a trxr inhibiting goldi nhc complex induces apoptosis through ask1p38mapk signaling in pancreatic cancer cells background cancer cells in the advanced stage show aberrant antioxidant capacity to detoxify excessive ros resulting in the compensation for intrinsic oxidative stress and therapeutic resistance pdac is one of the most lethal cancers and often associated with a high accumulation of ros recent studies identified goldi nhc complexes as potent trxr inhibitors suppressing cell growth in a wide spectrum of human malignant cell lines at the low micromolar concentration however the mechanism of action is not completely elucidated yetmethods to understand the biological function of goldi nhc complexes in pdac we used a recently published goldi nhc complex mc3 and evaluated its antiproliferative effect in four pdac cell lines determined by mtt and srb assays in further detailed analysis we analyzed cellular ros levels using the ros indicator dhe and mitochondrial membrane potential indicated by the dye jc1 in panc1 we also analyzed cell cycle arrest and apoptosis by facs to elucidate the role of specific cell signaling pathways in mc3induced cell death coincubation with ros scavengers a p38mapk inhibitor and sirna mediated depletion of ask1 were performed and results were analyzed by immunoblotting elisamicroarrays qrtpcr and immunoprecipitationresults our data demonstrate that mc3 efficiently suppressed cell growth and induced cell cycle arrest and apoptosis in pancreatic cancer cells in particular in the gemcitabineresistant cancer cells panc1 and aspc1 treatment with mc3 resulted in a substantial alteration of the cellular redox homeostasis leading to increased ros levels and a decrease in the mitochondrial membrane potential ros scavengers suppressed ros formation and rescued cells from damage on the molecular level mc3 blocked the interaction of trx with ask1 and subsequently activated p38associated signaling furthermore inhibition of this pathway by using ask1 sirna or a p38 inhibitor clearly attenuated the effect of mc3 on cell proliferation in panc1 and aspc1conclusions our results confirm that mc3 is a trxr inhibitor and show mc3 induced apoptosis in gemcitabineresistant pdacs mc3 mediated cell death could be blocked by using antioxidants ask1 sirna or p38 inhibitor suggesting that the trxask1p38 signal cascade played an important role in goldi nhc complexesmediated cellular damage