title: Anti-inflammatory Effects of Atorvastatin in Human Glioblastoma Spheroids Cultured in a Three-dimensional Model: Possible Relevance to Glioblastoma Treatment.
abstract: Glioblastoma multiform (GBM) is a primary malignant brain tumor with a few therapeutic targets available for it. The interaction between the immune system and glioma is an important factor that could lead to novel therapeutic approaches to fight glioma. In this study, we investigated in vitro anti-inflammatory and apoptotic activity of atorvastatin in different concentrations 1, 5, and 10 μM on glioma spheroid cells cultured in a three-dimensional model in fibrin gel that indicate the complex in vivo microenvironment better than a simple two-dimensional cell culture. A mechanistic insight into the role of IL-17RA, TRAF3IP2, and apoptotic genes in progression of glioma could provide an important way for therapy of malignant tumors with manipulation of this inflammatory axis. To reach for these aims, after 24 and 48 h exposure with different concentrations of atorvastatin, caspase-8, caspase-3, Bcl-2, TRAF3IP2, and IL-17RA gene expression were assayed. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and cell cycle assay were used for evaluating the cell apoptosis and proliferation. The results showed that atorvastatin has anti-inflammatory and apoptotic effects against glioma spheroids. Atorvastatin induced the expression of caspase-3 and caspase-8 and downregulated the expression of Bcl-2, TRAF3IP2, and IL-17RA especially at 10 μM concentration. These effects are dose dependent. The most likely mechanisms are the inhibition of inflammation by IL-17RA interaction with TRAF3IP2 and NF-κB signaling pathway. Finally, these results suggest that atorvastatin could be used as an anti-cancer agent for glioblastoma treatment.
authors.affiliation: Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Neda
authors.initials: N
authors.lastname: Bayat
authors.affiliation: Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. ebrahimi_s@sina.tums.ac.ir.
authors.forename: Somayeh
authors.initials: S
authors.lastname: Ebrahimi-Barough
authors.affiliation: Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Abbas
authors.initials: A
authors.lastname: Norouzi-Javidan
authors.affiliation: Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Hooshang
authors.initials: H
authors.lastname: Saberi
authors.affiliation: Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad Mehdi Mokhtari
authors.initials: MMM
authors.lastname: Ardakan
authors.affiliation: School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Arman
authors.initials: A
authors.lastname: Ai
authors.affiliation: Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Soleimannejad
authors.affiliation: Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. jafar_ai@tums.ac.ir.|Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. jafar_ai@tums.ac.ir.
authors.forename: Jafar
authors.initials: J
authors.lastname: Ai
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069059:Atorvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D018929:Cell Culture Techniques / Q000379:methods*; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D000069059:Atorvastatin
keywords: Apoptosis; Atorvastatin; Glioblastoma spheroids; IL-17RA; Inflammation; TRAF3IP2