The
enzyme NAD(P)H:
quinone oxidoreductase 1 (NQO1) has been found to be up-regulated in
pancreatic cancer as well as many other solid
tumors. A recent study showed that inhibition of NQO1 in
pancreatic cancer cells using the nonselective inhibitor
dicumarol suppressed the malignant phenotype. The authors suggested that inhibition of cell growth might result from an increase in intracellular
superoxide production due to inhibition of NQO1. We have recently shown that NQO1 can directly scavenge
superoxide and this effect may become physiologically relevant in cells containing high NQO1 levels. We therefore tested the hypothesis that 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]
indole-4,7-dione (ES936), a specific mechanism-based inhibitor of NQO1, would be an effective agent for the treatment of pancreatic
tumors. The human pancreatic tumor cell lines BxPC-3 and MIA PaCa-2 contain high levels of NQO1 activity and
protein as verified by immunoblot and immunocytochemical staining of human pancreatic
tumor cells. ES936 treatment inhibited NQO1 activity by >98% in MIA PaCa-2 and BxPC-3 cells. In addition, ES936 treatment induced growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide assay] in MIA PaCa-2 and BxPC-3 cells with an IC(50) of 108 and 365 nmol/L, respectively. Treatment of MIA PaCa-2 cells with ES936 also inhibited the ability of these cells to form colonies and grow in soft
agar in a dose-dependent manner. Treatment of mice carrying MIA PaCa-2 xenograft
tumors with ES936 resulted in a significant difference in growth rates in ES936-treated and
DMSO-treated (control)
tumors. Our data did not show an increase in either intracellular
superoxide production or oxygen consumption
after treatment of cells with ES936, contrary to the effects seen with
dicumarol. In summary, mechanism-based inhibitors of NQO1, such as ES936, may be useful therapeutic agents for the treatment of
pancreatic cancer, although the underlying mechanism seems to be independent of
superoxide generation.