PX 12 is a competitive, irreversible inhibitor of thioredoxin 1 (Trx1), acting by binding to Cys73 of this enzyme. As Trx1 is overexpressed in certain cancers, PX 12 is effective in suppressing the growth of cancer cells, with growth inhibition in a panel of 60 human tumors significantly correlated with expression of Trx1 mRNA. Through its effects on Trx1, PX 12 reduces hypoxia-induced HIF-1α protein levels (IC50 = 7.2 μM), as well as expression of VEGF (IC50 = 10.4 μM) and iNOS (IC50 = 18.1 μM), culminating in attenuation of the proliferation of MCF-7 cells (IC50 = 1.9 μM) and HT-29 cells (IC50 = 2.9 μM) as well as reduced microvessel density in MCF-7 tumor xenografts. PX 12 also blocks Trx-mediated activation of extracellular transglutaminase 2 (IC50 = ~3 μM) and Trx-1-increased expression and translation of CYP1B1.
