Flavonoids: Antioxidants or signalling molecules?

Free Radical Biology and Medicine

Volumn 36, Issue 7, 2004, Pages 838-849

  Williams, Robert J ^a   Spencer, Jeremy P E ^a   Rice Evans, Catherine ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Antioxidant; Apoptosis; Cell signalling; Epicatechin; Flavonoid; Flavonoid metabolite; Free radicals; MAP kinase; Quercetin

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; ANTINEOPLASTIC AGENT; DRUG METABOLITE; EPICATECHIN; EPICATECHIN GALLATE; EPIGALLOCATECHIN GALLATE; FLAVONOID; HESPERETIN; ISOFLAVONE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE; NARINGENIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHYTOESTROGEN; PROTEIN BAD; PROTEIN KINASE B; PROTEIN KINASE C; PROTEIN TYROSINE KINASE; QUERCETIN; RESVERATROL; STRESS ACTIVATED PROTEIN KINASE;

ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; CANCER CELL; CELL PROTECTION; CONCENTRATION RESPONSE; DRUG ABSORPTION; DRUG MECHANISM; DRUG METABOLISM; ENZYME INHIBITION; HUMAN; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SKIN DEFECT; STRUCTURE ACTIVITY RELATION; ULTRAVIOLET B RADIATION;

ANTIOXIDANTS; FLAVONOIDS; HUMANS; MOLECULAR STRUCTURE; OXIDATIVE STRESS; PROTECTIVE AGENTS; QUERCETIN; RECEPTORS, NEUROTRANSMITTER; SIGNAL TRANSDUCTION;

EID: 1542605222     PISSN: 08915849     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.freeradbiomed.2004.01.001     Document Type: Review

References (129)

1. Rice-Evans C. Flavonoid antioxidants. Curr. Med. Chem. 8:2001;797-807.
2. Rice-Evans C.A., Miller N.J., Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med. 20:1996;933-956.
3. Rice-Evans C. Plant polyphenols: free radical scavengers or chain-breaking antioxidants? Biochem. Soc. Symp. 61:1995;103-116.
4. Spencer J.P.E., Schroeter H., Crossthwaithe A.J., Kuhnle G., Williams R.J., Rice-Evans C. Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts. Free Radic. Biol. Med. 31:2001;1139-1146.
5. Spencer J.P.E., Schroeter H., Kuhnle G., Srai S.K., Tyrrell R.M., Hahn U., Rice-Evans C. Epicatechin and its in vivo metabolite, 3′-O-methyl epicatechin, protect human fibroblasts from oxidative-stress-induced cell death involving caspase-3 activation. Biochem. J. 354:2001;493-500.
6. Schroeter H., Spencer J.P., Rice-Evans C., Williams R.J. Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem. J. 358:2001;547-557.
7. Spencer J.P.E., Schroeter H., Rechner A.R., Rice-Evans C. Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid. Redox. Signal. 3:2001;1023-1039.
8. Spencer J.P.E., Srai S.K., Rice-Evans C. Metabolism in the small intestine and gastrointestinal tract. Rice-Evans C., Packer L. Flavonoids in health and disease. 2003;363-390 Marcel Dekker, New York.
9. Walle T., Walgren R.A., Walle U.K., Galijatovic A., Vaidyanathan J.B. Understanding the bioavailability of flavonoids through studies in Caco-2 cells. Rice-Evans C., Packer L. Flavonoids in health and disease. 2003;349-362 Marcel Dekker, New York.
10. Day A.J., Williamson G. Absorption of quercetin glycosides. Rice-Evans C., Packer L. Flavonoids in health and disease. 2003;391-412 Marcel Dekker, New York.
11. Donovan J.L., Waterhouse A.L. Bioavailability of flavanol monomers. Rice-Evans C., Packer L. Flavonoids in health and disease. 2003;413-440 Marcel Dekker, New York.
12. Spencer J.P.E., Chowrimootoo G., Choudhury R., Debnam E.S., Srai S.K., Rice-Evans C. The small intestine can both absorb and glucuronidate luminal flavonoids. FEBS Lett. 458:1999;224-230.
13. Scheline R.R. Metabolism of oxygen heterocyclic compounds. CRC handbook of mammalian metabolism of plant compounds. 1999;243-295 CRC Press, Boca Raton, FL.
14. Spencer J.P.E., Abd El Mohsen M.M., Rice-Evans C. Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch. Biochem. Biophys. 2003.
15. Spencer J.P.E., Kuhnle G.G., Williams R.J., Rice-Evans C. Intracellular metabolism and bioactivity of quercetin and its in vivo metabolites. Biochem. J. 372:2003;173-181.
16. Rice-Evans C.A., Miller N.J., Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med. 20:1996;933-956.
17. Bors W., Michel C., Stettmaier K. Structure-activity relationships governing antioxidant capacities of plant polyphenols. Methods Enzymol. 335:2001;166-180.
18. Bors W., Michel C. Antioxidant capacity of flavanols and gallate esters: pulse radiolysis studies. Free Radic. Biol. Med. 27:1999;1413-1426.
19. Miyake Y., Shimoi K., Kumazawa S., Yamamoto K., Kinae N., Osawa T. Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agri. Food Chem. 48:2000;3217-3224.
20. Terao J., Yamaguchi S., Shirai M., Miyoshi M., Moon J.H., Oshima S., Inakuma T., Tsushida T., Kato Y. Protection by quercetin and quercetin 3-O-beta-D-glucuronide of peroxynitrite-induced antioxidant consumption in human plasma low-density lipoprotein. Free Radic. Res. 35:2001;925-931.
21. Shirai M., Moon J.H., Tsushida T., Terao J. Inhibitory effect of a quercetin metabolite, quercetin 3-O-beta-D-glucuronide, on lipid peroxidation in liposomal membranes. J. Agric. Food Chem. 49:2001;5602-5608.
22. Yamamoto N., Moon J.H., Tsushida T., Nagao A., Terao J. Inhibitory effect of quercetin metabolites and their related derivatives on copper ion-induced lipid peroxidation in human low-density lipoprotein. Arch. Biochem. Biophys. 372:1999;347-354.
23. da Silva E.L., Piskula M.K., Yamamoto N., Moon J.H., Terao J. Quercetin metabolites inhibit copper ion-induced lipid peroxidation in rat plasma. FEBS Lett. 430:1998;405-408.
24. Abd El Mohsen M.M., Kuhnle G., Rechner A.R., Schroeter H., Rose S., Jenner P., Rice-Evans C.A. Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic. Biol. Med. 33:2002;1693-1702.
25. Halliwell B., Zhao K., Whiteman M. The gastrointestinal tract: a major site of antioxidant action? Free Radic. Res. 33:2000;819-830.
26. Schroeter H., Boyd C., Spencer J.P.E., Williams R.J., Cadenas E., Rice-Evans C. MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol. Aging. 23:2002;861-880.
27. Kobuchi H., Roy S., Sen C.K., Nguyen H.G., Packer L. Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am. J. Physiol. 277:1999;C403-C411.
28. Kong A.N., Yu R., Chen C., Mandlekar S., Primiano T. Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Arch. Pharm. Res. 23:2000;1-16.
29. Schroeter H., Williams R.J., Matin R., Iversen L., Rice-Evans C.A. Phenolic antioxidants attenuate neuronal cell death following uptake of oxidized low-density lipoprotein. Free Radic. Biol. Med. 29:2000;1222-1233.
30. Matter W.F., Brown R.F., Vlahos C.J. The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs. Biochem. Biophys. Res. Commun. 186:1992;624-631.
31. Vlahos C.J., Matter W.F., Hui K.Y., Brown R.F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 269:1994;5241-5248.
32. Agullo G., Gamet-Payrastre L., Manenti S., Viala C., Remesy C., Chap H., Payrastre B. Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem. Pharmacol. 53:1997;1649-1657.
33. Gamet-Payrastre L., Manenti S., Gratacap M.P., Tulliez J., Chap H., Payrastre B. Flavonoids and the inhibition of PKC and PI 3-kinase. Gen. Pharmacol. 32:1999;279-286.
34. Spencer J.P.E., Rice-Evans C., Williams R.J. Modulation of pro-survival Akt/PKB and ERK1/2 signalling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J. Biol. Chem. 2003.
35. Perkinton M.S., Sihra T.S., Williams R.J. Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signaling cascade in neurons. J. Neurosci. 19:1999;5861-5874.
36. Lin C.H., Yeh S.H., Lin C.H., Lu K.T., Leu T.H., Chang W.C., Gean P.W. A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron. 31:2001;841-851.
37. Sweatt J.D. Memory mechanisms: the yin and yang of protein phosphorylation. Curr. Biol. 11:2001;R391-R394.
38. Conseil G., Baubichon-Cortay H., Dayan G., Jault J.M., Barron D., Di Pietro A. Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc. Natl. Acad. Sci. USA. 95:1998;9831-9836.
39. Di Pietro A., Godinot C., Bouillant M.L., Gautheron D.C. Pig heart mitochondrial ATPase: properties of purified and membrane-bound enzyme. Effects of flavonoids. Biochimie. 57:1975;959-967.
40. 2+-transport ATPase from synaptosomal vesicles by flavonoids. Biochim. Biophys. Acta. 730:1983;245-254.
41. 2. Gen. Pharmacol. 29:1997;847-857.
42. Lee S.F., Lin J.K. Inhibitory effects of phytopolyphenols on TPA-induced transformation, PKC activation, and c-jun expression in mouse fibroblast cells. Nutr. Cancer. 28:1997;177-183.
43. Ursini F., Maiorino M., Morazzoni P., Roveri A., Pifferi G. A novel antioxidant flavonoid (IdB 1031) affecting molecular mechanisms of cellular activation. Free Radic. Biol. Med. 16:1994;547-553.
44. Kantengwa S., Polla B.S. Flavonoids, but not protein kinase C inhibitors, prevent stress protein synthesis during erythrophagocytosis. Biochem. Biophys. Res. Commun. 180:1991;308-314.
45. Rosenblat M., Belinky P., Vaya J., Levy R., Hayek T., Coleman R., Merchav S., Aviram M. Macrophage enrichment with the isoflavan glabridin inhibits NADPH oxidase-induced cell-mediated oxidation of low density lipoprotein: a possible role for protein kinase C. J. Biol. Chem. 274:1999;13790-13799.
46. Boege F., Straub T., Kehr A., Boesenberg C., Christiansen K., Andersen A., Jakob F., Kohrle J. Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I. J. Biol. Chem. 271:1996;262-2270.
47. Medina J.H., Viola H., Wolfman C., Marder M., Wasowski C., Calvo D., Paladini A.C. Overview - flavonoids: a new family of benzodiazepine receptor ligands. Neurochem. Res. JID-7613461. 22:1997;419-425.
48. Dekermendjian K., Kahnberg P., Witt M.R., Sterner O., Nielsen M., Liljefors T. Structure-activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABA(A) receptor complex. J. Med. Chem. 42:1999;4343-4350.
49. Fischer P.M., Lane D.P. Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr. Med. Chem. 7:2000;1213-1245.
50. Huang Y.T., Hwang J.J., Lee P.P., Ke F.C., Huang J.H., Huang C.J., Kandaswami C., Middleton E. Jr., Lee M.T. Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br. J. Pharmacol. 128:1999;999-1010.
51. So F.V., Guthrie N., Chambers A.F., Moussa M., Carroll K.K. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr. Cancer. 26:1996;167-181.
52. Panes J., Gerritsen M.E., Anderson D.C., Miyasaka M., Granger D.N. Apigenin inhibits tumor necrosis factor-induced intercellular adhesion molecule-1 upregulation in vivo. Microcirculation. 3:1996;279-286.
53. Gerritsen M.E., Carley W.W., Ranges G.E., Shen C.P., Phan S.A., Ligon G.F., Perry C.A. Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression. Am. J. Pathol. 147:1995;278-292.
54. Soriani M., Rice-Evans C., Tyrrell R.M. Modulation of the UVA activation of haem oxygenase, collagenase and cyclooxygenase gene expression by epigallocatechin in human skin cells. FEBS Lett. 439:1998;253-257.
55. Ferriola P.C., Cody V., Middleton E. Jr. Protein kinase C inhibition by plant flavonoids: kinetic mechanisms and structure-activity relationships. Biochem. Pharmacol. 38:1989;1617-1624.
56. Walker E.H., Pacold M.E., Perisic O., Stephens L., Hawkins P.T., Wymann M.P., Williams R.L. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell. 6:2000;909-919.
57. Enslen H., Tokumitsu H., Stork P.J., Davis R.J., Soderling T.R. Regulation of mitogen-activated protein kinases by a calcium/calmodulin- dependent protein kinase cascade. Proc. Natl. Acad. Sci. USA. 93:1996;10803-10808.
58. Zippel R., Balestrini M., Lomazzi M., Sturani E. Calcium and calmodulin are essential for Ras-GRF1-mediated activation of the Ras pathway by lysophosphatidic acid. Exp. Cell Res. 258:2000;403-408.
59. Green D.R., Reed J.C. Mitochondria and apoptosis. Science. 281:1998;1309-1312.
60. Tatton W.G., Olanow C.W. Apoptosis in neurodegenerative diseases: the role of mitochondria. Biochim. Biophys. Acta. 1410:1999;195-213.
61. Goyal L. Cell death inhibition: keeping caspases in check. Cell. 104:2001;805-808.
62. Srinivasula S.M., Hegde R., Saleh A., Datta P., Shiozaki E., Chai J., Lee R.A., Robbins P.D., Fernandes-Alnemri T., Shi Y., Alnemri E.S. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature. 410:2001;112-116.
63. Herdegen T., Skene P., Bahr M. The c-Jun transcription factor: bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci. 20:1997;227-231.
64. Castagne V., Clarke P.G. Inhibitors of mitogen-activated protein kinases protect axotomized developing neurons. Brain Res. 842:1999;215-219.
65. Castagne V., Gautschi M., Lefevre K., Posada A., Clarke P.G. Relationships between neuronal death and the cellular redox status: focus on the developing nervous system. Prog. Neurobiol. 59:1999;397-423.
66. Mielke K., Herdegen T. JNK and p38 stresskinases: degenerative effectors of signal-transduction-cascades in the nervous system. Prog. Neurobiol. 61:2000;45-60.
67. Yuan J., Yankner B.A. Apoptosis in the nervous system. Nature. 407:2000;802-809.
68. Xia Z., Dickens M., Raingeaud J., Davis R.J., Greenberg M.E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1995;1326-1331.
69. Anderson C.N., Tolkovsky A.M. A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J. Neurosci. 19:1999;664-673.
70. Bonni A., Brunet A., West A.E., Datta S.R., Takasu M.A., Greenberg M.E. Cell survival promoted by the Ras-MAPK signaling pathway by transcription- dependent and -independent mechanisms. Science. 286:1999;1358-1362.
71. Kaplan D.R., Miller F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10:2000;381-391.
72. Crossthwaite A.J., Hasan S., Williams R.J. Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. J. Neurochem. 80:2002;24-35.
73. Behrens A., Sibilia M., Wagner E.F. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat. Genet. 21:1999;326-329.
74. Davis R.J. Signal transduction by the JNK group of MAP kinases. Cell. 103:2000;239-252.
75. Torres M., Forman H.J. Redox signaling and the MAP kinase pathways. Biofactors. 17:2003;287-296.
76. 2 in vascular smooth muscle cells: potential involvement in vascular disease (review). Int. J. Mol. Med. 11:2003;229-234.
77. Ueda S., Masutani H., Nakamura H., Tanaka T., Ueno M., Yodoi J. Redox control of cell death. Antioxid. Redox Signal. 4:2002;405-414.
78. Owuor E.D., Kong A.N. Antioxidants and oxidants regulated signal transduction pathways. Biochem. Pharmacol. 64:2002;765-770.
79. Rincon M., Flavell R.A., Davis R.A. The JNK and P38 MAP kinase signaling pathways in T cell-mediated immune responses. Free Radic. Biol. Med. 28:2000;1328-1337.
80. Saeki K., Kobayashi N., Inazawa Y., Zhang H., Nishitoh H., Ichijo H., Saeki K., Isemura M., Yuo A. Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis. Biochem. J. 368:2002;705-720.
81. Kwon Y.W., Masutani H., Nakamura H., Ishii Y., Yodoi J. Redox regulation of cell growth and cell death. Biol. Chem. 384:2003;991-996.
82. Kim J.S., He L., Lemasters J.J. Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem. Biophys. Res. Commun. 304:2003;463-470.
83. Lemasters J.J., Qian T., He L., Kim J.S., Elmore S.P., Cascio W.E., Brenner D.A. Role of mitochondrial inner membrane permeabilization in necrotic cell death, apoptosis, and autophagy. Antioxid. Redox Signal. 4:2002;769-781.
84. Luo Y., Umegaki H., Wang X., Abe R., Roth G.S. Dopamine induces apoptosis through an oxidation-involved SAPK/JNK activation pathway. J. Biol. Chem. 273:1998;3756-3764.
85. Camandola S., Poli G., Mattson M.P. The lipid peroxidation product 4-hydroxy-2,3-nonenal increases AP-1-binding activity through caspase activation in neurons. J. Neurochem. 74:2000;159-168.
86. Parola M., Robino G., Marra F., Pinzani M., Bellomo G., Leonarduzzi G., Chiarugi P., Camandola S., Poli G., Waeg G., Gentilini P., Dianzani M.U. HNE interacts directly with JNK isoforms in human hepatic stellate cells. J. Clin. Invest. 102:1998;1942-1950.
87. Soh Y., Jeong K.S., Lee I.J., Bae M.A., Kim Y.C., Song B.J. Selective activation of the c-Jun N-terminal protein kinase pathway during 4-hydroxynonenal-induced apoptosis of PC12 cells. Mol. Pharmacol. 58:2000;535-541.
88. Maroney A.C., Finn J.P., Bozyczko-Coyne D., O'Kane T.M., Neff N.T., Tolkovsky A.M., Park D.S., Yan C.Y., Troy C.M., Greene L.A. CEP-1347 (KT7515), an inhibitor of JNK activation, rescues sympathetic neurons and neuronally differentiated PC12 cells from death evoked by three distinct insults. J. Neurochem. 73:1999;1901-1912.
89. Datta S.R., Brunet A., Greenberg M.E. Cellular survival: a play in three Akts. Genes Dev. 13:1999;2905-2927.
90. Coffer P.J., Jin J., Woodgett J.R. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem. J. 335(Pt. 1):1998;1-13.
91. Miller F.D., Kaplan D.R. Neurotrophin signalling pathways regulating neuronal apoptosis. Cell Mol. Life Sci. 58:2001;1045-1053.
92. Crowder R.J., Freeman R.S. Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. J. Neurosci. 18:1998;2933-2943.
93. Zha J., Harada H., Yang E., Jockel J., Korsmeyer S.J. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell. 87:1996;619-628.
94. Kennedy S.G., Wagner A.J., Conzen S.D., Jordan J., Bellacosa A., Tsichlis P.N., Hay N. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11:1997;701-713.
95. Datta S.R., Dudek H., Tao X., Masters S., Fu H., Gotoh Y., Greenberg M.E. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:1997;231-241.
96. del Peso L., Gonzalez-Garcia M., Page C., Herrera R., Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 278:1997;687-689.
97. Oyama Y., Fuchs P.A., Katayama N., Noda K. Myricetin and quercetin, the flavonoid constituents of ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca(2+)-loaded brain neurons. Brain Res. 635:1994;125-129.
98. Oyama Y., Noguchi S., Nakata M., Okada Y., Yamazaki Y., Funai M., Chikahisa L., Kanemaru K. Exposure of rat thymocytes to hydrogen peroxide increases annexin V binding to membranes: inhibitory actions of deferoxamine and quercetin. Eur. J. Pharmacol. 384:1999;47-52.
99. Metodiewa D., Jaiswal A.K., Cenas N., Dickancaite E., Segura-Aguilar J. Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product. Free Radic. Biol. Med. 26:1999;107-116.
100. Rzymowska J., Gawron A., Pawlikowska-Pawlega B., Jakubowicz-Gil J., Wojcierowski J. The effect of quercetin on induction of apoptosis. Fol. Histochem. Cytobiol. 37:1999;125-126.
101. Rong Y., Yang E.B., Zhang K., Mack P. Quercetin-induced apoptosis in the monoblastoid cell line U937 in vitro and the regulation of heat shock proteins expression. Anticancer Res. 20:2000;4339-4345.
102. Csokay B., Prajda N., Weber G., Olah E. Molecular mechanisms in the antiproliferative action of quercetin. Life Sci. 60:1997;2157-2163.
103. Kuo S.M. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett. 110:1996;41-48.
104. Wei Y.Q., Zhao X., Kariya Y., Fukata H., Teshigawara K., Uchida A. Induction of apoptosis by quercetin: involvement of heat shock protein. Cancer Res. 54:1994;4952-4957.
105. Wang I.K., Lin-Shiau S.Y., Lin J.K. Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur. J. Cancer. 35:1999;1517-1525.
106. Russo M., Palumbo R., Tedesco I., Mazzarella G., Russo P., Iacomino G., Russo G.L. Quercetin and anti-CD95(Fas/Apo1) enhance apoptosis in HPB-ALL cell line. FEBS Lett. 462:1999;322-328.
107. Wang L., Matsushita K., Araki I., Takeda M. Inhibition of c-Jun N-terminal kinase ameliorates apoptosis induced by hydrogen peroxide in the kidney tubule epithelial cells (NRK-52E). Nephron. 91:2002;142-147.
108. Uchida K., Shiraishi M., Naito Y., Torii Y., Nakamura Y., Osawa T. Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J. Biol. Chem. 274:1999;2234-2242.
109. Ishikawa Y., Kitamura M. Anti-apoptotic effect of quercetin: intervention in the JNK-and ERK-mediated apoptotic pathways. Kidney Int. 58:2000;1078-1087.
110. Levites Y., Amit T., Youdim M.B., Mandel S. Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action. J. Biol. Chem. 277:2002;30574-30580.
111. Bode A.M., Dong Z. Signal transduction pathways: targets for chemoprevention of skin cancer. Lancet Oncol. 1:2000;181-188.
112. Vergote D., Cren-Olive C., Chopin V., Toillon R.A., Rolando C., Hondermarck H., Le B.X. (-)-Epigallocatechin (EGC) of green tea induces apoptosis of human breast cancer cells but not of their normal counterparts. Breast Cancer Res. Treat. 76:2002;195-201.
113. Choi Y.J., Lim S.Y., Woo J.H., Kim Y.H., Kwon Y.K., Suh S.I., Lee S.H., Choi W.Y., Kim J.G., Lee I.S., Park J.W., Kwon T.K. Sodium orthovanadate potentiates EGCG-induced apoptosis that is dependent on the ERK pathway. Biochem. Biophys. Res. Commun. 305:2003;176-185.
114. Chen N.Y., Ma W.Y., Yang C.S., Dong Z. Inhibition of arsenite-induced apoptosis and AP-1 activity by epigallocatechin-3-gallate and theaflavins. J. Environ. Pathol. Toxicol. Oncol. 19:2000;287-295.
115. Chung J.Y., Huang C., Meng X., Dong Z., Yang C.S. Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure-activity relationship and mechanisms involved. Cancer Res. 59:1999;4610-4617.
116. Chung J.Y., Park J.O., Phyu H., Dong Z., Yang C.S. Mechanisms of inhibition of the Ras-MAP kinase signaling pathway in 30.7b Ras 12 cells by tea polyphenols (-)-epigallocatechin-3-gallate and theaflavin-3,3′-digallate. FASEB J. 15:2001;2022-2024.
117. Zachos G., Spandidos D.A. Expression of ras proto-oncogenes: regulation and implications in the development of human tumors. Crit. Rev. Oncol. Hematol. 26:1997;65-75.
118. Ahn H.Y., Hadizadeh K.R., Seul C., Yun Y.P., Vetter H., Sachinidis A. Epigallocathechin-3 gallate selectively inhibits the PDGF-BB-induced intracellular signaling transduction pathway in vascular smooth muscle cells and inhibits transformation of sis-transfected NIH 3T3 fibroblasts and human glioblastoma cells (A172). Mol. Biol. Cell. 10:1999;1093-1104.
119. Okabe S., Fujimoto N., Sueoka N., Suganuma M., Fujiki H. Modulation of gene expression by (-)-epigallocatechin gallate in PC-9 cells using a cDNA expression array. Biol. Pharm. Bull. 24:2001;883-886.
120. Masuda M., Suzui M., Weinstein I.B. Effects of epigallocatechin-3- gallate on growth, epidermal growth factor receptor signaling pathways, gene expression, and chemosensitivity in human head and neck squamous cell carcinoma cell lines. Clin. Cancer Res. 7:2001;4220-4229.
121. Masuda M., Suzui M., Lim J.T., Deguchi A., Soh J.W., Weinstein I.B. Epigallocatechin-3-gallate decreases VEGF production in head and neck and breast carcinoma cells by inhibiting EGFR-related pathways of signal transduction. J. Exp. Ther. Oncol. 2:2002;350-359.
122. Masuda M., Suzui M., Lim J.T., Weinstein I.B. Epigallocatechin-3-gallate inhibits activation of HER-2/neu and downstream signaling pathways in human head and neck and breast carcinoma cells. Clin. Cancer Res. 9:2003;3486-3491.
123. Pianetti S., Guo S., Kavanagh K.T., Sonenshein G.E. Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells. Cancer Res. 62:2002;652-655.
124. Katiyar S.K., Afaq F., Azizuddin K., Mukhtar H. Inhibition of UVB-induced oxidative stress-mediated phosphorylation of mitogen-activated protein kinase signaling pathways in cultured human epidermal keratinocytes by green tea polyphenol (-)-epigallocatechin-3-gallate. Toxicol. Appl. Pharmacol. 176:2001;110-117.
125. Nomura M., Ma W.Y., Huang C., Yang C.S., Bowden G.T., Miyamoto K., Dong Z. Inhibition of ultraviolet B-induced AP-1 activation by theaflavins from black tea. Mol. Carcinog. 28:2000;148-155.
126. Balasubramanian S., Efimova T., Eckert R.L. Green tea polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade to increase activator protein 1 factor-dependent involucrin gene expression in normal human keratinocytes. J. Biol. Chem. 277:2002;1828-1836.
127. Vayalil P.K., Elmets C.A., Katiyar S.K. Treatment of green tea polyphenols in hydrophilic cream prevents UVB-induced oxidation of lipids and proteins, depletion of antioxidant enzymes and phosphorylation of MAPK proteins in SKH-1 hairless mouse skin. Carcinogenesis. 24:2003;927-936.
128. Afaq F., Adhami V.M., Ahmad N., Mukhtar H. Inhibition of ultraviolet B-mediated activation of nuclear factor kappaB in normal human epidermal keratinocytes by green tea constituent (-)-epigallocatechin-3-gallate. Oncogene. 22:2003;1035-1044.
129. Chen C., Yu R., Owuor E.D., Kong A.N. Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch. Pharm. Res. 23:2000;605-612.