title: Biochemical and toxicological evaluation of nano-heparins in cell functional properties, proteasome activation and expression of key matrix molecules.
abstract: The glycosaminoglycan heparin and its derivatives act strongly on blood coagulation, controlling the activity of serine protease inhibitors in plasma. Nonetheless, there is accumulating evidence highlighting different anticancer activities of these molecules in numerous types of cancer. Nano-heparins may have great biological significance since they can inhibit cell proliferation and invasion as well as inhibiting proteasome activation. Moreover, they can cause alterations in the expression of major modulators of the tumor microenvironment, regulating cancer cell behavior. In the present study, we evaluated the effects of two nano-heparin formulations: one isolated from porcine intestine and the other from the sea squirt Styela plicata, on a breast cancer cell model. We determined whether these nano-heparins are able to affect cell proliferation, apoptosis and invasion, as well as proteasome activity and the expression of extracellular matrix molecules. Specifically, we observed that nano-Styela compared to nano-Mammalian analogue has higher inhibitory role on cell proliferation, invasion and proteasome activity. Moreover, nano-Styela regulates cell apoptosis, expression of inflammatory molecules, such as IL-6 and IL-8 and reduces the expression levels of extracellular matrix macromolecules, such as the proteolytic enzymes MT1-MMP, uPA and the cell surface proteoglycans syndecan-1 and -2, but not on syndecan-4. The observations reported in the present article indicate that nano-heparins and especially ascidian heparin are effective agents for heparin-induced effects in critical cancer cell functions, providing an important possibility in pharmacological targeting.
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece; Foundation for Research and Technology, Institute of Chemical Engineering Sciences (FORTH/ICE-HT), Patras, Greece.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Piperigkou
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece; Foundation for Research and Technology, Institute of Chemical Engineering Sciences (FORTH/ICE-HT), Patras, Greece.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Karamanou
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Afratis
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Bouris
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.
authors.forename: Chrysostomi
authors.initials: C
authors.lastname: Gialeli
authors.affiliation: Faculdade de Medicina, disciplina de Imunologia, Universidade Federal do Rio de Janeiro, Campus Macaé, Brazil.
authors.forename: Celso L R
authors.initials: CL
authors.lastname: Belmiro
authors.affiliation: Laboratório de Bioquímica e Biologia Cellular de Glicoconjugados, Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo De Meis and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Brazil. Electronic address: mpavao@hucff.ufrj.br.
authors.forename: Mauro S G
authors.initials: MS
authors.lastname: Pavão
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece. Electronic address: vynios@chemistry.upatras.gr.
authors.forename: Dimitrios H
authors.initials: DH
authors.lastname: Vynios
authors.affiliation: Center of Toxicology Science & Research, Medical School, University of Crete, Heraklion, Crete, Greece. Electronic address: aris@med.uoc.gr.
authors.forename: Aristidis M
authors.initials: AM
authors.lastname: Tsatsakis
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005109:Extracellular Matrix / Q000737:chemistry; D006493:Heparin / Q000633:toxicity*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D049329:Nanostructures / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000633:toxicity*
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D061988:Proteasome Inhibitors; D006493:Heparin; D046988:Proteasome Endopeptidase Complex
keywords: Ascidian; Breast cancer; Extracellular matrix; Heparin; Pharmacological targeting; Proteasome