ATPS-09A MITOCHONDRIAL METABOLISM INHIBITOR RADIO-SENSITIZES GLIOBLASTOMA TUMOURS IN MICE

Abstract

PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) is a mitochondrial metabolism inhibitor that is currently in Phase I clinical testing in patients with solid tumors refractory to standard therapy. PENAO is a cysteine mimetic trivalent arsenical that enters cells via an organic ion transporter and accumulates in the mitochondrial matrix where the arsenical moiety cross-links Cys160 and Cys257 on the matrix face of adenine nucleotide translocase (ANT), which inactivates the transporter. ANT inactivation leads to partial uncoupling of oxidative phosphorylation, increase in superoxide production, proliferation arrest and ultimately apoptosis of the cell. PENAO only reacts with ANT when cells are proliferating as Cys160 and Cys257 appear to be disulfide bonded in growth quiescent cells, and so unreactive towards PENAO. PENAO inhibited the proliferation of a panel of 13 glioblastoma cells, including cells from both primary and recurrent tumors, with IC50 values ranging from 0.3-4.5 µM. The IC50 values for proliferation arrest of normal lung fibroblasts and astrocytes are 9 µM and 7 µM, respectively, indicating selectivity for glioblastoma cells. Administration of PENAO (3 mg/kg/day) to mice bearing subcutaneous glioblastoma xenografts resulted in significant inhibition of tumor growth (7 partial and 3 complete responses). Ki67 and TUNEL staining of tumor sections showed that PENAO induced tumor cell growth arrest and death, respectively. Pharmacokinetic analysis demonstrated that PENAO readily crossed the blood-brain-barrier and accumulated specifically in tumor tissue. There were also no signs or symptoms of treatment toxicity. As PENAO induces superoxide production in glioblastoma cells, we hypothesized that PENAO in combination with radiation would synergise. Combining 2 Gy/day radiation (20 Gy total) with intraperitoneal administration of 20 mg/kg/day PENAO, resulted in significant improvement in median survival in an orthotopic glioblastoma murine model. These in-vitro and in-vivo results show that PENAO is a potential new therapeutic for glioblastoma, alone or in combination with radiation therapy