title: Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma.
abstract: Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis. Here, we studied the effects of phenformin, a mitochondrial complex I inhibitor and more potent chemical analog of the diabetes drug metformin on the inhibition of cell growth and induction of apoptosis of glioma stem cells (GSCs) using both in vitro and in vivo models. Phenformin inhibited the self-renewal of GSCs, decreased the expression of stemness and mesenchymal markers and increased the expression of miR-124, 137 and let-7. Silencing of let-7 abrogated phenformin effects on the self-renewal of GSCs via a pathway associated with inhibition of H19 and HMGA2 expression. Moreover, we demonstrate that phenformin inhibited tumor growth and prolonged the overall survival of mice orthotopically transplanted with GSCs. Combined treatments of phenformin and temozolomide exerted an increased antitumor effect on GSCs in vitro and in vivo. In addition, dichloroacetate, an inhibitor of the glycolysis enzyme pyruvate dehydrogenase kinase, that decreases lactic acidosis induced by biguanides, enhanced phenformin effects on the induction of cell death in GSCs and prolonged the survival of xenograft-bearing mice. Our results demonstrate for the first time that phenformin targets GSCs and can be efficiently combined with current therapies for GBM treatment and GSC eradication.
authors.affiliation: Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Finniss
authors.affiliation: Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Cazacu
authors.affiliation: Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Cunli
authors.initials: C
authors.lastname: Xiang
authors.affiliation: Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Brodie
authors.affiliation: Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Laila
authors.initials: L
authors.lastname: Poisson
authors.affiliation: Department of Pulmonary and Critical Care Medicine, UCLA David Geffen School of Medicine Los Angeles, CA, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Shackelford
authors.affiliation: Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.|Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Chaya
authors.initials: C
authors.lastname: Brodie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation; D003999:Dichloroacetic Acid / Q000494:pharmacology; D058492:Drug Repositioning; D020868:Gene Silencing; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D025743:HMGA2 Protein / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry; D016086:Lentivirus; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010629:Phenformin / Q000494:pharmacology*; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors
chemical_list: C094335:H19 long non-coding RNA; D025743:HMGA2 Protein; D007004:Hypoglycemic Agents; C509207:MIRN124 microRNA, human; C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; C487931:mirnlet7 microRNA, human; D003999:Dichloroacetic Acid; D010629:Phenformin
keywords: HMGA2; dichloroacetate; glioma stem cells; non-cording RNAs; phenformin