Abstract 3355: Inhibiting glyoxylase 1 as a strategy to target highly glycolytic cancer cells

Cancer cells typically display altered glucose metabolism characterized by a preference of aerobic glycolysis (Warburg effect) resulting in higher levels of glycolytic waste including methylglyoxal (MG). GLO1 (Glyoxalase 1) functions in the detoxification of MG: MG reacts with glutathione to form hemithioacetal, which is converted into S-D-Lactoylglutathione by GLO1 and further metabolised into D-lactate by GLO2. When not detoxified, MG acts as a cytotoxic reagent by forming DNA- and protein-adducts (advanced glycation end products = AGEs) that subsequently lead to cell death. Therefore, GLO1 has been discussed as a potential anti-tumor target for highly glycolytic cancers. We confirmed previous reports that GLO1 expression is elevated in several tumor entities as compared to normal tissue. Tumor cells with high GLO1 expression levels are proposed to be highly dependent on GLO1 for removal of toxic MG. Therefore sensitivity to GLO1 inhibition was probed in a panel of cell lines covering lung, colon, breast, prostate and skin cancer with varying GLO1 amplification and expression levels. siRNA-mediated knock down of GLO1 did neither cause significant reduction of cellular proliferation nor significant induction of apoptosis in any of the tested tumor cells. Furthermore, treatment of these cells with a potent GLO1 inhibitor (Chiba et al. Bioorg Med Chem Lett. 2012, IC50=11 nM) did not affect proliferation or induce apoptosis at sub-µM concentrations. In addition, no increase in...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Biology Source Type: research