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Beatrice and Samuel A. Seaver Laboratory, Division of Hematology-Oncology, Department of Medicine, Cornell University Medical College, New York, New York 10021
Few nonphagocytic cells are known to generate reactive oxygen intermediates. Based on horseradish peroxidase-dependent, catalase-inhibitable oxidation of fluorescent scopoletin, seven human tumor cell lines constitutively elaborated H2O2 at rates (up to 0.5 nmol/104 cells/h) large enough that cumulative amounts at 4 h were comparable to the amount of H2O2 produced by phorbol ester-triggered neutrophils. Superoxide dismutase-inhibitable ferricytochrome c reduction was detectable at much lower rates. H2O2 production was inhibited by diphenyleneiodonium, a flavoprotein binder (concentration producing 50% inhibition, 0.3 µM), and diethyldithiocarbamate, a divalent cation chelator (concentration producing 50% inhibition, 3 µM), but not by cyanide or azide, inhibitors of electron transport, or by agents that inhibit xanthine oxidase, polyamine oxidase, or cytochrome P450. Cytochrome b559, present in human phagocytes and lymphocytes, was undetectable in these tumor cells by a sensitive spectrophotometric method. Mouse fibroblasts transfected with human tyrosinase complementary DNA made melanin, but not H2O2. Constitutive generation of large amounts of reactive oxygen intermediates, if it occurs in vivo, might contribute to the ability of some tumors to mutate, inhibit antiproteases, injure local tissues, and therefore premote tumor heterogeneity, invasion, and metastasis.
1 This work was supported by National Cancer Institute Grant 5 PDI CA33049-08.
2 To whom requests for reprints should be addressed, at Division of Hematology-Oncology, Cornell University Medical College, 1300 York Avenue, Box 57, New York, NY 10021.
Received 8/16/90. Accepted 11/20/90.
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 R. D'Anna, H. Le Buanec, G. Alessandri, A. Caruso, A. Burny, R. Gallo, J.-F. Zagury, D. Zagury, and P. D'Alessio Selective Activation of Cervical Microvascular Endothelial Cells by Human Papillomavirus 16-E7 Oncoprotein J Natl Cancer Inst, December 19, 2001; 93(24): 1843 - 1851. [Abstract] [Full Text] [PDF]
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 S. Ehrt, D. Schnappinger, S. Bekiranov, J. Drenkow, S. Shi, T. R. Gingeras, T. Gaasterland, G. Schoolnik, and C. Nathan Reprogramming of the Macrophage Transcriptome in Response to Interferon-{gamma} and Mycobacterium tuberculosis: Signaling Roles of Nitric Oxide Synthase-2 and Phagocyte Oxidase J. Exp. Med., October 15, 2001; 194(8): 1123 - 1140. [Abstract] [Full Text] [PDF]
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R. S. Arnold, J. Shi, E. Murad, A. M. Whalen, C. Q. Sun, R. Polavarapu, S. Parthasarathy, J. A. Petros, and J. D. Lambeth Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1 PNAS, April 25, 2001; (2001) 101505898. [Abstract] [Full Text]
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X. Lin, K. Ramamurthi, M. Mishima, A. Kondo, and S. B. Howell p53 Interacts with the DNA Mismatch Repair System to Modulate the Cytotoxicity and Mutagenicity of Hydrogen Peroxide Mol. Pharmacol., April 13, 2001; 58(6): 1222 - 1229. [Abstract] [Full Text]
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K. HORINO, A. L. KINDEZELSKII, V. M. ELNER, B. A. HUGHES, and H. R. PETTY Tumor cell invasion of model 3-dimensional matrices: demonstration of migratory pathways, collagen disruption, and intercellular cooperation FASEB J, April 1, 2001; 15(6): 932 - 939. [Abstract] [Full Text] [PDF]
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S. S. Brar, T. P. Kennedy, A. R. Whorton, A. B. Sturrock, T. P. Huecksteadt, A. J. Ghio, and J. R. Hoidal Reactive oxygen species from NAD(P)H:quinone oxidoreductase constitutively activate NF-{kappa}B in malignant melanoma cells Am J Physiol Cell Physiol, March 1, 2001; 280(3): C659 - C676. [Abstract] [Full Text] [PDF]
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S. Adris, E. Chuluyan, A. Bravo, M. Berenstein, S. Klein, M. Jasnis, C. Carbone, Y. Chernajovsky, and O. L. Podhajcer Mice Vaccination with Interleukin 12-transduced Colon Cancer Cells Potentiates Rejection of Syngeneic Non-Organ-related Tumor Cells Cancer Res., December 1, 2000; 60(23): 6696 - 6703. [Abstract] [Full Text]
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S. Zienolddiny, D. Ryberg, and A. Haugen Induction of microsatellite mutations by oxidative agents in human lung cancer cell lines Carcinogenesis, August 1, 2000; 21(8): 1521 - 1526. [Abstract] [Full Text] [PDF]
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 E. Cavalieri, K. Frenkel, J. G. Liehr, E. Rogan, and D. Roy Chapter 4: Estrogens as Endogenous Genotoxic Agents--DNA Adducts and Mutations J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 75 - 94. [Abstract] [Full Text] [PDF]
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E. Shacter, J. A. Williams, R. M. Hinson, S. Senturker, and Y.-j. Lee Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis Blood, July 1, 2000; 96(1): 307 - 313. [Abstract] [Full Text] [PDF]
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R. I. Salganik, C. D. Albright, J. Rodgers, J. Kim, S. H. Zeisel, M. S. Sivashinskiy, and T. A. Van Dyke Dietary antioxidant depletion: enhancement of tumor apoptosis and inhibition of brain tumor growth in transgenic mice Carcinogenesis, May 1, 2000; 21(5): 909 - 914. [Abstract] [Full Text] [PDF]
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K. Suzukawa, K. Miura, J. Mitsushita, J. Resau, K. Hirose, R. Crystal, and T. Kamata Nerve Growth Factor-induced Neuronal Differentiation Requires Generation of Rac1-regulated Reactive Oxygen Species J. Biol. Chem., April 28, 2000; 275(18): 13175 - 13178. [Abstract] [Full Text] [PDF]
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S. Kondo, S. Toyokuni, T. Tanaka, H. Hiai, H. Onodera, H. Kasai, and M. Imamura Overexpression of the hOGG1 Gene and High 8-Hydroxy-2'-deoxyguanosine (8-OHdG) Lyase Activity in Human Colorectal Carcinoma: Regulation Mechanism of the 8-OHdG Level in DNA Clin. Cancer Res., April 1, 2000; 6(4): 1394 - 1400. [Abstract] [Full Text]
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 E Maellaro, S Dominici, B Del Bello, M. Valentini, L Pieri, P Perego, R Supino, F Zunino, E Lorenzini, A Paolicchi, et al. Membrane gamma-glutamyl transpeptidase activity of melanoma cells: effects on cellular H(2)O(2) production, cell surface protein thiol oxidation and NF-kappa B activation status J. Cell Sci., January 8, 2000; 113(15): 2671 - 2678. [Abstract] [PDF]
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G.-U. Bae, D.-W. Seo, H.-K. Kwon, H. Y. Lee, S. Hong, Z.-W. Lee, K.-S. Ha, H.-W. Lee, and J.-W. Han Hydrogen Peroxide Activates p70S6k Signaling Pathway J. Biol. Chem., November 12, 1999; 274(46): 32596 - 32602. [Abstract] [Full Text] [PDF]
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M. Wartenberg, H. Diedershagen, J. Hescheler, and H. Sauer Growth Stimulation Versus Induction of Cell Quiescence by Hydrogen Peroxide in Prostate Tumor Spheroids Is Encoded by the Duration of the Ca2+ Response J. Biol. Chem., September 24, 1999; 274(39): 27759 - 27767. [Abstract] [Full Text] [PDF]
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J. Wenk, P. Brenneisen, M. Wlaschek, A. Poswig, K. Briviba, T. D. Oberley, and K. Scharffetter-Kochanek Stable Overexpression of Manganese Superoxide Dismutase in Mitochondria Identifies Hydrogen Peroxide as a Major Oxidant in the AP-1-mediated Induction of Matrix-degrading Metalloprotease-1 J. Biol. Chem., September 3, 1999; 274(36): 25869 - 25876. [Abstract] [Full Text] [PDF]
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C. Patterson, J. Ruef, N. R. Madamanchi, P. Barry-Lane, Z. Hu, C. Horaist, C. A. Ballinger, A. R. Brasier, C. Bode, and M. S. Runge Stimulation of a Vascular Smooth Muscle Cell NAD(P)H Oxidase by Thrombin. EVIDENCE THAT p47phox MAY PARTICIPATE IN FORMING THIS OXIDASE IN VITRO AND IN VIVO J. Biol. Chem., July 9, 1999; 274(28): 19814 - 19822. [Abstract] [Full Text] [PDF]
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F. L. Meyskens Jr., J. A. Buckmeier, S. E. McNulty, and N. B. Tohidian Activation of Nuclear Factor-{{kappa}}B in Human Metastatic Melanoma Cells and the Effect of Oxidative Stress Clin. Cancer Res., May 1, 1999; 5(5): 1197 - 1202. [Abstract] [Full Text] [PDF]
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A. L. Jackson, R. Chen, and L. A. Loeb Induction of microsatellite instability by oxidative DNA damage PNAS, October 13, 1998; 95(21): 12468 - 12473. [Abstract] [Full Text] [PDF]
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 A. M. Zafari, M. Ushio-Fukai, M. Akers, Q. Yin, A. Shah, D. G. Harrison, W. R. Taylor, and K. K. Griendling Role of NADH/NADPH Oxidase–Derived H2O2 in Angiotensin II–Induced Vascular Hypertrophy Hypertension, September 1, 1998; 32(3): 488 - 495. [Abstract] [Full Text] [PDF]
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 L. Mabile, O. Meilhac, I. Escargueil-Blanc, M. Troly, M.-T. Pieraggi, R. Salvayre, and A. Negre-Salvayre Mitochondrial Function Is Involved in LDL Oxidation Mediated by Human Cultured Endothelial Cells Arterioscler Thromb Vasc Biol, August 1, 1997; 17(8): 1575 - 1582. [Abstract] [Full Text]
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 K. Irani, Y. Xia, J. L. Zweier, S. J. Sollott, C. J. Der, E. R. Fearon, M. Sundaresan, T. Finkel, and P. J. Goldschmidt-Clermont Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts Science, March 14, 1997; 275(5306): 1649 - 1652. [Abstract] [Full Text]
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T. J. Preston, W. J. Muller, and G. Singh Scavenging of Extracellular H2O2 by Catalase Inhibits the Proliferation of HER-2/Neu-transformed Rat-1 Fibroblasts through the Induction of a Stress Response J. Biol. Chem., March 16, 2001; 276(12): 9558 - 9564. [Abstract] [Full Text] [PDF]
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M. Wartenberg, F. C. Ling, M. Schallenberg, A. T. Baumer, K. Petrat, J. Hescheler, and H. Sauer Down-regulation of Intrinsic P-glycoprotein Expression in Multicellular Prostate Tumor Spheroids by Reactive Oxygen Species J. Biol. Chem., May 11, 2001; 276(20): 17420 - 17428. [Abstract] [Full Text] [PDF]
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R. S. Arnold, J. Shi, E. Murad, A. M. Whalen, C. Q. Sun, R. Polavarapu, S. Parthasarathy, J. A. Petros, and J. D. Lambeth Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1 PNAS, May 8, 2001; 98(10): 5550 - 5555. [Abstract] [Full Text] [PDF]
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S. S. Brar, T. P. Kennedy, A. B. Sturrock, T. P. Huecksteadt, M. T. Quinn, A. R. Whorton, and J. R. Hoidal An NAD(P)H oxidase regulates growth and transcription in melanoma cells Am J Physiol Cell Physiol, June 1, 2002; 282(6): C1212 - C1224. [Abstract] [Full Text] [PDF]
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