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Titolo:
Signal transduction events elicited by cancer prevention compounds
Autore:
Kong, ANT; Yu, R; Hebbar, V; Chen, C; Owuor, E; Hu, R; Ee, R; Mandlekar, S;
Indirizzi:
Univ Illinois, Coll Pharm, Ctr Pharmaceut Biotechnol, Dept Pharmaceut & Pharmacodynam, Chicago, IL 60607 USA Univ Illinois Chicago IL USA 60607 & Pharmacodynam, Chicago, IL 60607 USA
Titolo Testata:
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
, volume: 480, anno: 2001,
pagine: 231 - 241
SICI:
1386-1964(20010901)480:<231:STEEBC>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACTIVATED PROTEIN-KINASES; ANTIOXIDANT RESPONSIVE ELEMENTS; JUN NH2-TERMINAL KINASE-1; N-TERMINAL KINASE; YA-SUBUNIT GENE; CYTOCHROME-C; BUTYLATED HYDROXYANISOLE; OXIDATIVE STRESS; TEA POLYPHENOLS; CHEMOPREVENTIVE AGENT;
Keywords:
chemopreventive agents; signal transduction; MAPK; caspases; phase II drug metabolizing enzymes; apoptosis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
84
Recensione:
Indirizzi per estratti:
Indirizzo: Kong, ANT Univ Illinois, Coll Pharm, Ctr Pharmaceut Biotechnol, Dept Pharmaceut & Pharmacodynam, 900 S Ashland Ave,MC 870, Chicago, IL 60607 USA UnivIllinois 900 S Ashland Ave,MC 870 Chicago IL USA 60607 USA
Citazione:
A.N.T. Kong et al., "Signal transduction events elicited by cancer prevention compounds", MUT RES-F M, 480, 2001, pp. 231-241

Abstract

Many chemopreventive agents have been shown to modulate gene expression including induction of phase II detoxifying enzymes, such as glutathione S-transferases (GST) and quinone reductases (QR). Induction of phase II enzymesin general leads to protection of cells/tissues against exogenous and/or endogenous carcinogenic intermediates. The antioxidant or electrophile response element (ARE/EpRE) found at the 5 ' -flanking region of these phase II genes may play important role in mediating their induction by xenobiotics including chemopreventive agents. Members of the basic leucine zipper (bZIP)transcription factor, Nrf2 which heterodimerizes with Maf G/K, are found to bind to the ARE, and transcriptionally-activated ARE. Recently, we showedthat the mitogen-activated protein kinases (MAPK) were activated by phase II gene inducers such as phenolic antioxidant butylated hydroxyanisol (BHA)and isothiocyanate sulforaphane (SUL), and involved in the transcription activation of ARE-mediated reporter gene. Transfection studies with wild-type and dominant negative mutants of Nrf2 and MAPK showed synergistic response during co-transfection as well as to phase II gene inducers. However, increasing the concentrations of these compounds such as BHA. the activities of cell death signaling molecules, caspases, were stimulated and resulted inapoptotic cell death. At these concentrations, BHA stimulated loss of mitochondrial membrane potential, cytochrome c release, and activation of caspase 3, 8 and 9 preceding apoptosis. Further increase in concentrations led to rapid cell necrosis. A model is proposed for BHA and SUL, in that at low concentrations, these potential chemopreventive agents may modulate MAPK pathway leading to transcription activation of Nrf2 and ARE with subsequent induction of cellular defensive enzymes including phase II detoxifying enzymes as well as other defensive genes, which may protect the cells against cellular injury. which is a homeostatic response. At higher concentrations, these agents may activate the caspase pathways, leading to apoptosis, a potential beneficial effect if occurs at preneoplastic/neoplastic tissues, but a potential cytotoxic response if occurs in normal tissues. On the other hand. some phenolic compounds such as resveratrol inhibits TPA- or UV-inducedAP-1-mediated activity through the inhibition of c-Src non-receptor tyrosine kinase and MAPK pathways. It is possible that in proliferating or stimulated cells, these chemopreventive compounds may block proliferation by inhibiting these signaling kinases. whereas in non-proliferating or quiescent cells, some of these compounds may activate these signaling kinases leading to gene expression of cellular defensive enzymes such as phase II detoxifying enzymes. The studies of these and other signaling pathways may yield insights into the development of potential chemopreventive compounds. (C) 2001Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/04/20 alle ore 19:18:25