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Dicumarol Inhibition of NADPH:Quinone Oxidoreductase Induces Growth Inhibition of Pancreatic Cancer via a Superoxide-mediated Mechanism¹

Departments of Surgery [J. J. C.], Radiation Oncology [J. J. C., A. W. G., J. L., Y. P. Z., C. J. D. W., F. E. D., L. W. O.], and the Holden Comprehensive Cancer Center [J. J. C., F. E. D., L. W. O.], University of Iowa College of Medicine [M. G.], Iowa City, IA, and Veterans Affairs Medical Center [J. J. C., M. M. H.], Iowa City, Iowa 52242

NADPH:quinone oxidoreductase (NQO₁), a homodimeric, ubiquitous, flavoprotein, catalyzes the two-electron reduction of quinones to hydroquinones. This reaction prevents the one-electron reduction of quinones by cytochrome P450 reductase and other flavoproteins that would result in oxidative cycling with generation of superoxide (O₂^·-). NQO₁ gene regulation may be up-regulated in some tumors to accommodate the needs of rapidly metabolizing cells to regenerate NAD⁺. We hypothesized that pancreatic cancer cells would exhibit high levels of this enzyme, and inhibiting it would suppress the malignant phenotype. Reverse transcription-PCR, Western blots, and activity assays demonstrated that NQO₁ was up-regulated in the pancreatic cancer cell lines tested but present in very low amounts in the normal human pancreas. To determine whether inhibition of NQO₁ would alter the malignant phenotype, MIA PaCa-2 pancreatic cancer cells were treated with a selective inhibitor of NQO₁, dicumarol. Dicumarol increased intracellular production of O₂^·-, as measured by hydroethidine staining, and inhibited cell growth. Both of these effects were blunted with infection of an adenoviral vector containing the cDNA for manganese superoxide dismutase. Dicumarol also inhibited cell growth, plating efficiency, and growth in soft agar. We conclude that inhibition of NQO₁ increases intracellular O₂^·- production and inhibits the in vitro malignant phenotype of pancreatic cancer. These mechanisms suggest that altering the intracellular redox environment of pancreatic cancer cells may inhibit growth and delineate a potential strategy directed against pancreatic cancer.

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