Therapeutic effects of the Sp1 inhibitor mithramycin A in glioblastoma.

J Neurooncol 2011 Feb 17;101(3):365-77. Epub 2010 Jun 17.

Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076, Tübingen, Germany.

Mithramycin A (MitA) is a chemotherapeutic compound which has been used in the therapy of several types of cancer. For experimental cancer it has been shown that MitA mediates the expression of genes involved in tumor progression such as genes involved in immunosurveillance, cell motility or cell death. MitA works synergistically with Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and with antiangiogenic agents. We were therefore interested in analyzing whether MitA might be a suitable agent for glioma therapy. We demonstrate herein that the cell death sensitizing effects of MitA are cell line specific, independent of the endogenous status of the tumor suppressor p53 as well as of the endogenous expression of X-linked inhibitor of apoptosis (XIAP) or basal sensitivity towards death ligand-induced cell death. In glioma cells, MitA reduced the secretion and activity of the migration-involved matrix metalloproteinases (MMP), diminished vascular endothelial growth factor (VEGF), and increased recepteur d'origine nantais (RON) kinase messenger RNA (mRNA), paralleled by a significant reduction of glioma cell migration. In contrast to other cancer types, in glioma cells MitA did not alter the expression of the immunorelevant genes major histocompatibility complex I class related (MIC)-A, MIC-B or UL16 binding proteins (ULBP). We conclude that, whereas MitA-mediated reduction of XIAP expression and sensitization to Apo2L/TRAIL are cell line specific, its antimigratory effects are more general and might be the result of altered expression of MMP, VEGF, and/or RON kinase. Therefore, MitA might be a potential agent to reduce glioma cell migration.

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http://dx.doi.org/10.1007/s11060-010-0266-xDOI Listing
February 2011

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