TY - JOUR T1 - Antitumor Indolequinones Induced Apoptosis in Human Pancreatic Cancer Cells via Inhibition of Thioredoxin Reductase and Activation of Redox Signaling. JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.076091 SP - mol.111.076091 AU - Chao Yan AU - David Siegel AU - Jeffery Newsome AU - Aurelie Chilloux AU - Christopher J Moody AU - David Ross Y1 - 2011/12/06 UR - http://molpharm.aspetjournals.org/content/early/2011/12/06/mol.111.076091.abstract N2 - Indolequinones (IQs) were developed as potential antitumor agents against human pancreatic cancer. IQs exhibited potent antitumor activity against the human pancreatic cancer cell line MIA PaCa-2 with growth inhibitory IC50 values in the low nanomolar range. IQs were found to induce time- and concentration-dependent apoptosis and to be potent inhibitors of thioredoxin reductase 1 (TR1) in MIA PaCa-2 cells at concentrations equivalent to those inducing growth inhibitory effects. The mechanism of inhibition of TR1 by the IQs was studied in detail in cell-free systems using purified enzyme. The C-terminal selenocysteine of TR1 was characterized as the primary adduction site of the IQ-derived reactive iminium using LC-MS/MS analysis. Inhibition of TR1 by IQs in MIA PaCa-2 cells resulted in a shift of thioredoxin-1 redox state to the oxidized form and activation of the p38/JNK MAPK signaling pathway. Oxidized thioredoxin is known to activate apoptosis signal-regulating kinase 1 (ASK1), an upstream activator of p38/JNK in the MAPK signaling cascade and this was confirmed in our study providing a potential mechanism for IQ-induced apoptosis. These data describe the redox and signaling events involved in the mechanism of growth inhibition induced by novel inhibitors of TR1 in human pancreatic cancer cells. ER -