Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma
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Wei Jiang,1 Susan Finniss,1 Simona Cazacu,1 Cunli Xiang,1 Ziv Brodie,1 Tom Mikkelsen1, Laila Poisson2, David B. Shackelford3, Chaya Brodie1,4
1Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA
2Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA
3Department of Pulmonary and Critical Care Medicine, UCLA David Geffen School of Medicine Los Angeles, CA, USA
4Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
Chaya Brodie, email: email@example.com
Keywords: glioma stem cells, phenformin, non-cording RNAs, HMGA2, dichloroacetate
Received: April 21, 2016 Accepted: June 29, 2016 Published: July 29, 2016
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.
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