Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma

Wei Jiang,Tom Mikkelsen,Laila Poisson,David B Shackelford,Cunli Xiang,Ziv Brodie,Susan Finniss,Chaya Brodie,Simona Cazacu

doi:10.18632/oncotarget.10919

Wei Jiang, Tom Mikkelsen + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.10919

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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.

Highlights

Glioblastoma (GBM) is the most common and aggressive astrocytic tumor and is characterized by increased proliferation, invasion into the surrounding normal tissue, robust angiogenesis and resistance to conventional therapies [1]
We examined the effects of phenformin on the self-renewal and stemness of these cells and included metformin for comparison in some of these studies
We found that treatment of the HF2414 glioma stem cells (GSCs) with phenformin (100 μM) significantly decreased the proliferation of the GSCs (Figure 1A)

Summary

Introduction

Glioblastoma (GBM) is the most common and aggressive astrocytic tumor and is characterized by increased proliferation, invasion into the surrounding normal tissue, robust angiogenesis and resistance to conventional therapies [1]. Additional studies have shown that metformin can inhibit cancer cell proliferation and induce cell cycle arrest in multiple cancer types, including glioma [6,7,8,9,10]. Metformin inhibits the growth of cancer stem cells (including GSCs), induces tumor regression and prolongs tumor remission in xenograft models [8, 11].

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