title: 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, C-238, 4200 East 9th Avenue, Denver, CO 80262, USA.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Dehn
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.forename: Khan Shoeb
authors.initials: KS
authors.lastname: Zafar
authors.forename: Philip
authors.initials: P
authors.lastname: Reigan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Swann
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Moody
authors.forename: David
authors.initials: D
authors.lastname: Ross
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D045563:Indolequinones / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000032:analysis / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D013481:Superoxides / Q000032:analysis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C444919:5-methoxy-1,2-dimethyl-3-((4-nitrophenoxy)methyl)indole-4,7-dione; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D045563:Indolequinones; D013481:Superoxides; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human