Unknown

PMX464 (AW464) differentially inhibits Trx1 function in colorectal tumour (HT29), endothelial (HUVEC) and fibroblast (MRCV) cells. PMX464 inhibits the Trx1-dependent reduction of insulin in assays with pure enzymes, giving an IC50 of 10 μM. PMX464 inhibited Trx1 function, under normoxia, at doses of 0.5 and 1 μM (20% inhibition). Trx1 inhibition was greater under hypoxic conditions and was observed at lower drug doses. This inhibition, combined with the lack of effect on Trx1 protein levels and the concomitant increase in TrxR1 protein levels, suggests a functional inhibition of Trx1. Enzyme assay results: cell lysate system – insulin reduction experiments for percentage of functional Trx1 per cell in HT29, proliferating HUVEC and quiescent HUVEC treated with PMX464 (0.01–1 μM for HT29; 0.5 μM for HUVEC) for 72 h under normoxia or hypoxia (1% O2, final 48 of the 72 h drug incubation period).