Role of Reactive Oxygen Intermediates in Cellular Responses to Dietary Cancer Chemopreventive Agents

Abstract

Epidemiological studies continue to support the premise that diets rich in fruits and vegetables may offer protection against cancer of various anatomic sites. This correlation is quite persuasive for vegetables including Allium (e. g., garlic) and cruciferous (e. g., broccoli and watercress) vegetables. The bioactive food components responsible for the cancer chemopreventive effects of various edible plants have been identified. For instance, the anticancer effects of Allium and cruciferous vegetables are attributed to organosulfur compounds (e. g., diallyl trisulfide) and isothiocyanates (e. g., sulforaphane and phenethyl isothiocyanate), respectively. Bioactive food components with anticancer activity are generally considered to be antioxidants due to their ability to modulate expression/activity of antioxidative and phase 2 drug-metabolizing enzymes and scavenging free radicals. At the same time, more recent studies have provided convincing evidence to indicate that certain dietary cancer chemopreventive agents cause generation of reactive oxygen species (ROS) to trigger signal transduction culminating in cell cycle arrest and/or programmed cell death (apoptosis). Interestingly, the ROS generation by some dietary anticancer agents is tumor cell specific and does not occur in normal cells. This review summarizes experimental evidence supporting the involvement of ROS in cellular responses to cancer chemopreventive agents derived from common edible plants.

Abbreviations

AITC:allyl isothiocyanate

ARE:antioxidant response element

BITC:benzyl isothiocyanate

DAS:diallyl sulfide

DADS:diallyl disulfide

DATS:diallyl trisulfide

DR5:death receptor 5

ERK:extracellular signal-regulated kinase

ITCs:isothiocyanates

JNK:c-Jun N-terminal kinase

MMP:mitochondrial membrane potential

NAC:N-acetylcysteine

OSCs:organosulfur compounds

PEITC:phenethyl isothiocyanate

ROS:reactive oxygen species

SAC:S-allylcysteine

SAMC:S-allylmercaptocysteine

Key words

organosulfur compounds - isothiocyanates - isoflavones - curcumin - ROS - apoptosis - chemoprevention

References

• 1 Sporn M B. Chemoprevention of cancer.  Lancet. 1993;  342 1211-3
• 2 Wattenberg L W. Inhibitors of chemical carcinogenesis.  Adv Cancer Res. 1978;  26 197-226
• 3 Kelloff G J. Perspectives on cancer chemoprevention research and drug development.  Adv Cancer Res. 2000;  78 199-334
• 4 World Cancer Research Fund. Food, nutrition and the prevention of cancer: a global perspective. Washington DC; American Institute for Cancer Research 1997
• 5 Milner J A. Molecular targets for bioactive food components.  J Nutr. 2004;  134 2492S-8S
• 6 Liu R H. Health benefits of fruit and vegetables and from additive and synergistic combinations of phytochemicals.  Am J Clin Nutr. 2003;  78 517s-20s
• 7 Verhoeven D TH, Goldbohm R A, van Poppel G, Verhagen H, van den Brandt P A. Epidemiological studies on Brassica vegetables and cancer risk.  Cancer Epidemiol Biomarkers Prev. 1996;  5 733-48
• 8 Challier B, Perarnau J M, Viel J F. Garlic, onion and cereal fiber as protective factors for breast cancer: a French case-control study.  Eur J Epidemiol. 1998;  14 737-47
• 9 Davis C D, Milner J A. Diet and cancer prevention. In: Temple NJ, Wilson T, Jacobs DV, editors Nutritional health: strategies for disease prevention. Totowa; Humana Press 2006: 151-71
• 10 Surh Y J. Cancer chemoprevention with dietary phytochemicals.  Nat Rev Cancer. 2003;  3 768-80
• 11 Hu X, Benson P J, Srivastava S K, Mack L M, Xia H, Gupta V. et al . Glutathione S-transferases of female A/J mouse liver and forestomach and their differential induction by anti-carcinogenic organosulfides from garlic.  Arch Biochem Biophys. 1996;  336 199-214
• 12 Singh S V, Pan S S, Srivastava S K, Xia H, Hu X, Zaren H A. et al . Differential induction of NAD(P)H:quinone oxidoreductase by anti-carcinogenic organosulfides from garlic.  Biochem Biophys Res Commun. 1998;  244 917-20
• 13 Singh S V, Mack L M, Xia H, Srivastava S K, Hu X, Benson P J. et al . Differential induction of glutathione redox-cycle enzymes by anti-carcinogenic organosulfides from garlic.  Clin Chem Enzymol Commun. 1997;  7 287-97
• 14 Herman-Antosiewicz A, Singh S V. Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review.  Mutat Res. 2004;  555 121-31
• 15 Hecht S S. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism.  J Nutr. 1999;  129 768-74
• 16 Shishodia S, Chaturvedi M M, Aggarwal B B. Role of curcumin in cancer therapy.  Curr Probl Cancer. 2007;  31 243-305
• 17 Amagase H, Petesch B L, Matsuura H, Kasuga S, Itakura Y. Intake of garlic and its bioactive components.  J Nutr. 2001;  131 955S-62S
• 18 You W C, Blot W J, Chang Y S, Ershow A, Yang Z T, An Q. et al . Allium vegetables and reduced risk of stomach cancer.  J Natl Cancer Inst. 1989;  81 162-4
• 19 Steinmetz K A, Kushi L H, Bostick R M, Folsom A R, Potter J D. Vegetables, fruit, and colon cancer in the Iowa Women's Health Study.  Am J Epidemiol. 1994;  139 1-15
• 20 Hsing A W, Chokkalingam A P, Gao Y T, Madigan M P, Deng J, Gridley G. et al . Allium vegetables and risk of prostate cancer: a population-based study.  J Natl Cancer Inst. 2002;  94 1648-51
• 21 Belman S. Onion and garlic oils inhibit tumor promotion.  Carcinogenesis. 1983;  4 1063-5
• 22 Wargovich M J. Diallyl sulfide, a flavor component of garlic (Allium sativum) inhibits dimethylhydrazine-induced colon cancer.  Carcinogenesis. 1987;  8 487-9
• 23 Sparnins V L, Barany G, Wattenberg L W. Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse.  Carcinogenesis. 1989;  9 131-4
• 24 Wargovich M J, Woods C, Eng V WS, Stephens L C, Gray K. Chemoprevention of N-nitrosomethylbenzylamine-induced esophageal cancer in rats by the naturally occurring thioether, diallyl sulfide.  Cancer Res. 1988;  48 6872-5
• 25 Chen C, Pung D, Leong V, Hebbar V, Shen G, Nair S. et al . Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals.  Free Radic Biol Med. 2004;  37 1578-90
• 26 Herman-Antosiewicz A, Powolny A A, Singh S V. Molecular targets of cancer chemoprevention by garlic-derived organosulfides.  Acta Pharmacol Sin. 2007;  28 1355-64
• 27 Pedraza-Chaverrí J, González-Orozco A E, Maldonado P D, Barrera D, Medina-Campos O N, Hernández-Pando R. Diallyl disulfide ameliorates gentamicin-induced oxidative stress and nephropathy in rats.  Eur J Pharmacol. 2003;  18 71-8
• 28 Koh S H, Kwon H, Park K H, Ko J K, Kim J H, Hwang M S. et al . Protective effect of diallyl disulfide on oxidative stress-injured neuronally differentiated PC12 cells.  Brain Res Mol Brain Res. 2005;  133 176-86
• 29 Mizuguchi S, Takemura S, Minamiyama Y, Kodai S, Tsukioka T, Inoue K. et al . S-allyl cysteine attenuated CCl4-induced oxidative stress and pulmonary fibrosis in rats.  Biofactors. 2006;  26 81-92
• 30 Kim J M, Lee J C, Chang N, Chun H S, Kim W K. S-Allyl-L-cysteine attenuates cerebral ischemic injury by scavenging peroxynitrite and inhibiting the activity of extracellular signal-regulated kinase.  Free Radic Res. 2006;  40 827-35
• 31 Kim J M, Chang H J, Kim W K, Chang N, Chun H S. Structure-activity relationship of neuroprotective and reactive oxygen species scavenging activities for allium organosulfur compounds.  J Agric Food Chem. 2006;  54 6547-53
• 32 Liu K L, Chen H W, Wang R Y, Lei Y P, Sheen L Y, Lii C K. DATS reduces LPS-induced iNOS expression, NO production, oxidative stress, and NF-κB activation in RAW 264.7 macrophages.  J Agric Food Chem. 2006;  54 3472-8
• 33 Ravi R, Bedi A. NF-κB in cancer – a friend turned foe.  Drug Resist Updat. 2004;  7 53-67
• 34 Filomeni G, Aquilano K, Rotilio G, Ciriolo M R. Reactive oxygen species-dependent c-Jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide.  Cancer Res. 2003;  63 5940-9
• 35 Xiao D, Choi D, Johnson D E, Vogel V G, Johnson C S, Trump D L. et al . Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2.  Oncogene. 2004;  23 5594-606
• 36 Kim Y A, Xiao D, Xiao H, Powolny A A, Lew K L, Reilly M L. et al . Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak.  Mol Cancer Ther. 2007;  6 1599-609
• 37 Das A, Banik N L, Ray S K. Garlic compounds generate reactive oxygen species leading to activation of stress kinases and cysteine proteases for apoptosis in human glioblastoma T98G and U87MG cells.  Cancer. 2007;  110 1083-94
• 38 Xiao D, Herman-Antosiewicz A, Antosiewicz J, Xiao H, Brisson M, Lazo J S. et al . Diallyl trisulfide-induced G₂-M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc25C.  Oncogene. 2005;  24 6256-68
• 39 Knowles L M, Milner J A. Diallyl disulfide inhibits p34(cdc2) kinase activity through changes in complex formation and phosphorylation.  Carcinogenesis. 2000;  21 1129-34
• 40 Hosono T, Fukao T, Ogihara J, Ito Y, Shiba H, Seki T. et al . Diallyl trisulfide suppresses the proliferation and induces apoptosis of human colon cancer cells through oxidative modification of beta-tubulin.  J Biol Chem. 2005;  280 41 487-93
• 41 Wu X J, Kassie F, Mersch-Sundermann V. The role of reactive oxygen species (ROS) production on diallyl disulfide (DADS) induced apoptosis and cell cycle arrest in human A549 lung carcinoma cells.  Mutat Res. 2005;  579 115-24
• 42 Herman-Antosiewicz A, Singh S V. Checkpoint kinase 1 regulates diallyl trisulfide-induced mitotic arrest in human prostate cancer cells.  J Biol Chem. 2005;  280 28 519-28
• 43 Herman-Antosiewicz A, Stan S D, Hahm E R, Xiao D, Singh S V. Activation of a novel ataxia-telangiectasia mutated and Rad3 related/checkpoint kinase 1-dependent prometaphase checkpoint in cancer cell by diallyl trisulfide, a promising cancer chemopreventive constituent of processed garlic.  Mol Cancer Ther. 2007;  6 1249-61
• 44 Liu Q, Guntuku S, Cui X S, Matsuoka S, Cortez D, Tamai K. et al . Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.  Genes Dev. 2000;  14 1448-59
• 45 Pinto J T, Krasnikov B F, Cooper A JL. Redox-sensitive proteins are potential targets of garlic-derived mercaptocysteine derivatives.  J Nutr. 2006;  136 835S-41S
• 46 Antosiewicz J, Herman-Antosiewicz A, Marynowski S W, Singh S V. c-Jun NH2-terminal kinase signaling axis regulates diallyl trisulfide-induced generation of reactive oxygen species and cell cycle arrest in human prostate cancer cells.  Cancer Res. 2006;  66 5379-86
• 47 Munday R, Munday J S, Munday C M. Comparative effects of mono-, di-, tri-, and tetrasulfides derived from plants of the Allium family: redox cycling in vitro and hemolytic activity and Phase 2 enzyme induction in vivo.  Free Radic Biol Med. 2003;  34 1200-11
• 48 Fahey J W, Zalcmann A T, Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants.  Phytochemistry. 2001;  56 5-51
• 49 Cohen J H, Kristal A R, Stanford J L. Fruit and vegetable intakes and prostate cancer risk.  J Natl Cancer Inst. 2001;  92 61-8
• 50 Ambrosone C B, McCann S E, Freudenheim J L, Marshall J R, Zhang Y, Shields P G. Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli a source of isothiocyanates, but is not modified by GST genotype.  J Nutr. 2004;  134 1134-8
• 51 Zhang Y, Talalay P, Cho C G, Posner G H. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure.  Proc Natl Acad Sci USA. 1992;  89 2399-403
• 52 Zhang Y, Kensler T W, Choi C G, Posner G H, Talalay P. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates.  Proc Natl Acad Sci USA. 1994;  91 3147-50
• 53 Chung F L, Conaway C C, Rao C V, Reddy B S. Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate.  Carcinogenesis. 2000;  21 2287-91
• 54 Fahey J W, Haristoy X, Dolan P M, Kensler T W, Scholtus I, Stephenson K K. et al . Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors.  Proc Natl Acad Sci USA. 2002;  99 7610-5
• 55 Gills J J, Jeffery E H, Matusheski N V, Moon R C, Lantvit D D, Pezzuto J M. Sulforaphane prevents mouse skin tumorigenesis during the stage of promotion.  Cancer Lett. 2006;  236 72-9
• 56 Thejass P, Kuttan G. Antimetastatic activity of sulforaphane.  Life Sci. 2006;  78 3043-50
• 57 Barcelo S, Gardiner J M, Gescher A, Chipman J K. CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane.  Carcinogenesis. 1996;  17 277-82
• 58 Brooks J D, Paton V G, Vidanes G. Potent induction of phase 2 enzymes in human prostate cells by sulforaphane.  Cancer Epidemiol Biomarkers Prev. 2001;  10 949-54
• 59 Wattenberg L W. Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds.  J Natl Cancer Inst. 1977;  58 395-8
• 60 Wattenberg L W. Inhibitory effects of benzyl isothiocyanate administered shortly before diethylnitrosamine or benzo[a]pyrene on pulmonary and forestomach neoplasia in A/J mice.  Carcinogenesis. 1987;  8 1971-3
• 61 Hirose M, Yamaguchi T, Kimoto N, Ogawa K, Futakuchi M, Sano M. et al . Strong promoting activity of phenethyl isothiocyanate and benzyl isothiocyanate on urinary bladder carcinogenesis in F344 male rats.  Int J Cancer. 1998;  77 773-7
• 62 Singh A V, Xiao D, Lew K L, Dhir R, Singh S V. Sulforaphane induces caspase-mediated apoptosis in cultured PC-3 human prostate cancer cells and retards growth of PC-3 xenografts in vivo.  Carcinogenesis. 2004;  25 83-90
• 63 Myzak M C, Tong P, Dashwood W M, Dashwood R H, Ho E. Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects.  Exp Biol Med. 2007;  232 227-34
• 64 Xiao D, Zeng Y, Choi S, Lew K L, Nelson J B, Singh S V. Caspase dependent apoptosis induction by phenethyl isothiocyanate, a cruciferous vegetable derived cancer chemopreventive agent, is mediated by Bak and Bax.  Clin Cancer Res. 2005;  11 2670-9
• 65 Xiao D, Lew K L, Zeng Y, Xiao H, Marynowski S W, Dhir R. et al . Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential.  Carcinogenesis. 2006;  27 2223-34
• 66 Srivastava S K, Xiao D, Lew K L, Hershberger P, Kokkinakis D M, Johnson C S. et al . Allyl isothiocyanate, a constituent of cruciferous vegetables, inhibits growth of PC-3 human prostate cancer xenografts in vivo.  Carcinogenesis. 2003;  24 1665-70
• 67 Fahey J W, Talalay P. Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes.  Food Chem Toxicol. 1999;  37 973-9
• 68 Keum Y S, Yu S, Chang P PJ, Yuan X, Kim J H, Xu C. et al . Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells.  Cancer Res. 2006;  66 8804-13
• 69 Gao X, Dinkova-Kostova A T, Talalay P. Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: the indirect antioxidant effects of sulforaphane.  Proc Natl Acad Sci USA. 2001;  98 15 221-6
• 70 Wang W, Wang S, Howie A F, Beckett G J, Mithen R, Bao Y. Sulforaphane, erucin, and iberin up-regulate thioredoxin reductase 1 expression in human MCF-7 cells.  J Agric Food Chem. 2005;  53 1417-21
• 71 Bacon J R, Plumb G W, Howie A F, Beckett G J, Wang W, Bao Y. Dual action of sulforaphane in the regulation of thioredoxin reductase and thioredoxin in human HepG2 and Caco-2 cells.  J Agric Food Chem. 2007;  55 1170-6
• 72 Miyoshi N, Takabayashi S, Osawa T, Nakamura Y. Benzyl isothiocyanate inhibits excessive superoxide generation in inflammatory leukocytes: implication for prevention against inflammation-related carcinogenesis.  Carcinogenesis. 2004;  25 567-75
• 73 Nakamura Y, Ohigashi H, Masuda S, Murakami A, Morimitsu Y, Kawamoto Y. et al . Redox regulation of glutathione S-transferase induction by benzyl isothiocyanate: correlation of enzyme induction with the formation of reactive oxygen intermediates.  Cancer Res. 2000;  60 219-25
• 74 Nakamura Y, Kawakami M, Yoshihiro A, Miyoshi N, Ohigashi H, Kawai K. et al . Involvement of the mitochondrial death pathway in chemopreventive benzyl isothiocyanate-induced apoptosis.  J Biol Chem. 2002;  277 8492-9
• 75 Payen L, Courtois A, Loewert M, Guillouzo A, Fardel O. Reactive oxygen species-related induction of multidrug resistance-associated protein 2 expression in primary hepatocytes exposed to sulforaphane.  Biochem Biophys Res Commun. 2001;  282 257-63
• 76 Singh S V, Srivastava S K, Choi S, Lew K L, Antosiewicz J, Xiao D. et al . Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species.  J Biol Chem. 2005;  280 19 911-24
• 77 Pham N A, Jacobberger J W, Schimmer A D, Cao P, Gronda M, Hedley D W. The dietary isothiocyanate sulforaphane targets pathways of apoptosis, cell cycle arrest, and oxidative stress in human pancreatic cancer cells and inhibits tumor growth in severe combined immunodeficient mice.  Mol Cancer Ther. 2004;  3 1239-48
• 78 Yeh C T, Yen G C. Effect of sulforaphane on metallothionein expression and induction of apoptosis in human hepatoma HepG2 cells.  Carcinogenesis. 2005;  26 2138-48
• 79 Kim H, Kim E H, Eom Y W, Kim W H, Kwon T K, Lee S J. et al . Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant hepatoma cells to TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of DR5.  Cancer Res. 2006;  66 1740-50
• 80 Cho S D, Li G, Hu H, Jiang C, Kang K S, Lee Y S. et al . Involvement of c-Jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by sulforaphane in DU145 prostate cancer cells.  Nutr Cancer. 2005;  52 213-24
• 81 Xiao D, Vogel V, Singh S V. Benzyl isothiocyanate-induced apoptosis in human breast cancer cells is initiated by reactive oxygen species and regulated by Bax and Bak.  Mol Cancer Ther. 2006;  5 2931-45
• 82 Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H. et al . Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate.  Cancer Cell. 2006;  10 241-52
• 83 Chang W H, Liu J J, Chen C H, Huang T S, Lu F J. Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by fermented soy milk.  Nutr Cancer. 2002;  43 214-26
• 84 Salvi M, Brunati A M, Clari G, Toninello A. Interaction of genistein with the mitochondrial electron transport chain results in opening of the membrane transition pore.  Biochim Biophys Acta. 2002;  1556 187-96
• 85 Macho A, Blazquez M V, Navas P, Munoz E. Induction of apoptosis by vanilloid compounds does not require de novo gene transcription and activator protein 1 activity.  Cell Growth Differ. 1998;  9 277-86
• 86 Kim S, Moon A. Capsaicin-induced apoptosis of H-ras-transformed human breast epithelial cells is Rac-dependent via ROS generation.  Arch Pharm Res. 2004;  27 845-9
• 87 Hail J r. N, Lotan R. Examining the role of mitochondrial respiration in vanilloid-induced apoptosis.  J Natl Cancer Inst. 2002;  94 1281-92
• 88 Fujisawa S, Atsumi T, Ishihara M, Kadoma Y. Cytotoxicity, ROS-generation activity and radical-scavenging activity of curcumin and related compounds.  Anticancer Res. 2004;  24 563-9
• 89 Shishodia S, Chaturvedi M M, Aggarwal B B. Role of curcumin in cancer therapy.  Curr Probl Cancer. 2007;  31 243-305
• 90 Ahsan H, Parveen N, Khan N U, Hadi S M. Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin.  Chem Biol Interact. 1999;  121 161-75
• 91 Bhaumik S, Anjum R, Rangaraj N, Pardhasaradhi B VV, Khar A. Curcumin mediated apoptosis in AK-5 tumor cells involves the production of reactive oxygen intermediates.  FEBS Lett. 1999;  456 311-4
• 92 Atsumi T, Fujisawa S, Tonosaki K. Relationship between intracellular ROS production and membrane mobility in curcumin- and tetrahydrocurcumin-treated human gingival fibroblasts and human submandibular gland carcinoma cells.  Oral Dis. 2005;  11 236-42
• 93 Atsumi T, Tonosaki K, Fujisawa S. Comparative cytotoxicity and ROS generation by curcumin and tetrahydrocurcumin following visible-light irradiation or treatment with horseradish peroxidase.  Anticancer Res. 2007;  27 363-71
• 94 Chen J, Wanming D, Zhang D, Liu Q, Kang J. Water-soluble antioxidants improve the antioxidant and anticancer activity of low concentrations of curcumin in human leukemia cells.  Pharmazie. 2005;  60 57-61
• 95 Elchuri S, Oberley T D, Qi W, Eisenstein R S, Roberts L J, Van Remmen H. et al . CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life.  Oncogene. 2005;  24 367-80
• 96 Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe S R. et al . Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging.  Physiol Genomics. 2003;  16 29-37
• 97 Ishii K, Zhen L X, Wang D H, Funamori Y, Ogawa K, Taketa K. Prevention of mammary tumorigenesis in acatalasemic mice by vitamin E supplementation.  Jpn J Cancer Res. 1996;  87 680-4
• 98 Egler R A, Fernandes E, Rothermund K, Sereika S, de Souza-Pinto N, Jaruga P. et al . Regulation of reactive oxygen species, DNA damage, and c-myc function by peroxiredoxin 1.  Oncogene. 2005;  24 8038-50
• 99 Ough M, Lewis A, Zhang Y, Hinkhouse M M, Ritchie J M, Oberley L W. et al . Inhibition of cell growth by overexpression of manganese superoxide dismutase (MnSOD) in human pancreatic carcinoma.  Free Radic Res. 2004;  38 1223-33
• 100 Venkataraman S, Jiang X, Weydert C, Zhang Y, Zhang H J, Goswami P C. et al . Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells.  Oncogene. 2005;  24 77-89
• 101 Cooke M S, Evans M D, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease.  FASEB J. 2003;  17 1195-214
• 102 Evans M D, Dizdaroglu M, Cooke M S. Oxidative DNA damage and disease: induction, repair and significance.  Mutat Res. 2004;  567 1-61
• 103 Dizdaroglu M, Jaruga P, Birincioglu M, Rodriguez H. Free radical-induced damage to DNA: mechanisms and measurement.  Free Radic Biol Med. 2002;  32 1102-15
• 104 Hawkins C L, Davies M J. Hypochlorite-induced damage to DNA, RNA, and polynucleotides: formation of chloramines and nitrogen-centered radicals.  Chem Res Toxicol. 2002;  15 83-92
• 105 Kawai Y, Morinaga H, Kondo H, Miyoshi N, Nakamura Y, Uchida K. et al . Endogenous formation of novel halogenated 2′-deoxycytidine. Hypohalous acid-mediated DNA modification at the site of inflammation.  J Biol Chem. 2004;  279 51 241-9
• 106 Doulias P T, Barbouti A, Galaris D, Ischiropoulos H. SIN-1-induced DNA damage in isolated human peripheral blood lymphocytes as assessed by single cell gel electrophoresis (comet assay).  Free Radic Biol Med. 2001;  30 679-85
• 107 Xiao D, Lew K L, Kim Y A, Zeng Y, Hahm E R, Dhir R. et al . Diallyl trisulfide suppresses growth of PC-3 human prostate cancer xenograft in vivo in association with Bax and Bak induction.  Clin Cancer Res. 2006;  15 6836-43
• 108 Choi S, Singh S V. Bax and Bak are required for apoptosis induction by sulforaphane, a cruciferous vegetable derived cancer chemopreventive agent.  Cancer Res. 2005;  65 2035-43