title: Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia.
abstract: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer, with a median survival of less than 2 years after diagnosis. The tumor microenvironment plays a critical role in tumor invasion and progression. Microglia and infiltrating macrophages are the most abundant immune cells in the tumor. In the present study, we demonstrate that systemic propentofylline (PPF), an atypical methylxanthine with central nervous system (CNS) glial modulating and anti-inflammatory actions, significantly decreased tumor growth in a CNS-1 rat model of GBM by targeting microglia and not tumor cells. Rats received tumor injections of 1 × 10(5) CNS-1 cells in the right striatum with daily intraperitonial injections of PPF (50 mg/kg) or saline beginning the day of tumor injection. PPF did not cause apoptosis or decrease proliferation of CNS-1 tumor cells. Furthermore, we demonstrate, using in vitro methods, that PPF decreased microglial migration toward CNS-1 tumor cells and decreased MMP-9 expression. The effects of PPF were shown to be specific to microglia and not peripheral macrophages. These results support a differential functional role of resident microglia and infiltrating macrophages in the brain tumor environment. Our data highlight microglia as a crucial target for future therapeutic development and present PPF as a possible drug for treatment of human GBM.
authors.affiliation: Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Jacobs
authors.forename: Russell P
authors.initials: RP
authors.lastname: Landry
authors.forename: Yingna
authors.initials: Y
authors.lastname: Liu
authors.forename: Edgar Alfonso
authors.initials: EA
authors.lastname: Romero-Sandoval
authors.forename: Joyce A
authors.initials: JA
authors.lastname: De Leo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology; D051381:Rats; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D014970:Xanthines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014970:Xanthines; C032114:propentofylline; D020780:Matrix Metalloproteinase 9
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