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Signal transduction events elicited by natural products: Role of MAPK and caspase pathways in homeostatic response and induction of apoptosis

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Abstract

Many natural products elicit diverse pharmacological effects. Using two classes of potential chemopreventive compounds, the phenolic compounds and the isothiocyanates, we review the potential utility of two signaling events, the mitogen-activated protein kinases (MAPKs) and the ICE/Ced-3 proteases (caspases) stimulated by these agents in mammalian cell lines. Studies with phenolic antioxidants (BHA, tBHQ), and natural products (flavonoids; EGCG, ECG, and isothiocyanates; PEITC, sulforaphane), provided important insights into the signaling pathways induced by these compounds. At low concentrations, these chemicals may activate the MAPK (ERK2, JNK1, p38) leading to gene expression of survival genes (c-Fos, c-Jun) and defensive genes (Phase II detoxifying enzymes; GST, QR) resulting in survival and protective mechanisms (homeostasis response). Increasing the concentrations of these compounds will additionally activate the caspase pathway, leading to apoptosis (potential cytotoxicity). Further increment to suprapharmacological concentrations will lead to nonspecific necrotic cell death. The wider and narrow concentration ranges between the activation of MAPK/gene induction and caspases/cell death exhibited by phenolic compounds and isothiocyanates, respectively, in mammalian cells, may reflect their respective therapeutic windowsin vivo. Consequently, the studies of signaling pathways elicited by natural products will advance our understanding of their efficacy and safety, of which many may become important therapeutic drugs of the future.

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References

  • NSAIDs may prevent colon cancer through apoptosis, not anti- inflammatory effects [news].Oncology, 10, 624 (1996).

  • Prevention of cancer in the next millenium: Report of the chemoprevention working group to the American Association for Cancer Research.Cancer Research, 59, 4743–4758 (1999).

    Google Scholar 

  • Ahmad, N., Feyes, D. K., Nieminen, A. L., Agarwal, R. and Mukhtar, H., Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells.J Natl Cancer Inst, 89, 1881–1886 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Alam, J., Stewart, D., Touchard, C., Boinapally, S., Choi, A. M. and Cook, J. L., Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene.J Biol Chem, 274, 26071–26078 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Alnemri, E. S., Livingston, D. J., Nicholson, D. W., Salvesen, G., Thornberry, N. A., Wong, W. W. and Yuan, J., Human ICE/CED-3 protease nomenclature [letter].Cell, 87, 171 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Alvarez, E., Northwood, I. C., Gonzalez, F. A., Latour, D. A., Seth, A., Abate, C., Curran, T. and Davis, R. J., Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation. Characterization of the phosphorylation of c- myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase.J Biol Chem, 266, 15277–15285 (1991).

    PubMed  CAS  Google Scholar 

  • Ashkenazi, A. and Dixit, V. M., Death receptors: signaling and modulation.Science, 281, 1305–1308 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Batzinger, R. P., Ou, S. Y. and Bueding, E., Antimutagenic effects of 2(3)-tert-butyl-4-hydroxyanisole and of antimicrobial agents.Cancer Res, 38, 4478–4485 (1978).

    PubMed  CAS  Google Scholar 

  • Benson, A. M., Barretto, P. B. and Stanley, J. S., Induction of DT-diaphorase by anticarcinogenic sulfur compounds in mice.J Natl Cancer Inst, 76, 467–473 (1986).

    PubMed  CAS  Google Scholar 

  • Benson, A. M., Batzinger, R. P., Ou, S. Y., Bueding, E., Cha, Y. N. and Talalay, P., Elevation of hepatic glutathione S-transferase activities and protection against mutagenic metabolites, of benzo(a)pyrene by dietary antioxidants.Cancer Res, 38, 4486–4495 (1978).

    PubMed  CAS  Google Scholar 

  • Bogaards, J. J., van Ommen, B., Falke, H. E., Willems, M. I. and van Bladeren, P. J., Glutathione S-transferase subunit induction patterns of Brussels sprouts, allyl isothiocyanate and goitrin in rat liver and small intestinal mucosa: a new approach for the identification of inducing xenobiotics.Food Chem Toxicol, 28, 81–88 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Brewster, J. L., de Valoir, T., Dwyer, N. D., Winter, E. and Gustin, M. C. An osmosensing signal transduction pathway in yeast.Science, 259, 1760–1763 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Briehl, M. M. and Baker, A. F., Modulation of the antioxidant defense as a factor in apoptosis.Cell Death and Differentiation, 3, 63–70 (1996).

    PubMed  CAS  Google Scholar 

  • Buetler, T. M., Gallagher, E. P., Wang, C., Stahl, D. L., Hayes, J. D. and Eaton, D. L., Induction of phase I and phase II drug-metabolizing enzyme mRNA, protein, and activity by BHA, ethoxyquin, and oltipraz.Toxicol Appl Pharmacol, 135, 45–57 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Burgering, B. M. and Bos, J. L., Regulation of Ras-mediated signalling: more than one way to skin a cat.Trends Biochem Sci, 20, 18–22 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Busciglio, J. and Yankner, B. A., Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro.Nature, 378, 776–779 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Buttke, T. M. and Sandstrom, P. A., Oxidative stress as a mediator of apoptosis [see comments].Immunol Today, 15, 7–10 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Cano, E., Hazzalin, C. A. and Mahadevan, L. C., Anisomycin-activated protein kinases p45 and p55 but not mitogen-activated protein kinases ERK-1 and −2 are implicated in the induction of c-fos and c-jun.Mol Cell Biol, 14, 7352–7362 (1994).

    PubMed  CAS  Google Scholar 

  • Cano, E. and Mahadevan, L. C., Parallel signal processing among mammalian MAPKs.Trends Biochem Sci, 20, 117–122 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Castillo, M. H., Perkins, E., Campbell, J. H., Doerr, R., Hassett, J. M., Kandaswami, C. and Middleton, E., Jr., The effects of the bioflavonoid quercetin on squamous cell carcinoma of head and neck origin.Am J Surg, 158, 351–355 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Cha, Y. N. and Bueding, E., Effects of 2(3)-tert-butyl-4-hydroxyanisole administration on the activities of several hepatic microsomal and cytoplasmic enzymes in mice.Biochem Pharmacol, 28, 1917–1921 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Cha, Y. N. and Heine, H. S., Comparative effects of dietary administration of 2(3)-tert-butyl-4-hydroxyanisole and 3,5-di-tert-butyl-4-hydroxytoluene on several hepatic enzyme activities in mice and rats.Cancer Res, 42, 2609–2615 (1982).

    PubMed  CAS  Google Scholar 

  • Chan, K. and Kan, Y. W., Nrf2 is essential for protection against acute pulmonary injury in mice [In Process Citation].Proc Natl Acad Sci U S A, 96, 12731–12736 [Record as supplied by publisher] (1999).

    Article  PubMed  CAS  Google Scholar 

  • Chen, Y. R., Meyer, C. F. and Tan, T. H., Persistent activation of c-Jun N-terminal kinase 1 (JNK1) in gamma radiation-induced apoptosis.J Biol Chem, 271, 631–634 (1996a).

    Article  PubMed  CAS  Google Scholar 

  • Chen, Y. R., Wang, X., Templeton, D., Davis, R. J. and Tan, T. H., The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation.J Biol Chem, 271, 31929–31936 (1996b).

    Article  PubMed  CAS  Google Scholar 

  • Chinnaiyan, A. M., K, O. R., Lane, B. R. and Dixit, V. M., Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death [see comments].Science, 275, 1122–1126 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Choi, H. S. and Moore, D. D., Induction of c-fos and c-jun gene expression by phenolic antioxidants.Mol Endocrinol, 7, 1596–1602 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Clayson, D. B., Iverson, F., Nera, E. A. and Lok, E., The significance of induced forestomach tumors.Annu Rev Pharmacol Toxicol, 30, 441–463 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Cobb, M. H. and Goldsmith, E. J., How MAP kinases are regulated.J Biol Chem, 270 14843–14846 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Conney, A. H., Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture.Cancer Res, 42, 4875–4917 (1982).

    PubMed  CAS  Google Scholar 

  • Crowell, P. L., Prevention and therapy of cancer by dietary monoterpenes.J Nutr, 129, 775S-778S (1999).

    PubMed  CAS  Google Scholar 

  • Darzynkiewicz, Z., Juan, G., Li, X., Gorczyca, W., Murakami, T. and Traganos, F., Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis).Cytometry, 27, 1–20 (1997).

    Article  PubMed  CAS  Google Scholar 

  • De Long, M. J., Prochaska, H. J. and Talalay, P., Tissue-specific induction patterns of cancer-protective enzymes in mice by tert-butyl-4-hydroxyanisole and related substituted phenols.Cancer Res, 45, 546–551 (1985).

    PubMed  Google Scholar 

  • Delia, D., Aiello, A., Lombardi, L., Pelicci, P. G., Grignani, F., Formelli, F., Menard, S., Costa, A., Veronesi, U. andet al., N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid.Cancer Res, 53, 6036–6041 (1993).

    PubMed  CAS  Google Scholar 

  • Derijard, B., Raingeaud, J., Barrett, T., Wu, I. H., Han, J., Ulevitch, R. J. and Davis, R. J., Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms [published erratum appears in Science 1995 Jul 7;269(5220):17].Science, 267, 682–685 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Egan, S. E., Giddings, B. W., Brooks, M. W., Buday, L., Sizeland, A. M. and Weinberg, R. A., Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation [see comments].Nature, 363, 45–51 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Favreau, L. V. and Pickett, C. B., Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants.J. Biol Chem, 266, 4556–4561 (1991).

    PubMed  CAS  Google Scholar 

  • Fei, P., Matwyshyn, G. A., Rushmore, T. H. and Kong, A. N. T., Transcription regulation of rat glutathione S-transferase Ya subunit gene expression by chemopreventive agents.Pharm Res., 13, 1043–1048 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Fernandes-Alnemri, T., Litwack, G. and Alnemri, E. S., CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme.J Biol Chem, 269, 30761–30764 (1994).

    PubMed  CAS  Google Scholar 

  • Fesus, L., Szondy, Z. and Uray, I., Probing the molecular program of apoptosis by cancer chemopreventive agents.J Cell Biochem Suppl, 22, 151–161 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Freshney, N. W., Rawlinson, L., Guesdon, F., Jones, E., Cowley, S., Husan, J. and Saklatvala, J., Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27.Cell, 78, 1039–1049 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Friling, R. S., Bensimon, A., Tichauer, Y. and Daniel, V., Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element.Proc Natl Acad Sci U S A, 87, 6258–6262 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Fuijta, Y., Yamane, T., Tanaka, M., Kuwata, K., Okuzumi, J., Takahashi, T., Fujiki, H. and Okuda, T., Inhibitory effect of (-)-epigallocatechin gallate on carcinogenesis with N-ethyl-N′-nitro-N-nitrosoguanidine in mouse duodenum.Jpn J Cancer Res, 80, 503–505 (1989).

    Google Scholar 

  • Gerhauser, C., You, M., Liu, J., Moriarty, R. M., Hawthorne, M., Mehta, R. G., Moon, R. C. and Pezzuto, J. M., Cancer chemopreventive potential of sulforamate, a novel analogue of sulforaphane that induces phase 2 drug-metabolizing enzymes.Cancer Res, 57, 272–278 (1997).

    PubMed  CAS  Google Scholar 

  • Glatt, H., Sulfation and sulfotransferases 4: bioactivation of mutagens via sulfation.Faseb J, 11, 314–321 (1997).

    PubMed  CAS  Google Scholar 

  • Gonzalez, F. A., Raden, D. L. and Davis, R. J., Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases.J. Biol Chem, 266, 22159–22163 (1991).

    PubMed  CAS  Google Scholar 

  • Green, D. R. and Reed, J. C., Mitochondria and apoptosis.Science, 281, 1309–1312 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Guenthner, T., Epoxide Hydrolase. In Mulder, G., (Eds).Conjugation Reactions in Drug Metabolism. Taylor & Francis, London, pp. 365–404, 1990.

    Google Scholar 

  • Guo, Z., Smith, T. J., Wang, E., Eklind, K. I., Chung, F. L. and Yang, C. S., Structure-activity relationships of arylalkyl isothiocyanates for the inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism and the modulation of xenobiotic-metabolizing enzymes in rats and mice.Carcinogenesis, 14, 1167–1173 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Guo, Z., Smith, T. J., Wang, E., Sadrieh, N., Ma, Q., Thomas, P. E. and Yang, C. S., Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats.Carcinogenesis, 13, 2205–2210 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Han, J., Lee, J. D., Bibbs, L. and Ulevitch, R. J., A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells.Science, 265, 808–811 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Hecht, S. S., Chemoprevention by isothiocyanates.J Cell Biochem Suppl, 22, 195–209 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Hengstler, J. G., Arand, M., Herrero, M. F. and Oesch, F., Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases, influence on cancer susceptibility.Recent Results Cancer Res, 154, 47–85 (1998).

    PubMed  CAS  Google Scholar 

  • Hibi, M., Lin, A., Smeal, T., Minden, A. and Karin, M., Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain.Genes Dev, 7, 2135–2148 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Hirano, T., Oka, K. and Akiba, M., Antiproliferative effects of synthetic and naturally occurring flavonoids on tumor cells of the human breast carcinoma cell line, ZR-75-1.Res Commun Chem Pathol Pharmacol, 64, 69–78 (1989).

    PubMed  CAS  Google Scholar 

  • Igarashi, K., Kataoka, K., Itoh, K., Hayashi, N., Nishizawa, M. and Yamamoto, M., Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins [see comments].Nature, 367, 568–572 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., Yamamoto, M. and Nabeshima, Y., An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.Biochem Biophys Res Commun, 236, 313–322 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D. and Yamamoto, M., Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain.Genes Dev, 13, 76–86 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Jaiswal, A. K., Jun and Fos regulation of NAD(P)H: quinone oxidoreductase gene expression.Pharmacogenetics, 4, 1–10 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W., Fong, H. H., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C. and Pezzuto, J. M., Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.Science, 275, 218–220 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Jiao, D., Smith, T. J., Yang, C. S., Pittman, B., Desai, D., Amin, S. and Chung, F. L., Chemopreventive activity of thiol conjugates of isothiocyanates for lung tumorigenesis.Carcinogenesis, 18, 2143–2147 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Karin, M., The regulation of AP-1 activity by mitogenactivated protein kinases.J Biol Chem, 270, 16483–16486 (1995).

    PubMed  CAS  Google Scholar 

  • Karin, M., Mitogen-activated protein kinase cascades as regulators of stress responses.Ann N Y Acad Sci, 851, 139–146 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Kashfi, K., Yang, E. K., Chowdhury, J. R., Chowdhury, N. R. and Dannenberg, A. J., Regulation of uridine diphosphate glucuronosyltransferase expression by phenolic antioxidants.Cancer Res, 54, 5856–5859 (1994).

    PubMed  CAS  Google Scholar 

  • Kataoka, K., Noda, M. and Nishizawa, M., Maf nuclear oncoprotein recognizes sequences related to an AP-1 site and forms heterodimers with both Fos and Jun.Mol Cell Biol, 14, 700–712 (1994).

    PubMed  CAS  Google Scholar 

  • Katiyar, S. K., Agarwal, R. and Mukhtar, H., Protection against malignant conversion of chemically induced benign skin papillomas to squamous cell carcinomas in SENCAR mice by a polyphenolic fraction isolated from green tea.Cancer Res, 53, 5409–5412 (1993).

    PubMed  CAS  Google Scholar 

  • Kelloff, G. J., Boone, C. W., Steele, V. E., Crowell, J. A., Lubet, R. A., Greenwald, P., Hawk, E. T., Fay, J. R. and Sigman, C. C., Mechanistic considerations in the evaluation of chemopreventive data.IARC Sci Publ, 203–219 (1996).

  • Kensler, T. W., Egner, P. A., Dolan, P. M., Groopman, J. D. and Roebuck, B. D., Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones.Cancer Res, 47, 4271–4277 (1987).

    PubMed  CAS  Google Scholar 

  • Kensler, T. W., Groopman, J. D., Eaton, D. L., Curphey, T. J. and Roebuck, B. D., Potent inhibition of aflatoxin-induced hepatic tumorigenesis by the monofunctional enzyme inducer 1,2-dithiole-3-thione.Carcinogenesis, 13, 95–100 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Kim, N. D. and Kim, S. G., Chemopreventive effects of 2-(allylthio)pyrazine.Arch Pharm Res, 22, 99–107 (1999).

    Article  PubMed  CAS  Google Scholar 

  • King, M. M. and McCay, P. B., Modulation of tumor incidence and possible mechanisms of inhibition of mammary carcinogenesis by dietary antioxidants.Cancer Res, 43, 2485s-2490s (1983).

    PubMed  CAS  Google Scholar 

  • Kirlin, W. G., Cai, J., DeLong, M. J., Patten, E. J. and Jones, D. P., Dietary compounds that induce cancer preventive phase 2 enzymes activate apoptosis at comparable doses in HT29 colon carcinoma cells.J Nutr, 129, 1827–1835 (1999).

    PubMed  CAS  Google Scholar 

  • Kitchen, I., Tremblay, J., Andre, J., Dring, L. G., Idle, J. R., Smith, R. L. and Williams, R. T., Interindividual and interspecies variation in the metabolism of the hallucinogen 4-methoxyamphetamine.Xenobiotica, 9, 397–404 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Kluck, R. M., Bossy-Wetzel, E., Green, D. R. and Newmeyer, D. D., The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis [see comments].Science, 275, 1132–1136 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis, J. M. and Avruch, J., Protein kinase cascades activated by stress and inflammatory cytokines.Bioessays, 18, 567–577 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis, J. M., Banerjee, P., Nikolakaki, E., Dai, T., Rubie, E. A., Ahmad, M. F., Avruch, J. and Woodgett, J. R., The stress-activated protein kinase subfamily of c-Jun kinases.Nature, 369, 156–160 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Lam, L. K., Fladmoe, A. V., Hochalter, J. B. and Wattenberg, L. W., Short time interval effects of butylated hydroxyanisole on the metabolism of benzo(a)pyrene.Cancer Res, 40, 2824–2828 (1980).

    PubMed  CAS  Google Scholar 

  • Langman, M. and Boyle, P., Chemoprevention of colorectal cancer.Gut, 43, 578–585 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Lee, J. C., Laydon, J. T., McDonnell, P. C., Gallagher, T. F., Kumar, S., Green, D., McNulty, D., Blumenthal, M. J., Heys, J. R., Landvatter, S. W. and et al., A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.Nature, 372, 739–746 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Lei, W., Yu, R., Mandlekar, S. and Kong, A. N., Induction of apoptosis and activation of interleukin 1beta-converting enzyme/Ced-3 protease (caspase-3) and c-Jun NH2-terminal kinase 1 by benzo(a)pyrene.Cancer Res, 58, 2102–2106 (1998).

    PubMed  CAS  Google Scholar 

  • Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S. and Wang, X., Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.Cell, 91, 479–489 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Li, Y. and Jaiswal, A. K., Regulation of human NAD (P)H: quinone oxidoreductase gene. Role of AP1 binding site contained within human antioxidant response element [published erratum appears in J Biol Chem 1993 Oct 5;268(28):21454].J Biol Chem, 267, 15097–15104 (1992).

    PubMed  CAS  Google Scholar 

  • Lin, J. K., Liang, Y. C. and Lin-Shiau, S. Y., Cancer chemoprevention by tea polyphenols through mitotic signal transduction blockade.Biochem Pharmacol, 58, 911–915 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Liu, X., Zou, H., Slaughter, C. and Wang, X., DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis.Cell, 89, 175–184 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Lotan, R., Retinoids in cancer chemoprevention.Faseb J, 10, 1031–1039 (1996).

    PubMed  CAS  Google Scholar 

  • Lupulescu, A. P., Hormones, vitamins, and growth factors in cancer treatment and prevention. A critical appraisal.Cancer, 78, 2264–2280 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Mackenzie, P. I., Owens, I. S., Burchell, B., Bock, K. W., Bairoch, A., Belanger, A., Fournel-Gigleux, S., Green, M., Hum, D. W., Iyanagi, T., Lancet, D., Louisot, P., Magdalou, J., Chowdhury, J. R., Ritter, J. K., Schachter, H., Tephly, T. R., Tipton, K. F. and Nebert, D. W., The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence.Pharmacogenetics, 7, 255–269 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Marshall, C. J., MAP kinase kinase kinase, MAP kinase kinase and MAP kinase.Curr Opin Genet Dev, 4, 82–89 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Martin, S. J. and Green, D. R., Protease activation during apoptosis: death by a thousand cuts?Cell, 82, 349–352 (1995).

    Article  PubMed  CAS  Google Scholar 

  • McGowan, A. J., Ruiz-Ruiz, M. C., Gorman, A. M., Lopez-Rivas, A. and Cotter, T. G., Reactive oxygen intermediate(s) (ROI): common mediator(s) of poly (ADP-ribose)polymerase (PARP) cleavage and apoptosis.FEBS Lett, 392, 299–303 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Mizutani, T., Nomura, H., Nakanishi, K. and Fujita, S., Hepatotoxicity of butylated hydroxytoluene and its analogs in mice depleted of hepatic glutathione.Toxicol Appl Pharmacol, 87, 166–176 (1987).

    Article  PubMed  CAS  Google Scholar 

  • Moi, P., Chan, K., Asunis, I., Cao, A. and Kan, Y. W., Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region.Proc Natl Acad Sci U S A, 91, 9926–9930 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Moinova, H. R. and Mulcahy, R. T., Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element.Biochem Biophys Res Commun, 261, 661–668 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Mulder, G., Coughtrie, MWH, and Burchell, B., Glucuronidation. In GJ, M., (Eds).Conjugation Reactions in Drug Metabolism. Taylor & Francis, London, pp. 51–106, 1990.

    Google Scholar 

  • Munzel, P. A., Schmohl, S., Heel, H., Kalberer, K., Bock-Hennig, B. S. and Bock, K. W., Induction of human UDP glucuronosyltransferases (UGT1A6, UGT1A9, and UGT2B7) by t-butylhydroquinone and 2,3,7,8-tetrachlorodibenzo-p-dioxin in Caco-2 cells.Drug Metab Dispos, 27, 569–573 (1999).

    PubMed  CAS  Google Scholar 

  • Nagata, S., Apoptosis by death factor.Cell, 88, 355–365 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Nelson, D. R., Kamataki, T., Waxman, D. J., Guengerich, F. P., Estabrook, R. W., Feyereisen, R., Gonzalez, F. J., Coon, M. J., Gunsalus, I. C., Gotoh, O. and et al., The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature.DNA Cell Biol, 12, 1–51 (1993).

    PubMed  CAS  Google Scholar 

  • Okuda, A., Imagawa, M., Maeda, Y., Sakai, M. and Muramatsu, M., Structural and functional analysis of an enhancer GPEI having a phorbol 12-O-tetradecanoate 13-acetate responsive element-like sequence found in the rat glutathione transferase P gene.J Biol Chem, 264, 16919–16926 (1989).

    PubMed  CAS  Google Scholar 

  • Pascale, R. M., Marras, V., Simile, M. M., Daino, L., Pinna, G., Bennati, S., Carta, M., Seddaiu, M. A., Massarelli, G. and Feo, F., Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study.Cancer Res, 52, 4979–4986 (1992).

    PubMed  CAS  Google Scholar 

  • Patten, E. J. and DeLong, M. J., Temporal effects of the detoxification enzyme inducer, benzyl isothiocyanate: activation of c-jun N-terminal kinase prior to the transcription factors AP-1 and NFkappaB.Biochem Biophys Res Commun, 257, 149–155 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Pezzuto, J.,Cancer chemopreventive agents: from plant materials to clinical intervention trials. American Chemical Society Books, Washington, DC, 1993.

    Google Scholar 

  • Pezzuto, J.,Natural product cancer chemopreventive agents. Plenum Press, New York, 1995.

    Google Scholar 

  • Pezzuto, J. M., Plant-derived anticancer agents.Biochem Pharmacol, 53, 121–133 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Pinkus, R., Weiner, L. M. and Daniel, V., Role of oxidants and antioxidants in the induction of AP-1, NF-kappaB, and glutathione S-transferase gene expression.J Biol Chem, 271, 13422–13429 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Prestera, T., Holtzclaw, W. D., Zhang, Y. and Talalay, P., Chemical and molecular regulation of enzymes that detoxify carcinogens.Proc Natl Acad Sci U S A, 90, 2965–2969 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Prochaska, H. J. and Talalay, P., Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver.Cancer Res, 48, 4776–4782 (1988).

    PubMed  CAS  Google Scholar 

  • Raingeaud, J., Gupta, S., Rogers, J. S., Dickens, M., Han, J., Ulevitch, R. J. and Davis, R. J., Pro-inflammatory cytokines and environmental stress cause p38 mitogenactivated protein kinase activation by dual phosphorylation on tyrosine and threonine.J Biol Chem, 270, 7420–7426 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Rouse, J., Cohen, P., Trigon, S., Morange, M., Alonso-Llamazares, A., Zamanillo, D., Hunt, T. and Nebreda, A. R., A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins.Cell, 78, 1027–1037 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Rushmore, T., Pickett, CB, and Lu AYH.,Regulation fo expression of rat liver glutathione S-transferases: Xenobiotic and antioxidant induction of the Ya subunit gene. Springer-Verlag, Berlin Heidelberg, 1994.

    Google Scholar 

  • Rushmore, T. H., Morton, M. R. and Pickett, C. B., The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity.J Biol Chem, 266, 11632–11639 (1991).

    PubMed  CAS  Google Scholar 

  • Rushmore, T. H. and Pickett, C. B., Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants.J Biol Chem, 265, 14648–14653 (1990).

    PubMed  CAS  Google Scholar 

  • Samaha, H. S., Kelloff, G. J., Steele, V., Rao, C. V. and Reddy, B. S., Modulation of apoptosis by sulindac, curcumin, phenylethyl-3-methylcaffeate, and 6-phenylhexyl isothiocyanate: apoptotic index as a biomarker in colon cancer chemoprevention and promotion.Cancer Res, 57, 1301–1305 (1997).

    PubMed  CAS  Google Scholar 

  • Shao, Z. M., Wu, J., Shen, Z. Z. and Barsky, S. H., Genistein exerts multiple suppressive effects on human breast carcinoma cells.Cancer Res, 58, 4851–4857 (1998).

    PubMed  CAS  Google Scholar 

  • Skolnik, E. Y., Lee, C. H., Batzer, A., Vicentini, L. M., Zhou, M., Daly, R., Myers, M. J., Jr., Backer, J. M., Ullrich, A., White, M. F. and et al., The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling.Embo J, 12, 1929–1936 (1993).

    PubMed  CAS  Google Scholar 

  • Slater, A., Stefan, C, Nobel, I, Van Den Dobbelsteen, DJ, and Orrenius, S., Intracellular redox changes during apoptosis.Cell Death and Differentiation, 3, 57–62 (1996).

    PubMed  CAS  Google Scholar 

  • Smith, C. A., Farrah, T. and Goodwin, R. G., The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death.Cell, 76, 959–962 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Sparnins, V. L., Chuan, J. and Wattenberg, L. W., Enhancement of glutathione S-transferase activity of the esophagus by phenols, lactones, and benzyl isothiocyanate.Cancer Res, 42, 1205–1207 (1982a).

    PubMed  CAS  Google Scholar 

  • Sparnins, V. L., Venegas, P. L. and Wattenberg, L. W., Glutathione S-transferase activity: enhancement by compounds inhibiting chemical carcinogenesis and by dietary constituents.J Natl Cancer Inst, 68, 493–496 (1982b).

    PubMed  CAS  Google Scholar 

  • Steller, H., Mechanisms and genes of cellular suicide.Science, 267, 1445–1449 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Stokoe, D., Macdonald, S. G., Cadwallader, K., Symons, M. and Hancock, J. F., Activation of Raf as a result of recruitment to the plasma membrane [see comments] [published erratum appears in Science 1994 Dec 16;266(5192):1792-3].Science, 264, 1463–1467 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Stoner, G. D., Morrissey, D. T., Heur, Y. H., Daniel, E. M., Galati, A. J. and Wagner, S. A., Inhibitory effects of phenethyl isothiocyanate on N-nitrosobenzylmethylamine carcinogenesis in the rat esophagus.Cancer Res, 51, 2063–2068 (1991).

    PubMed  CAS  Google Scholar 

  • Talalay, P., De Long, M.J., and Prochaska, H.J.,Molecular Mechanisms in protection against carcinogenesis. Plenum, New York, 1987.

    Google Scholar 

  • Talalay, P., Mechanisms of induction of enzymes that protect against chemical carcinogenesis.Adv Enzyme Regul, 28, 237–250 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Tartaglia, L. A., Rothe, M., Hu, Y. F. and Goeddel, D. V., Tumor necrosis factor’s cytotoxic activity is signaled by the p55 TNF receptor.Cell, 73, 213–216 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Tewari, M., Quan, L. T., K, O. R., Desnoyers, S., Zeng, Z., Beidler, D. R., Poirier, G. G., Salvesen, G. S. and Dixit, V. M., Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase.Cell, 81, 801–809 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Thompson, C. B., Apoptosis in the pathogenesis and treatment of disease.Science, 267, 1456–1462 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Thornberry, N. A. and Lazebnik, Y., Caspases: enemies within.Science, 281, 1312–1316 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Ulland, B. M., Weisburger, J. H., Yamamoto, R. S. and Weisburger, E. K., Antioxidants and carcinogenesis: butylated hydroxytoluene, but not diphenyl-p-phenylenediamine, inhibits cancer induction by N-2-fluorenylacetamide and by N-hydroxy-N-2-fluorenylacetamide in rats.Food Cosmet Toxicol, 11, 199–207 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Venugopal, R. and Jaiswal, A. K., Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene.Proc Natl Acad Sci U S A, 93, 14960–14965 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Verheij, M., Bose, R., Lin, X. H., Yao, B., Jarvis, W. D., Grant, S., Birrer, M. J., Szabo, E., Zon, L. I., Kyriakis, J. M., Haimovitz-Friedman, A., Fuks, Z. and Kolesnick, R. N., Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis.Nature, 380, 75–79 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Wang, X. S., Diener, K., Manthey, C. L., Wang, S., Rosenzweig, B., Bray, J., Delaney, J., Cole, C. N., Chan-Hui, P.Y., Mantlo, N., Lichenstein, H. S., Zukowski, M. and Yao, Z., Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase.J Biol Chem, 272, 23668–23674 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Wang, Z. Y., Cheng, S. J., Zhou, Z. C., Athar, M., Khan, W. A., Bickers, D. R. and Mukhtar, H., Antimutagenic activity of green tea polyphenols.Mutat Res, 223, 273–285 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Wang, Z. Y., Huang, M. T., Lou, Y. R., Xie, J. G., Reuhl, K. R., Newmark, H. L., Ho, C. T., Yang, C. S. and Conney, A. H., Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induced skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated SKH-1 mice.Cancer Res, 54, 3428–3435 (1994).

    PubMed  CAS  Google Scholar 

  • Wasserman, W. W. and Fahl, W. E., Functional antioxidant responsive elements.Proc Natl Acad Sci U S A, 94, 5361–5366 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Wattenberg, L. W., Inhibition of chemical carcinogen-induced pulmonary neoplasia by butylated hydroxyanisole.J Natl Cancer Inst, 50, 1541–1544 (1973).

    PubMed  CAS  Google Scholar 

  • Wattenberg, L. W., Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds.J. Natl Cancer Inst, 58, 395–398 (1977).

    PubMed  CAS  Google Scholar 

  • Wattenberg, L. W., Inhibition of neoplasia by minor dietary constituents.Cancer Res, 43, 2448s-2453s. (1983).

    PubMed  CAS  Google Scholar 

  • Wattenberg, L. W., Chemoprevention of cancer.Cancer Res, 45, 1–8 (1985).

    Article  PubMed  CAS  Google Scholar 

  • Wattenberg, L. W., Protective effects of 2(3)-tert-butyl-4-hydroxyanisole on chemical carcinogenesis.Food Chem Toxicol, 24, 1099–1102 (1986).

    Article  PubMed  CAS  Google Scholar 

  • Wattenberg, L. W., Prevention-therapy-basic science and the resolution of the cancer problem.Cancer Res, 53, 5890–5896 (1993).

    PubMed  CAS  Google Scholar 

  • Wattenberg, L. W. and Bueding, E., Inhibitory effects of 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (Oltipraz) on carcinogenesis induced by benzo[a]pyrene, diethyl-nitrosamine and uracil mustard.Carcinogenesis, 7, 1379–1381 (1986).

    Article  PubMed  CAS  Google Scholar 

  • Wattenberg, L. W., Coccia, J. B. and Lam, L. K., Inhibitory effects of phenolic compounds on benzo(a)pyrene-induced neoplasia.Cancer Res, 40, 2820–2823 (1980).

    PubMed  CAS  Google Scholar 

  • Wattenberg, L. W., Lam, L. K., Fladmoe, A. V. and Borchert, P., Inhibits of of colon carcinogenesis.Cancer, 40, 2432–2435 (1977).

    Article  PubMed  CAS  Google Scholar 

  • Weinshilboum, R. M., Otterness, D. M., Aksoy, I. A., Wood, T. C., Her, C. and Raftogianis, R. B., Sulfation and sulfotransferases 1: Sulfotransferase molecular biology: cDNAs and genes.Faseb J, 11, 3–14 (1997).

    PubMed  CAS  Google Scholar 

  • Weinstein, I. B., Begemann, M., Zhou, P., Han, E. K., Sgambato, A., Doki, Y., Arber, N., Ciaparrone, M. and Yamamoto, H., Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy.Clin Cancer Res, 3, 2696–2702 (1997).

    PubMed  CAS  Google Scholar 

  • Weisburger, E. K. and Evarts, R. P., Inhibitory effect of butylated hydroxytoluene (BHT) on intestinal carcinogenesis in rats by azoxymethane.Food Cosmet Toxicol, 15, 139–141 (1977).

    Article  PubMed  CAS  Google Scholar 

  • Williams, R. T., Species variations in the pathways of drug metabolism.Environ Health Perspect, 22, 133–138 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Wormhoudt, L. W., Commandeur, J. N. and Vermeulen, N. P., Genetic polymorphisms of human N-acetyl-transferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity.Crit Rev Toxicol, 29, 59–124 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Xu, Y., Ho, C. T., Amin, S. G., Han, C. and Chung, F. L., Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants.Cancer Res, 52, 3875–3879 (1992).

    PubMed  CAS  Google Scholar 

  • Yan, Y. S., [Effect of Chinese green tea extracts on the human gastric carcinoma cell in vitro].Chung Hua Yu Fang I Hsueh Tsa Chih, 24, 80–82 (1990).

    PubMed  CAS  Google Scholar 

  • Yang, C. S., Brady, J. F. and Hong, J. Y., Dietary effects on cytochromes P450, xenobiotic metabolism, and toxicity.Faseb J, 6, 737–744 (1992).

    PubMed  CAS  Google Scholar 

  • Yang, C. S., Smith, T. J. and Hong, J. Y., Cytochrome P-450 enzymes as targets for chemoprevention against chemical carcinogenesis and toxicity: opportunities and limitations.Cancer Res, 54, 1982s-1986s (1994).

    PubMed  CAS  Google Scholar 

  • Yang, C. S. and Wang, Z. Y., Tea and cancer.J Natl Cancer Inst, 85, 1038–1049 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Yang, G. Y., Liao, J., Kim, K., Yurkow, E. J. and Yang, C. S., Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols.Carcinogenesis, 19, 611–616 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T. I., Jones, D. P. and Wang, X., Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked [see comments].Science, 275, 1129–1132 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Ye, H., Kelly, T. F., Samadani, U., Lim, L., Rubio, S., Overdier, D. G., Roebuck, K. A. and Costa, R. H., Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues.Mol Cell Biol, 17, 1626–1641 (1997).

    PubMed  CAS  Google Scholar 

  • Yu, R., Mandlekar, S., Harvey, K.J., Ucker, D.S., and Kong, A.-N. T., Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity.Cancer Res., 58, 402–408 (1998a).

    PubMed  CAS  Google Scholar 

  • Yu, R., Mandlekar, S., and Kong, A.-N.T., Distinct roles of intracellular calcium in the activation of c-jun N-terminal kinases and caspases during apoptosis induced by phenolic antioxidant BHA. In37th Annual Meeting of Society of Toxicology, Seattle, WA, Toxicological Sciences (Formerly Fund. Appl. Tox.). pp. 356. Seattle, WA (1998b).

  • Yu, R., Mandlekar, S., Lei, W., Fahl, W.E., Tan, T.-H., and Kong, A.-N.T., p38 mitogen-activated protein kinase negatively regulates the induction of phase II drug metabolizing enzymes that detoxify carcinogens.J. Biol. Chem., 275 (February 2000 (in the press)).

  • Yu, R., Jiao, J. J., Duh, J. L., Gudehithlu, K., Tan, T. H. and Kong, A. N. T., Activation of mitogen-activated protein kinases by green tea polyphenols: potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression.Carcinogenesis, 18, 451–456 (1997a).

    Article  PubMed  CAS  Google Scholar 

  • Yu, R., Jiao, J. J., Duh, J. L., Tan, T. H. and Kong, A. N. T., Phenethyl isothiocyanate, a natural chemopreventive agent, activates c-Jun N-terminal kinase 1.Cancer Res, 56, 2954–2959 (1996a).

    PubMed  CAS  Google Scholar 

  • Yu, R., Lei, W., Mandlekar, S., Weber, M. J., Der, C. J., Wu, J. and Kong, A. T., Role of a Mitogen-activated Protein Kinase Pathway in the Induction of Phase II Detoxifying Enzymes by Chemicals.J Biol Chem, 274, 27545–27552 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Yu, R., Shtil, A. A., Tan, T. H., Roninson, I. B. and Kong, A. N. T., Adriamycin activates c-jun N-terminal kinase in human leukemia cells: a relevance to apoptosis.Cancer Lett, 107, 73–81 (1996b).

    Article  PubMed  CAS  Google Scholar 

  • Yu, R., Tan, T. H. and Kong, A. T., Butylated hydroxyanisole and its metabolite tert-butylhydroquinone differentially regulate mitogen-activated protein kinases. The role of oxidative stress in the activation of mitogen-activated protein kinases by phenolic antioxidants.J Biol Chem, 272, 28962–28970 (1997b).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Y., Kolm, R. H., Mannervik, B. and Talalay, P., Reversible conjugation of isothiocyanates with glutathione catalyzed by human glutathione transferases.Biochem Biophys Res Commun, 206, 748–755 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Y. and Talalay, P., Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms.Cancer Res., 54, 1976s-1981s (1994).

    PubMed  CAS  Google Scholar 

  • Zhang, Y., Talalay, P., Cho, C. G. and Posner, G. H., A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure.Proc Natl Acad Sci U S A, 89, 2399–2403 (1992).

    Article  PubMed  CAS  Google Scholar 

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Kong, AN.T., Yu, R., Chen, C. et al. Signal transduction events elicited by natural products: Role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Arch Pharm Res 23, 1–16 (2000). https://doi.org/10.1007/BF02976458

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