Tissue Injuries; Tendons; Treatment Outcome

Several naturally occurring cationic antimicrobial peptides (CAPs), including bovine lactoferricin (LfcinB), display promising anticancer activities. These peptides are unaffected by multidrug resistance mechanisms and have been shown to induce a protective immune response against solid tumors, thus making them interesting candidates for developing novel lead structures for anticancer treatment. Recently, we showed that the anticancer activity by LfcinB was inhibited by the presence of heparan sulfate (HS) on the surface of tumor cells. Based on extensive structure-activity relationship studies performed on LfcinB, shorter and more potent peptides have been constructed. In the present study, we have investigated the anticancer activity of three chemically modified 9-mer peptides and the influence of HS and chondroitin sulfate (CS) on their cytotoxic activity.. Various cell lines and red blood cells were used to investigate the anticancer activity and selectivity of the peptides. The cytotoxic effect of the peptides against the different cell lines was measured by use of a colorimetric MTT viability assay. The influence of HS and CS on their cytotoxic activity was evaluated by using HS/CS expressing and HS/CS deficient cell lines. The ability of soluble HS and CS to inhibit the cytotoxic activity of the peptides and the peptides' affinity for HS and CS were also investigated.. The 9-mer peptides displayed selective anticancer activity. Cells expressing HS/CS were equally or more susceptible to the peptides than cells not expressing HS/CS. The peptides displayed a higher affinity for HS compared to CS, and exogenously added HS inhibited the cytotoxic effect of the peptides.. In contrast to the previously reported inhibitory effect of HS on LfcinB, the present study shows that the cytotoxic activity of small lytic peptides was increased or not affected by cell surface HS.

Topics: Animals; Antimicrobial Cationic Peptides; Apoptosis; Cattle; Cell Line; Chondroitin Sulfates; Erythrocytes; Hemolysis; Heparitin Sulfate; Lactoferrin; Neoplasms; Peptide Fragments; Protein Engineering; Structure-Activity Relationship

Topics: Abnormalities, Multiple; Chondroitin Sulfates; Craniofacial Abnormalities; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Genotype; Germ-Line Mutation; Heart Defects, Congenital; Human Growth Hormone; Humans; Neoplasms; Phenotype; Syndrome

CD97, a membrane protein expressed at high levels on inflammatory cells and some carcinomas, is a member of the adhesion G protein-coupled receptor family, whose members have bipartite structures consisting of an extracellular peptide containing adhesion motifs noncovalently coupled to a class B 7-transmembrane domain. CD97alpha, the extracellular domain of CD97, contains 3 to 5 fibrillin class 1 epidermal growth factor (EGF)-like repeats, an Arg-Gly-Asp (RGD) tripeptide, and a mucin stalk. We show here that CD97alpha promotes angiogenesis in vivo as demonstrated with purified protein in a directed in vivo angiogenesis assay (DIVAA) and by enhanced vascularization of developing tumors expressing CD97. These data suggest that CD97 can contribute to angiogenesis associated with inflammation and tumor progression. Strong integrin alpha5beta1 interactions with CD97 have been identified, but alpha v beta3 also contributes to cell attachment. Furthermore, soluble CD97 acts as a potent chemoattractant for migration and invasion of human umbilical vein endothelial cells (HUVECs), and this function is integrin dependent. CD97 EGF-like repeat 4 is known to bind chondroitin sulfate. It was found that coengagement of alpha5beta1 and chondroitotin sulfate proteoglycan by CD97 synergistically initiates endothelial cell invasion. Integrin alpha5beta1 is the first high-affinity cellular counterreceptor that has been identified for a member within this family of adhesion receptors.

Topics: Animals; Antigens, CD; Cell Adhesion; Chondroitin Sulfates; Endothelium, Vascular; Epidermal Growth Factor; HT29 Cells; Humans; Integrin alpha5beta1; Integrin alphaVbeta3; Membrane Glycoproteins; Mice; Neoplasms; Neovascularization, Physiologic; NIH 3T3 Cells; Oligopeptides; Phenotype; Protein Structure, Tertiary; Rats; Receptors, G-Protein-Coupled; Umbilical Veins

Heparin-induced thrombocytopenia (HIT) is a common immunological drug reaction. After exposure to heparin, some patients develop heparin dependent antibodies with no evidence of thrombosis, while others are at risk of thrombocytopenia, thrombosis, limb loss, and death. We conducted a retrospective chart review on all patients serologically positive for HIT by HPIA ELISA in a single tertiary-care hospital, to determine whether patients with malignancy had an increased risk of thrombotic complications. Medical records of 55 patients who tested positive for HIT and met clinical criteria for HIT were analyzed. All patients had been treated with unfractionated heparin. Malignancy was diagnosed in 11 patients, either at surgery or post-mortem examination. A higher rate of venous thrombosis and pulmonary embolism was observed in patients with HIT and malignant disease when compared to patients with no underlying malignancy (odds ratio 13.6, 95% CI 2.9-63.8).

Topics: Aged; Aged, 80 and over; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Retrospective Studies; Risk Factors; Thrombocytopenia; Thrombosis; Venous Thrombosis

Patients with malignancy often present with a variety of coagulation abnormalities which may ultimately lead to recurrent arterial and venous thromboses. Recently the presence of antiphospholipid antibodies in cancer patients has been proposed as one of the potential mechanisms promoting hypercoagulability. Here we report two consecutive patients with localized tumors, one suffering from breast cancer and another presenting with colorectal cancer, who experienced dramatic exacerbation of the antiphospholipid antibody syndrome (APAS) within 4 weeks after surgery. In the first patient who had also received one course of adjuvant chemotherapy, major ischemic stroke and recurrent venous thromboembolism were paralleled by the development of ulcerative livedoid vasculitis and pancytopenia, constituting the diagnosis of systemic lupus erythematosus with secondary APAS. In the second patient, progressive thrombotic occlusion of the superior and inferior vena cava was associated with bilateral pulmonary embolism, acute renal failure, and disabling soft tissue edema. Although not fulfilling the classic criteria of "catastrophic" APAS, the clinical features were life threatening and appeared to be refractory to oral anticoagulation with phenprocoumon. In addition, a diagnosis of Trousseau's syndrome was unlikely due to missing evidence of gross metastatic disease. Besides a suggested treatment strategy comprising high doses of low-molecular-weight heparin, potential pathogenic mechanisms are discussed in consideration of a recently proposed "thrombotic storm," which may cause multiple thromboses after an initial provocation in patients with known hypercoagulability.

Topics: Adult; Antiphospholipid Syndrome; Breast Neoplasms; Chemotherapy, Adjuvant; Chondroitin Sulfates; Colorectal Neoplasms; Dermatan Sulfate; Drug Combinations; Female; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Lupus Erythematosus, Systemic; Middle Aged; Neoplasms; Stroke; Thromboembolism; Thrombophilia

We established a highly sensitive quantitative analytical method for chondroitin/dermatan sulfates by LC/MS method. By this method, the unsaturated disaccharides produced after the enzymatic digestion of chondroitin/dermatan sulfates can be determined in the amounts as low as 0.5 pmol levels. The use of tetrabutylammonium hydroxide as an ion-pair reagent for LC/MS allowed us to separate unsaturated 4-sulfated disaccharide and unsaturated 6-sulfated disaccharide. Furthermore, the peak areas of unsaturated disaccharides were increased almost 10 times by the postcolumn addition of acetonitrile. We applied this LC/MS method to the analyses of unsaturated disaccharides from chondroitin/dermatan sulfates in the tissues sections on glass slides, which were prepared from MethA tumor-bearing mice. This method brought about considerable reduction in the time distance from sample collection to preparation of analytical results.

Topics: Chondroitin Sulfates; Chromatography, High Pressure Liquid; Dermatan Sulfate; Mass Spectrometry; Neoplasms; Reproducibility of Results

Substantial weight loss in individuals with AIDS or cancer is associated with a poor prognosis and increased mortality. We have isolated and partially characterized a proteoglycan (named azaftig) from the urine of a cancer patient experiencing weight loss. Furthermore, we have raised a polyclonal antibody to azaftig in rabbits and developed a procedure to measure the level of this proteoglycan in urine by Western blot. We report the presence of azaftig in the urine of cancer and AIDS patients experiencing weight loss, but not in the control or weight-stable subjects. The azaftig-like immunoreactivity was present in 69.2% (9/13) of patients with weight loss, but only in 27.0% (3/11) of weight-stable cancer or AIDS patients and none of the control subjects (n = 8).

Topics: Adult; Blotting, Western; Cachexia; Case-Control Studies; Chondroitin Sulfates; HIV Wasting Syndrome; Humans; Neoplasms; Proteoglycans

Chondroitin sulfate is significantly increased in tumors (10 to 100 times) when compared to the amounts present in normal adjacent tissues. To investigate if the changes in concentration of chondroitin sulfate could be reflected in the urine of cancer patients we have analyzed the chondroitin sulfate excreted by 44 patients with different types of tumors, 50 normal individuals and 15 patients with unrelated diseases.. The identification and structural analyses of the sulfated glycosaminoglycans were made by electrophoresis and degradation with specific enzymes (chondroitinases AC and ABC), identification/quantitation of their disaccharide products by chromatography (paper and HPLC) and chemical determinations.. The disaccharide products formed from chondroitin sulfate of the 44 cancer patients by action of chondroitinase ABC show a substantial relative increase of non sulfated disaccharide (32.1% +/- 15.2) with a relative decrease of 6-sulfated disaccharide (28.9% +/- 11.5) and 4-sulfated disaccharide (39.0% +/- 13.5) when compared to the chondroitin sulfate of normal subjects (9.1% +/- 2.2, 40.6% +/- 4.5 and 50.2% +/- 4.5, respectively) or from patients with unrelated diseases. There is a direct correlation between the non sulfated disaccharide content and the stage of malignancy of the cancer patients. A significant change of the ratio of chondroitin sulfate and heparan sulfate and a decrease in the electrophoretic migration of chondroitin sulfate were also observed in cancer patients.. All the cancer patients analyzed so far have shown the structural anomaly of the urinary chondroitin sulfate and this may be useful in the diagnosis and follow up of cancer therapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Child; Child, Preschool; Chondroitin Sulfates; Chromatography, High Pressure Liquid; Disaccharides; Electrophoresis, Agar Gel; Glycosaminoglycans; Heparitin Sulfate; Humans; Middle Aged; Neoplasms; Postoperative Period; Reference Values

Topics: Animals; Chondroitin Sulfates; Electrophoresis, Cellulose Acetate; Glycosaminoglycans; Heparitin Sulfate; Humans; Keratan Sulfate; Neoplasms; Nitrous Acid

Intercellular glycosaminoglycans (GAGs) from various tissues were analyzed by cellulose acetate electrophoresis and enzymatic treatment with specific mucopolysaccharidases. Each tissue exhibits a particular composition of sulfate and unsulfated molecular species. Invariably, malignant human neoplasias and their metastases show striking variations in the electrophoretic pattern typical of the corresponding normal tissue. An absolute or relative increase in surface ChS A/C and HA seems to be a consistent feature of neoplastic transformation. On the other hand, the GAGs composition of benign noninfiltrative tumors does not vary greatly with respect to the original normal tissue.

Topics: Animals; Chondroitin Sulfates; Chromatography, Paper; Electrophoresis, Cellulose Acetate; Glycosaminoglycans; Humans; Neoplasm Metastasis; Neoplasms

Intercellular glycosaminoglycans have been isolated from normal and neoplastic mammalian tissues. They have been characterized by cellulose acetate electrophoresis and by chemical and enzymatic degradation. The electrophoretic pattern of the intercellular glycosaminoglycans is tissue specific. Furthermore, the electrophoretic patterns of all spontaneous neoplasias analyzed differ significantly from patterns obtained from the tissues of origin.

Topics: Animals; Cell Membrane; Chondroitin Sulfates; Dermatan Sulfate; Glycosaminoglycans; Guinea Pigs; Heparitin Sulfate; Humans; Hyaluronic Acid; Mice; Neoplasms; Neoplasms, Experimental; Tissue Distribution; Trypsin

Topics: Animals; Binding Sites; Brain; Cell Adhesion; Cell Aggregation; Chondroitin; Chondroitin Sulfates; Dermatan Sulfate; Glycosaminoglycans; Guinea Pigs; Heparitin Sulfate; Humans; Ileum; Kidney; Molecular Weight; Muscles; Neoplasms; Organ Specificity; Rabbits; Species Specificity

The distribution of sulfated mucopolysaccharides in different tissues during growth and in cancer tissues is reported. It is shown that most of the tissues of 1 day-old rats and rabbits contain chondroitin sulfate A/C, chondroitin sulfate B and heparan sulfate in about the same proportions, whereas in adult animals chondroitin sulfate A/C decreases in concentration or disappears. Changes in the relative proportions of chondroitin sulfate B and heparan sulfate were also observed in most of the tissues. In rats, these changes occur in the first 25 days of extrauterine development. A great increase of chondroitin sulfate A/C was observed in human tumors of different origins when compared with the normal adjacent tissues. Changes in the relative proportions of chondroitin sulfate B and heparan sulfate were also observed in most of the tumors analysed. The possible role of chondroitin sulfate A/C in cell division is discussed in view of the present findings.

Topics: Aging; Animals; Animals, Newborn; Brain; Chondroitin; Chondroitin Sulfates; Glycosaminoglycans; Guinea Pigs; Heparitin Sulfate; Humans; Kidney; Liver; Neoplasms; Organ Specificity; Rabbits; Rats; Species Specificity

Topics: Chondroitin; Chondroitin Sulfates; Humans; Ions; Neoplasms; Sensitivity and Specificity; Sulfates