PX-12 (PX12) (1-methylpropyl 2-imidazolyl disulfide) is a small-molecule inhibitor of Trx-1 (thioredoxin-1), stimulates apoptosis, down-regulates HIF-1α and vascular endothelial growth factor (VEGF) and inhibits tumor growth in animal models. Since high levels of Trx-1 have been associated with colorectal, gastric and lung cancers, PX-12 is indicated as a potential cancer treatment in combination with chemotherapy for patients with advanced metastatic cancer. Initial trials correlated doses of Px-12 with increased patient survival.

HT29 cells:2.9 μM, MCF-7 cells:1.9 μM

In MCF-7 and HT-29 cells, PX-12 prevents the hypoxia (1% oxygen)-induced increase in HIF-1alpha protein, and decreases HIF-1-trans-activating activity, VEGF formation, and inducible nitric oxide synthase. PX-12 also inhibits the growth of MCF-7 and HT-29 cells with IC50s of 1.9 μM and 2.9 μM, respectively. [1] PX-12 also inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase. [2] In A549 cells, PX-12 inhibits cell growth via G2/M phase arrest, and Bax-mediated and ROS-dependent apoptosis. [3] In hepatocelluar carcinoma cells, PX-12 exerts a synergistic effect with 5-FU to significantly suppress tumorigenicity. [4]

In mice bearing MCF-7 tumor xenografts, PX-12 (12 mg/kg, i.p.) decreases HIF-1α and VEGF protein levels and microvessel density. [1]

Cell growth is measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cells are exposed to a range of concentrations of PX-12 or pleurotin for 16 h in air or hypoxia (1% oxygen). The cells are then washed with warm drug-free medium and grown in air for the remainder of the 72-h incubation.(Only for Reference)