title: In vitro study of low molecular weight heparin effect on cell growth and cell invasion in primary cell cultures of high-grade gliomas.
abstract: Heparins represent the first choice for prevention and treatment of venous thromboembolism. In particular, low molecular weight heparins (LMWHs) provide pharmacokinetic advantages compared to unfractionated heparin (UFH): longer half-life, better bioavailability, and lower binding to plasma proteins. In the last years results of preclinical and clinical studies have suggested that LMWH may be able to inhibit cell growth, cell invasion, and angiogenesis, which are key mechanisms involved in tumor progression, possibly influencing favorable clinical outcome in at least a proportion of cancer patients. In this work we investigated the effect of LMWH (enoxaparin) on cell growth and cell invasion in primary cell cultures obtained from high-grade glioma specimens: 5 anaplastic astrocytoma (AA) and 13 glioblastoma multiforme (GBM). Apoptosis and expression of the thrombin receptor PAR1 were also assessed. A significant decrease in tumor cell growth was observed after treatment with 10 U/ml (-21%; p = 0.001) and 100 U/ml (-26%; p < 0.001); tumor cells from AA (grade III; WHO) were more affected by LMWH treatment compared to cell lines from GBM (grade IV; WHO). The antiproliferative effect was more pronounced in cell cultures displaying higher expression of PAR1. Glioma cell cultures were able to invade a model of basement membrane (Matrigel matrix) in standard culture conditions, but migration was not modulated significantly by LMWH treatment at any of the concentrations tested (1, 10, 100 U/ml). In conclusion, our results confirm the antineoplastic effect of LMWH, suggesting a potential direct role on tumor cell growth in high grade gliomas.
authors.affiliation: Laboratory of Clinical Investigation, Department of Neurology, Department of Neurosurgery, National Neurological Institute "C. Besta," Via Celoria 11, 20133 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Balzarotti
authors.forename: Federica
authors.initials: F
authors.lastname: Fontana
authors.forename: Carlo
authors.initials: C
authors.lastname: Marras
authors.forename: Amerigo
authors.initials: A
authors.lastname: Boiardi
authors.forename: Danilo
authors.initials: D
authors.lastname: Croci
authors.forename: Emilio
authors.initials: E
authors.lastname: Ciusani
authors.forename: Andrea
authors.initials: A
authors.lastname: Salmaggi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D017984:Enoxaparin / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D009361:Neoplasm Invasiveness; D044463:Receptor, PAR-1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D017984:Enoxaparin; D044463:Receptor, PAR-1