Abstract 1701: PENAO, a novel mitochondria-targeted agent, has shown potent antitumor effect on glioblastoma <i>in vitro</i> and <i>in vivo</i>.
Authors: Han Shen, Peter P. Luk, Sylvia A. Chung, Stephanie Decollogne, Pierre J. Dilda, Philip J. Hogg, Kerrie L. McDonald
Journal: Cancer Research (2013)

Abstract Despite advances in multimodal therapy, the prognosis in the great majority of patients with glioblastoma (GBM) is still dismal as almost all tumors relapse and result in disease-related death. New therapeutic strategies are urgently needed. PENAO, (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) is a novel mitochondria-targeted agent that inactivates adenine nucleotide translocase (ANT) located on the inner-membrane of mitochondria. PENAO blocks ANT delivery of ATP to mitochondrial-bound hexokinase II. This blockage inhibits glucose metabolism and triggers the mitochondrial permeability transition pore to leak which results in proliferation arrest and apoptotic cell death. In vitro, we tested the efficacy of PENAO on a panel of glioblastoma cell lines including immortalized and primary glioblastoma neural stem (GNS) cell lines. PENAO demonstrated potent anti-proliferative activity in all cells. The half-maximal inhibitory concentration (IC50) values for PENAO were in the range of 0.3-6 μM. Blocking ANT with PENAO resulted in inhibition of glioblastoma cell migration at concentration of 1.4 μM. PENAO (0.3-5 μM) increased caspase 3 and 9 activity levels indicative of the intrinsic apoptotic pathway. Proper functioning of ANT is also of importance for maintaining mitochondrial integrity. Low micromolar concentrations of PENAO inhibited oxygen utilization, increased the cytosolic levels of superoxide and depolarized the mitochondrial trans-membrane potential, which are responsible for the activation of mitochondria-mediated apoptosis in glioblastoma cells. In vivo, PENAO was found to cross the intact blood-brain-barrier in mice and continuous administration of 1 mg/kg/day PENAO to 10 mice bearing subcutaneous glioblastoma tumors for 28 days resulted in 8 partial and 2 complete tumor remissions. No signs or symptoms of treatment toxicity were noticed. To further inhibit glucose metabolism of glioblastoma, we tested the effectiveness of PENAO in combination with 2-deoxy-D-glucose, a glucose analogue that inhibits glycolysis via competitive inhibition of hexokinase. This dual-targeting of glucose metabolism by inhibiting both mitochondrial respiration and glycolysis led to synergistic effects and improved efficacy when measuring proliferation arrest in vitro. By targeting the glioblastoma aberrant metabolism of glucose better treatments for this cancer may arise. Citation Format: Han Shen, Peter P. Luk, Sylvia A. Chung, Stephanie Decollogne, Pierre J. Dilda, Philip J. Hogg, Kerrie L. McDonald. PENAO, a novel mitochondria-targeted agent, has shown potent antitumor effect on glioblastoma in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1701. doi:10.1158/1538-7445.AM2013-1701