The indolequinone ES936 {5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]
indole-4,7-dione} was previously developed in our lab as an
antitumor agent against
pancreatic cancer. The objective of this study was to identify
indolequinones with improved potency against
pancreatic cancer and to define their mechanisms of action.
Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and BxPC-3 were used in in vitro assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) and clonogenic assays];
indolequinones displayed potent cytotoxicity against all three cell lines, and two specific classes of indolequinone were particularly potent agents. These
indolequinones induced caspase-dependent apoptosis but no redox cycling or oxidative stress in MIA PaCa-2 and BxPC-3 cells. Selected
indolequinones were also screened against the NCI-60 cell line panel and were found to be particularly effective against colon, renal, and
melanoma cancer cells. A potential target of these
indolequinones was identified as
thioredoxin reductase.
Indolequinones were found to be potent inhibitors of
thioredoxin reductase activity both in
pancreatic cancer cells and in cell-free systems. The mechanism of action of the
indolequinones was shown to involve metabolic reduction, loss of a leaving group to generate a reactive electrophile resulting in alkylation of the
selenocysteine residue in the active site of
thioredoxin reductase. In vivo efficacy of the
indolequinones was also tested in the MIA PaCa-2 pancreatic
tumor xenograft in nude mice, and lead
indolequinones demonstrated high efficacy and low toxicity. Inhibition of
thioredoxin reductase represents a potential novel target in
pancreatic cancer and may provide a
biomarker of effect of lead
indolequinones in this type of
cancer.