This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cullen, J. J. Articles by Oberley, L. W. Search for Related Content PubMed PubMed Citation Articles by Cullen, J. J. Articles by Oberley, L. W.

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.

This article has been cited by other articles:

				C. Polytarchou, R. Pfau, M. Hatziapostolou, and P. N. Tsichlis The JmjC Domain Histone Demethylase Ndy1 Regulates Redox Homeostasis and Protects Cells from Oxidative Stress Mol. Cell. Biol., December 15, 2008; 28(24): 7451 - 7464. [Abstract] [Full Text] [PDF]

				I. V. Lebedeva, Z.-z. Su, N. Vozhilla, L. Chatman, D. Sarkar, P. Dent, M. Athar, and P. B. Fisher Mechanism of In vitro Pancreatic Cancer Cell Growth Inhibition by Melanoma Differentiation-Associated Gene-7/Interleukin-24 and Perillyl Alcohol Cancer Res., September 15, 2008; 68(18): 7439 - 7447. [Abstract] [Full Text] [PDF]

				A. Miyanaga, A. Gemma, R. Noro, K. Kataoka, K. Matsuda, M. Nara, T. Okano, M. Seike, A. Yoshimura, A. Kawakami, et al. Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model Mol. Cancer Ther., July 1, 2008; 7(7): 1923 - 1930. [Abstract] [Full Text] [PDF]

				T Qi, J Han, Y Cui, M Zong, X Liu, and B Zhu Comparative proteomic analysis for the detection of biomarkers in pancreatic ductal adenocarcinomas J. Clin. Pathol., January 1, 2008; 61(1): 49 - 58. [Abstract] [Full Text] [PDF]

				S.-O. Lee, Y.-C. Chang, K. Whang, C.-H. Kim, and I.-S. Lee Role of NAD(P)H:quinone oxidoreductase 1 on tumor necrosis factor-{alpha}-induced migration of human vascular smooth muscle cells Cardiovasc Res, November 1, 2007; 76(2): 331 - 339. [Abstract] [Full Text] [PDF]

				J. Du, D. H. Daniels, C. Asbury, S. Venkataraman, J. Liu, D. R. Spitz, L. W. Oberley, and J. J. Cullen Mitochondrial Production of Reactive Oxygen Species Mediate Dicumarol-induced Cytotoxicity in Cancer Cells J. Biol. Chem., December 8, 2006; 281(49): 37416 - 37426. [Abstract] [Full Text] [PDF]

				M. S. Bentle, K. E. Reinicke, E. A. Bey, D. R. Spitz, and D. A. Boothman Calcium-dependent Modulation of Poly(ADP-ribose) Polymerase-1 Alters Cellular Metabolism and DNA Repair J. Biol. Chem., November 3, 2006; 281(44): 33684 - 33696. [Abstract] [Full Text] [PDF]

				W. Guo, P. Reigan, D. Siegel, J. Zirrolli, D. Gustafson, and D. Ross The Bioreduction of a Series of Benzoquinone Ansamycins by NAD(P)H:Quinone Oxidoreductase 1 to More Potent Heat Shock Protein 90 Inhibitors, the Hydroquinone Ansamycins Mol. Pharmacol., October 1, 2006; 70(4): 1194 - 1203. [Abstract] [Full Text] [PDF]

				K. S. Ahn, G. Sethi, A. K. Jain, A. K. Jaiswal, and B. B. Aggarwal Genetic Deletion of NAD(P)H:Quinone Oxidoreductase 1 Abrogates Activation of Nuclear Factor-{kappa}B, I{kappa}B{alpha} Kinase, c-Jun N-terminal Kinase, Akt, p38, and p44/42 Mitogen-activated Protein Kinases and Potentiates Apoptosis J. Biol. Chem., July 21, 2006; 281(29): 19798 - 19808. [Abstract] [Full Text] [PDF]

				D. L. Dehn, D. Siegel, K. S. Zafar, P. Reigan, E. Swann, C. J. Moody, and D. Ross 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. Mol. Cancer Ther., July 1, 2006; 5(7): 1702 - 1709. [Abstract] [Full Text] [PDF]

				W. Guo, P. Reigan, D. Siegel, J. Zirrolli, D. Gustafson, and D. Ross Formation of 17-Allylamino-Demethoxygeldanamycin (17-AAG) Hydroquinone by NAD(P)H:Quinone Oxidoreductase 1: Role of 17-AAG Hydroquinone in Heat Shock Protein 90 Inhibition Cancer Res., November 1, 2005; 65(21): 10006 - 10015. [Abstract] [Full Text] [PDF]

				A. Lewis, M. Ough, L. Li, M. M. Hinkhouse, J. M. Ritchie, D. R. Spitz, and J. J. Cullen Treatment of Pancreatic Cancer Cells with Dicumarol Induces Cytotoxicity and Oxidative Stress Clin. Cancer Res., July 1, 2004; 10(13): 4550 - 4558. [Abstract] [Full Text] [PDF]

				D. Siegel, D. L. Gustafson, D. L. Dehn, J. Y. Han, P. Boonchoong, L. J. Berliner, and D. Ross NAD(P)H:Quinone Oxidoreductase 1: Role as a Superoxide Scavenger Mol. Pharmacol., May 1, 2004; 65(5): 1238 - 1247. [Abstract] [Full Text]