Abstract C176: Activity of novel indolequinone inhibitors of thioredoxin reductase 1 in pancreatic and colon cancers and in melanomas. Signaling mechanisms underlying antiproliferative activity.

Abstract

Abstract Novel indolequinones (including QG001, 5-methoxy-1-methyl-3-[(2,4,6-trifluorophenoxy)methyl]-1H-indole-4,7-dione and NJ824, 2-(hydroxymethyl)-5-methoxy-1-methyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione) demonstrated marked anti-proliferative activity in MIAPaCa-2 and BxPC-3 pancreatic cancer cells as well as in colon, melanoma and renal cell lines as indicated by testing in the NCI-60 cell line screen. In studies using MIAPaCa-2 and BxPC-3 cell lines we examined the mechanism of action of lead IQs and results demonstrated inhibition of the selenoprotein thioredoxin reductase 1 (TR1) and induction of apoptosis in pancreatic cell lines at doses approximating their IC50 values obtained from MTT growth inhibition assays. Other selenoproteins such as glutathione peroxidase were not inhibited and the depletion of cellular thiols was not observed following treatment with lead IQs indicating target selectivity. The mechanisms underlying IQ-induced apoptosis were investigated and lead IQs were found to induce oxidation of cellular thioredoxin subsequent to inhibition of thioredoxin reductase 1 and downstream activation of p38 and JNK leading to apoptosis. IQ-induced apoptosis could be inhibited by the use of p38 and JNK inhibitors in MIAPaCa-2 cells confirming the importance of this pathway. The role of ASK1 as an intermediary MAPKKK modulating signaling from oxidation of thioredoxin to activation of p38 and JNK was investigated in MIAPaCa-2 cells overexpressing ASK1 and lead IQs were found to induce ASK1 phosphorylation. Studies were extended to panels of eighteen human colorectal cancers and nineteen pancreatic cancer cell lines and lead IQs were found to exhibit marked growth inhibitory activity with IC50 values ranging from 0.05 to 0.5 micromolar. In vivo studies were performed in xenograft systems and lead IQs demonstrated significant growth inhibitory activity in both pancreatic and melanoma xenografts. These data demonstrate that this class of IQ has marked growth inhibitory activity in pancreatic, colon and melanoma tumors and are worthy of further translational evaluation as potential therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C176.