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Cancer chemoprevention by phytochemicals:potential molecular targets,biomarkers and animal models

Acta Pharmacologica Sinica 2007年第9期28卷 1409-1421页

作者： Ki Han KWON avantika barve Siwang Yu Mou-Tuan HUANG Ah-Ng Tony KONG Center for Cancer Prevention Research Department of Pharmaceutics Center for Cancer Prevention Research Graduate Program in Pharmaceutical Science Center for Cancer Prevention Research Susan Lehman Cullman Laboratory for Cancer Research Center for Cancer Prevention Research Department of Pharmaceutics Department of Chemical Biology Ernest Mario School of Pharmacy RutgersThe State University of New JerseyPiscatawayNJ 08854USA

Recent studies have strongly indicated that certain daily-consumed dietaryphytochemicals could have cancer protective effects against transgenic mice can-cer models and cancers mediated by carcinogens,irradiations and carcinogenicmetabolites derived from exogenous or endogenous *** cancer-protec-tive effects elicited by these dietary compounds are believed to be due at least inpart to the induction of cellular defense systems including the detoxifying andantioxidant enzymes system,as well as the inhibition of anti-inflammatory andanti-cell growth signaling pathways culminating in cell cycle arrest and/or cell-death,in this review,we summarize the potential mechanisms including the modu-lation of nuclear factor kappaB (NF-kB),cyclooxygenases-2 (COX-2),activatorprotein-1 (AP-1),mitogen-activated protein kinases (MAPKs) and the inductionof phase Ⅱ cellular detoxifying and antioxidant enzymes mediated mainly by theantioxidant response elements (ARE) within the promoter regions of these genesthrough nuclear factor-erythroid 2-related factor 2 (Nff2),a member of the Cap‘n’collar (CNC) family of the basic region-leucine zipper transcription ***,we also review several animal models of carcinogenesis and cancerchemopreventive efficacy studies of these animal models using dietarychemopreventive ***,we discuss the cellular signaling cascadesmediated by Nrf2,NF-kB,AP-1,MAPKs and COX-2,which have been consideredto play pivotal roles in tumor initiation,promotion and progression processes,and could be promising molecular targets for the design of drugs targeting cancerprevention and therapy.

关键词： chemoprevention dietary cancer chemopreventive compounds nuclear factor E2related factor 2 nuclear factor-kappaB activator protein-l mitogen-activated protein kinases

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Nrf2-mediated antioxidant and detoxifying enzyme induction by a combination of curcumin and sulforaphane

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Journal of Chinese Pharmaceutical Sciences 2016年第8期25卷 559-569页

作者： Francisco Fuentes Yury Gomez Ximena Paredes-Gonzalez avantika barve Sujit Nair Siwang Yu Constance Lay Lay Saw Ah-Ng Tony Kong Facultad de Agronomia e Ingenieria Forestal Pontificia Universidad Cato1ica de Chile Casilla 306-22 Santiago Chile Department of Pharmaceutics Ernest Mario School of Pharmacy Rutgers The State University of New Jersey New Jersey 08854 USA Novartis Institutes for Biomedical Research East Hanover NJ-07470 USA Amrita Cancer Discovery Biology Laboratory Amrita Vishwa Vidyapeetham University Amritapuri Clappana P.O. Kollam Kerala-690525 India School of Pharmaceutical Sciences Peking University Health Science Center Beo'ing 100191 China

The dietary phytochemicals curcumin （CUR） and sulforaphane （SFN） have shown remarkable cancer chemopreventive effects in many model systems. This study was designed to investigate the induction of Nrf2-mediated antioxidant enzymes by combining doses of CUR and SFN and the effect of their combination on the Nrf2-ARE （antioxidant response element） response in HepG2-C8 cells. We hypothesized that the combination of the polyphenol CUR and the isothiocyanate SFN could enhance the induction of AREs and Nrf2-target enzymes. HepG2-C8 cells were treated with a combination of low doses of CUR, SFN or both. The induction of Nrf2-mediated antioxidant and phase II detoxifying enzymes-heme oxygenase-1 （HO-I） and UDP-glucuronosyltransferase-1A （UGT1A）-was measured by real-time RT-PCR and western blotting. ARE-luciferase activity was also quantified. Low doses of CUR （10 ~tM） and SFN （12.5 ~tM） significantly induced the expression of HO-1 and UGT 1 A1 proteins. Through the use of chemical inhibitors of mRNA and protein synthesis, the combination of CUR and SFN was shown to affect the transcriptional regulation of both HO-1 and UGT1A1. Additionally, the combination of CUR and SFN synergistically induced the expression of Nrf2- and ARE-luciferase activity in HepG2-C8 cells. Thus, CUR and SFN at low concentrations augment therapeutic effects in HepG2-C8 cells. The enhanced ARE-luciferase activity of combined CUR and SFN treatment could partly explain the significant induction of the Nrf2-target enzymes HO-1 and UGT1A1. Taken together, our results suggest that combining low doses of CUR and SNF could be a promising strategy for cancer chemoprevention in humans.

关键词： Antioxidant response element, Curcumin, HepG2-C8 cell-s, HO-1, Nrf2, Sulforaphane, UGT 1A1

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