title: Glioblastoma stem cells: a new target for metformin and arsenic trioxide.
abstract: The high malignancy of glioblastoma has been recently attributed to the presence, within the tumor, of glioblastoma stem cells (GSC) poorly responsive to chemo- and radiotherapy. Here, the potential employment of metformin and arsenic trioxide (ATO) in glioblastoma therapy is discussed focusing on their effects on GSC. Metformin exerts anticancer effects by primarily blocking the pivotal LKB1/AMPK/mTOR/S6K1 pathway-dependent cell growth, induces selective lethal effects on GSC by impairing the GSC-initiating spherogenesis and inhibits the proliferation of CD133+ cells, while having a low or null effect on differentiated glioblastoma cells and normal human stem cells. Metformin and ATO induce autophagy and apoptosis in glioma cells by inhibiting and stimulating the PI3K/Akt and the mitogen-activated protein kinase pathways, respectively. Both drugs promote differentiation of GSC into non-tumorigenic cells. In this regard, metformin acts via activation of the AMPK-FOXO3 axis, whereas ATO blocks the interleukin 6-induced promotion of STAT3 phosphorylation. Blood-brain barrier, easily crossed by metformin but not by ATO, undergoes important glioblastoma-induced alterations that increase its permeability, thus allowing ATO to distribute more into the glioblastoma bulk than in the normal brain parenchyma. A prompt clinical assessment of metformin and ATO in glioblastoma patients would represent a valid attempt to improve their survival.
authors.affiliation: Laboratory of Pharmacology and Toxicologyy, Department of Life, Health and Environmental Sciences, University of L'Aquila, Coppito, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Carmignani
authors.affiliation: Laboratory of Pharmacology and Toxicologyy, Department of Life, Health and Environmental Sciences, University of L'Aquila, Coppito, Italy.
authors.forename: A R
authors.initials: AR
authors.lastname: Volpe
authors.affiliation: Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
authors.forename: M
authors.initials: M
authors.lastname: Aldea
authors.affiliation: Department of Immunology, Ion Chiricuta Comprehensive Cancer Center, Cluj Napoca, Romania.
authors.forename: O
authors.initials: O
authors.lastname: Soritau
authors.affiliation: Departments of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
authors.forename: A
authors.initials: A
authors.lastname: Irimie
authors.affiliation: Neurosurgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
authors.forename: I S
authors.initials: IS
authors.lastname: Florian
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Tomuleasa
authors.affiliation: Neurosurgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
authors.forename: A
authors.initials: A
authors.lastname: Baritchii
authors.affiliation: Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
authors.forename: B
authors.initials: B
authors.lastname: Petrushev
authors.affiliation: Pharmaceutical Botany, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
authors.forename: G
authors.initials: G
authors.lastname: Crisan
authors.affiliation: Nuclear Medicine Unit, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Valle
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010087:Oxides / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011836:Radiation Tolerance
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000077237:Arsenic Trioxide