Plasma membrane drug efflux pumps of the multidrug resistance associated protein (MRP) family blunt the effectiveness of anticancer drugs and are often associated with drug resistance. GSAO, a tripeptide trivalent arsenical that targets a key mitochondrial transporter in angiogenic endothelial cells, is an example of a compound whose efficacy is limited by tumor cell expression of MRP isoforms 1 and 2. A cysteine mimetic analogue of GSAO was made, PENAO, which accumulates in cells 85 times faster than GSAO due to increased rate of entry and decreased rate of export via MRP1/2. The faster rate of accumulation of PENAO corresponds to a 44-fold increase in antiproliferative activity in vitro and approximately 20-fold better antitumor efficacy in vivo. This information could be used to improve the efficacy of other small molecule cancer therapeutics.

Background Here, we report on the occurrence of neural tube defects (NTDs) in four related Shetland sheepdog puppies. NTDs present as a range of congenital malformations affecting the spine, skull and associated structures. Despite the severity of these malformations and their relatively high prevalence in humans, the aetiology is not well understood. It is even less well characterised in veterinary medicine. Case report Affected puppies were investigated using computed tomography (CT) and then necropsy. CT identified a range of brain and spine abnormalities in the affected animals, including caudal anencephaly, encephalocele, spina bifida and malformed vertebrae. Other observed abnormalities in these puppies, including cranioschisis, atresia ani and hydrocephalus, may be secondary to, or associated with, the primary NTDs identified. Conclusion This case report describes multiple related cases of NTDs in an Australian cohort of dogs. This study also highlights the potential of advanced imaging techniques in identifying congenital anomalies in stillborn and neonatal puppies. Further research is required to investigate the aetiology of NTDs in this group of affected Shetland sheepdogs.

Tumors reorganize the metabolic steps used by normal tissues for glucose utilization and ATP production. Normal tissues rely heavily on oxidative phosphorylation for ATP, while tumor cells employ a route that includes a much greater dependency on glycolysis. This aberrant metabolism allows for tumor survival when oxygen is limiting while providing a mechanism to poison the extracellular environment with acid, which facilitates invasion and metastasis. In particular, tumors harness a crucial enzyme, hexokinase II (HKII), to entrap and channel glucose toward glycolysis. HKII is bound to mitochondria via interaction with the voltage dependent anion channel (VDAC). This affords HKII preferential access to the mitochondrial ATP via inner-membrane adenine nucleotide translocase (ANT) to rapidly phosphorylate and trap the incoming glucose, effectively initiating and regulating the glycolytic flux across the tumor cytosol. We have developed a novel covalent inhibitor of ANT called PENAO, (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) (1). This molecule blocks ANT delivery of ATP to VDAC-bound HKII, thus inhibiting tumor cell metabolism, and triggers the mitochondrial permeability transition pore, resulting in proliferation arrest and apoptotic cell death. PENAO rapidly enters the cell via an organic ion transporter and reacts with Cys160 and Cys257 on the matrix face of ANT, which leads to arrest of proliferation of the cell and then apoptosis. PENAO targets both proliferating endothelial and tumor cells. It is very well tolerated in mice and has potent anti-tumor activity in murine tumor models when administered either subcutaneously or intravenously. PENAO is the most potent anti-tumor compound of its type so far reported and will enter a Phase I/IIa clinical trial in adults with solid tumors refractory to standard therapy in 2011. 1. Dilda PJ, Decollogne S, Weerakoon L, et al. Optimization of the antitumor efficacy of a synthetic mitochondrial toxin by increasing the residence time in the cytosol. J Med Chem 2009;52(20):6209-16. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2824. doi:10.1158/1538-7445.AM2011-2824