Chapter 13
Prevention of Cancer by Agents That Suppress Production of Oxidants
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W. Troll, J. S. Lim, and K. Frenkel Department of Environmental Medicine, New York University Medical Center, New York, NY 10016
Structurally different cancer preventive agents suppress superoxide anion radical (Ο2 •) and hydrogen peroxide (H O ) production by phorbol ester tumor promoter-activated human neutrophils. This inhibition of H O generation can serve as a facile system for iden tifying and measuring the activity of cancer preventive agents. Those agents inhibit inflammation and oxidative D N A damage as well as tumor promotion. H O causes formation of strand breaks in D N A and oxidation of D N A bases. Cancer preventive agents include retinoids, garlic oil, protease inhibitors (PIs) isolated from natural sources (e.g., soybeans, potatoes and tomatoes), (-)•epigallocatechin gallate (EGCG) (isolated from green tea), vitamin Β 3 (nicotinic acid), and trans-tamoxifen (ΤΑΜ). Nicotinic acid and ΤΑΜ are the new additions to this growing group of inhibitors. Nico tinic acid may act through formation of the cofactor [e.g., nicotine -adenine-dinucleotide (NAD )] of many dehydrogenases. Phorbol ester-mediated H O induction in neutrophils — which is not in habitable by estradiol — is suppressed by the antiestrogen ΤΑΜ, which points to additional properties of ΤΑΜ that contribute to the prevention of breast cancer but are not estrogenic in nature. -
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The epidemiological data on cancer identified vegetarian populations as having significantly lower incidences of breast, colon and prostate cancer than do nonvegetarian popuations. The cause of this lower occurrence may be related to their low-fat diet. The formation of oxidized D N A bases elicited by the consumption of a diet with a high meat/fat content has been shown in human volunteers (1). Dietary fat has been identified as a tumor promoter and acts in a manner similar to the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The promoting action of fat may be mediated by fatty acid metabolites such as arachidonic acid, which mimics the action of TPA by inducing H2O2 formation (2). The contribution of fat to the increased rate of breast cancer in the world population was shown by the epidemiological studies of Carroll (3). Armstrong and Doll (4)
0097-6156/94/0547-0116$06.00/0 © 1994 American Chemical Society
Ho et al.; Food Phytochemicals for Cancer Prevention II ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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reported the lowest rate of breast cancer to be in the population in Thailand, where the food staples are rice and soybeans, and the highest rate in the Netherlands, where meat and dairy products contribute to a high fat content in the diet. Another factor, which is perhaps more important than fat as a promoting agent, is the abundance of chemopreventive agents in vegetarian diets. These compounds that can prevent cancer were recognized and described by Wattenberg (5). The first agents to be identified as suppressors of tumor promotion were Pis, which occur in all seeds presumably to prevent their consumption by insects. Pis have been shown to interfere with insect digestive enzymes (6). While Pis are widely distributed in vegetable products, they are not available in pure form in sufficient quantités to use in human studies. Dietary Protease Inhibitors Suppress Cancer The 'western' diet, which consists of a high proportion of meat and a relatively low proportion of vegetables, appears to be responsible for the higher occurrence rate of breast, colon and prostate cancers. People who eat diets rich in rice, maize and beans have lower incidences of these cancers. Since seeds contain high concentrations of Pis, they may limit the occurrence of these cancers in humans (3,4,7-9). The initial clue for this possibility was discovered when the synthetic Pis trypsin or chymotrypsin were applied to mouse skin where they interfered with TPA-induced tumor promotion in the two-stage carcinogenesis model (10). Further observations demonstrated that tumor development was suppressed by feeding Pis to animals. ε-Amino caproic acid, an inhibitor of plasminogen activator, blocks dimethylhydrazine-induced colon cancer in mice when added to the drinking water (77). Diets containing soybean Pis reduce the size of tumors in mouse skin treated with 4-nitroquinoline-N-oxide and TPA (72), breast tumors in Sprague-Dawley rats subjected to ionizing radiation (73), spontaneous liver cancer in C 3 H mice (14) and colon cancer in mice (75). The possible mechanisms of this anticarcinogenesis include interference with oxyradical formation by neutrophils, suppression of oncogene expression and modulation of adenosine diphosphate ribosyltransferase, which are described in the next section. Interference with Formation of Reactive Oxygen Species (ROS) Tumor promoters, including phorbol esters, teleocidin and aplysiatoxin, induce an oxidative burst in polymorphonuclear leukocytes (PMNs), which results in the for mation of Ο2"·, H2O2, hydroxyl radicals and singlet oxygen (16-21). Phorbol derivatives that are inactive as tumor promoters (i.e., phorbol, phorbol diacetate and 4- 0-methyl-TPA) fail to elicit production of 0 · and H 0 by PMNs (22,23). Pis have been shown to suppress the formation of Ο2"· and H2O2 in human neutrophils treated with tumor promoters. In an extensive study by Frenkel et al. (23), the Pis that inhibited chymotrypsin were identified as the primary agents responsible for this effect. Nicotinamide, benzamide and 3-aminobenzamide preferentially inhibit chy motrypsin and suppress the production of Ο2"· by TPA-treated human neutrophils, as shown by measuring SOD-inhibitable cytochrome reduction (Table I) (24,25). Oxygen radicals, H2O2 and organic peroxides have been identified as agents that contribute to tumor promotion, perhaps by forming oxidized D N A bases [e.g., 5- hydroxymethyl uracil (HMU), thymine glycol (TG) or 8-hydroxylguanine 2
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(8-OHG)] (26,27). Moreover, all chemopreventive agents tested, including Pis, garlic oil, retinoids, sarcophytol A , E G C G , vitamin Β 3 , nicotinamide and ΤΑΜ, interfere with oxidative processes by suppressing the generation of Ο2"·, H2O2 and other active oxygen species induced by promoting carcinogens in various cell systems (27).
Table I. Inhibition of Carcinogenesis, ROS and Oxidative DNA Base Damage by Chemopreventive Agents
Agent
Carcinogenesis
Sarcophytol A EGCG Tamoxifen Protease inhibitors Potato inhibitors 1 & 2 Chicken ovoinhibitor Bowman-Birk inhibitor Garlic and onion oils Nicotinic acid Nicotinamide Benzamide 3 - Aminobenzamide
Inhibition of: ROS H M U , T G or 8-OHG Reference
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+ + + +
21,28-30 27,31-33 27,34,35 15,23,24,28
+ + + + +
+ + + + +
nd nd nd nd nd
36-38 39 39 39 39
nd: Not determined.
Tumor promoter-induced oxidative modification of D N A bases is a conse quence of H2O2 production due to TPA-mediated stimulation of neutrophils, which may lead to the activation of oncogenes (22,27,40,41). The contribution of onco genes to promotion was demonstrated by Balmain and his colleagues (42), who showed in mouse skin that transfection by some oncogenes mimicked promotion. Like oxidant formation, oncogene expression also can be suppressed by chemo preventive agents. For example, ras oncogene transformation of NIH-3T3 cells is inhibited by Pis, retinoids, sarcophytol A and ΤΑΜ. The decrease in oncogeneinduced transformation serves as a useful method for measuring and identifying these anticarcinogenic agents, and may present another important mechanism of chemoprevention that is related to the formation of oxidized D N A bases. Fos and jun oncogenes have been shown to be induced by TPA and by oxidants (27,43). Tamoxifen — A Novel Chemopreventive Agent Clinicians have successfully used ΤΑΜ as therapy for estrogen-dependent human breast cancer and in the prevention of its recurrence. This prevention was thought to be due to T A M ' s interference with estrogen-mediated tumor promotion, but ΤΑΜ has wider anticarcinogenic properties, placing it in the class of chemo preventive agents that suppress tumor promotion in two-stage carcinogenesis by interfering with protein kinase C activity.
Ho et al.; Food Phytochemicals for Cancer Prevention II ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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ΤΑΜ at a low dose (5 μΜ) totally inhibits HC>2 formation by TPA-treated human neutrophils. Interestingly, β-estradiol (10 μΜ) also slightly inhibits the oxidative burst of neutrophils. ΤΑΜ and β-estradiol additively inhibit H2O2 form ation with pretreatment of the phagocytes (34). TPA-treated neutrophils (44) and HeLa cells (45) contain increased levels of HMU. Dietary fat, which is a risk factor for breast cancer, also induces the for mation of HMU in the DNA of human white blood cells (7). ΤΑΜ prevents the TPA-induced cellular formation of HMU, both in cell culture and mouse skin (46 and unpublished data). Rather than acting as an antiestrogen, ΤΑΜ may suppress the dietary fat-induced HMU in the same manner as it inhibits HMU formation in duced by TPA-activated neutrophils. 2
Conclusions The formation of oxidized DNA bases by active oxygen species is qualitatively similar to damage caused by ionizing radiation, which can act as a cancer initiator as well as a promoter. The formation of oxidized DNA bases may lead to muta tions, a characteristic of initiation of cancer by oxidants and other carcinogens. Therefore, preventing the formation of these oxidized DNA bases may block the process of tumorigenesis. Chemopreventive substances are a large group of structurally varied agents that interfere with one or more steps of carcinogenesis. They may suppress the activation of carcinogens or the promotion and progression of cancer, some of them by suppressing the formation of H2O2 and Ο2"·. ΤΑΜ inhibits neutrophil infiltration, as well as formation of H2O2 and oxidized DNA bases in TPA-treated mouse skin (27). It also suppresses formation of H2O2 by TPA-activated human neutrophils when used at a concentration that is comparable to that present in the plasma of patients who received ΤΑΜ (34). Hence ΤΑΜ may be capable of preventing initiation as well as promotion of breast cancer, a possibility that can be explored by further epidemiological studies of Τ AM's role in cancer prevention. Literature Cited 1. Djuric, Z.; Heilbrun, L. K.; Reading, Β. Α.; Boomer, Α.; Valeriote, F. Α.; Martino, S. J. Natl. Cancer Inst. 1991, 83, 766-769. 2. Badwey, J. Α.; Curnutte, J. T.; Robinson, J. M.; Berde, C. B.; Karnovsky, M . J.; Karnovsky, M. L. J. Biol. Chem. 1984, 259(12), 7870-7877. 3. Carroll, K. Cancer Res. 1975, 35, 3374-3383. 4. Armstrong, B.; Doll, R. Int. J. Cancer 1975, 15, 617-631. 5. Wattenberg, L. W. In Carcinogenesis; Slaga, T. J., Ed.; Raven Press: New York, 1980; Vol. 5, pp. 85-98. 6. Birk, Y. Int. J. Peptide Protein Res. 1985, 25, 113-131. 7. Wynder, E.; Mabuchi, K.; Whitmore, W. Cancer 1971, 28, 344-360. 8. Phillips, R. L. Cancer Res. 1975, 35, 3513-3522. 9. Correa, P. Cancer Res. 1981, 41, 3685-3690. 10. Troll, W.; Klassen, Α.; Janoff, A. Science 1970, 169, 1211-1213. 11. Corasanti, J. G.; Hobika, G.H.; Markus, G. Science 1982, 216, 1020-1021. 12. Troll, W.; Belman, S.; Wiesner, R.; Shellabarger, C. J. In Biological Function of Proteinases; Holzer, H.; Tschesche, H., Eds.; Springer-Verlag: Berlin, 1979; pp 165-170.
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Ho et al.; Food Phytochemicals for Cancer Prevention II ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
