Search results

A hallmark of cancer cells is their ability to reprogram nutrient metabolism. Thus, disruption to this phenotype is a potential avenue for anti-cancer therapy. Herein we used a phenotypic chemical library screening approach to identify molecules that disrupted nutrient metabolism (by increasing cellular oxygen consumption rate) and were toxic to cancer cells. From this screen we discovered a 1,4-Naphthoquinone (referred to as BH10) that is toxic to a broad range of cancer cell types. BH10 has improved cancer-selective toxicity compared to doxorubicin, 17-AAG, vitamin K3, and other known anti-cancer quinones. BH10 increases glucose oxidation via both mitochondrial and pentose phosphate pathways, decreases glycolysis, lowers GSH:GSSG and NAPDH/NAPD(+) ratios exclusively in cancer cells, and induces necrosis. BH10 targets mitochondrial redox defence as evidenced by increased mitochondrial peroxiredoxin 3 oxidation and decreased mitochondrial aconitase activity, without changes in markers of cytosolic or nuclear damage. Over-expression of mitochondria-targeted catalase protects cells from BH10-mediated toxicity, while the thioredoxin reductase inhibitor auranofin synergistically enhances BH10-induced peroxiredoxin 3 oxidation and cytotoxicity. Overall, BH10 represents a 1,4-Naphthoquinone with an improved cancer-selective cytotoxicity profile via its mitochondrial specificity. ; Hope Funds for Cancer Research [HFCR-14-06-04]; Cancer Institute NSW ECF [2018/ECF003]; UNSW; Cancer Institute NSW CDF; Australian Postgraduate AwardAustralian Government; UNSW Sydney ; FLB was supported by a postdoctoral fellowship from the Hope Funds for Cancer Research (HFCR-14-06-04) and is currently supported by a Cancer Institute NSW ECF (2018/ECF003). Financial support was provided in part by a UNSW faculty collaboration grant to KLH and NK. JM is supported by a Cancer Institute NSW CDF. GEM was supported by an Australian Postgraduate Award. KGRQ is supported by a UNSW Sydney Scientia Fellowship.

Understanding the status of contaminants in the marine environment is a requirement of European Union Directives and the Regional Seas Conventions, so that measures to reduce pollution can be identified and their efficacy assessed. The international ICON workshop (Hylland et al., 2017) was developed in order to test an integrated approach to assessing both contaminant concentrations and their effects. This paper describes and assesses the concentrations of trace metals, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls in sediments, mussels, and fish collected from estuarine, coastal and offshore waters from Iceland to the Mediterranean Sea. For organic contaminants, concentrations progressively increased from Iceland, to the offshore North Sea, to the coastal seas, and were highest in estuaries. Metals had a more complex distribution, reflecting local anthropogenic inputs, natural sources and hydrological conditions. Use of internationally recognised assessment criteria indicated that at no site were concentrations of all contaminants at background and that concentrations of some contaminants were of significant concern in all areas, except the central North Sea. ; Postprint ; 1,953