Abstract 1131: Blocking ATP delivery to hexokinase II in glioblastoma is a promising therapeutic strategy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.1131-1131
• Main Authors: Luk, Peter P., Chung, Sylvia A., Shen, Han, Decollogne, Stephanie, Dilda, Pierre J., McDonald, Kerrie L., Hogg, Philip J.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-1131

Glioblastoma has a 5-year survival of less than 5% and is responsible for more years of life lost than any other malignancy, making it a challenging therapeutic problem. Healthy cells mainly rely on oxidative phosphorylation to catabolize glucose, while glioblastoma cells use aerobic glycolysis. The first step in glycolysis, conversion of glucose to glucose-6-phosphate using ATP, is catalyzed by hexokinase and glioblastoma tumors employ an isoform (HKII) that is bound to mitochondria via interaction with the outer-membrane voltage dependent anion channel. The prevailing theory is that this localization affords HKII preferential access to the mitochondrial ATP via inner-membrane adenine nucleotide translocase (ANT) to rapidly phosphorylate and trap glucose, thus initiating glycolysis across the cell cytosol. We have tested this hypothesis using a novel water-soluble organoarsenical, PENAO, to inactivate ANT (1). Treatment of glioblastoma cell lines and primary glioma initiating cells with PENAO inhibited acid (lactate) production, a measure of cancer cell glycolysis, at a half-maximal inhibitory concentration (IC50) of 1.5 µM, which supports the hypothesis. Proper functioning of ANT is also important for mitochondrial integrity and low micromolar concentrations of PENAO increased the cytosolic levels of superoxide, disrupted the mitochondrial trans-membrane potential and inhibited O2 utilization in glioblastoma cells. Blocking ANT with PENAO resulted in inhibition of glioblastoma cell migration at IC50 value of 1.4 µM, proliferation arrest at IC50 values of 0.3-4.5 µM and mitochondrial-mediated apoptotic cell death at PENAO concentrations of 0.3-5 µM. These effects were observed under both normoxic and hypoxic (1% O2) conditions. PENAO has up to 440- and 171-fold greater anti-proliferative activity than temozolomide or carboplatin, typical drugs used to treat glioblastoma, in glioblastoma cell lines and primary glioma initiating cells. PENAO was found to cross the intact blood-brain-barrier in mice and administration of 1 mg/kg/day PENAO to ten mice bearing subcutaneous glioblastoma tumors resulted in eight partial and two complete tumor responses. There were no signs or symptoms of treatment toxicity. These findings indicate that blocking ATP delivery to hexokinase II in glioblastoma by inhibiting mitochondrial ANT is a promising therapeutic strategy. The efficacy of PENAO in in vitro and in vivo models of glioblastoma supports its clinical development as