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Natural dietary anti-cancer chemopreventive compounds:redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells

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Acta Pharmacologica Sinica 2007年第4期28卷 459-472页

作者： sujit nair Ah-Ng Tony KONG Graduate Program in Pharmaceutical Sciences Department of Pharmaceutics Ernest Mario School of PharmacyRutgersThe StateUniversity of New JerseyPiscatawayNew Jersey 08854USA

Many dietary phytochemicals exhibit health-beneficial effects including preven-tion of diseases such as cancer,as well as neurological,cardiovascular,inflam-matory,and metabolic ***,herbivorous and omnivorousanimals have been ingesting *** interaction between"animal-plant"ecosystems has resulted in an elaborate system of detoxification and defensemechanisms evolved by animals including *** cells,includinghuman cells,respond to these dietary phytochemicals by"non-classical receptorsensing"mechanisms of electrophilic chemical-stress typified by"thiol-modu-lated"cellular signaling events primarily leading to the gene expression of phar-macologically beneficial effects,but sometimes unwanted cytotoxicity *** has been studying two groups of dietary phytochemical cancer-chemopreventive compounds (isothiocyanates and polyphenols),which areeffective in chemical-induced,as well as genetically-induced,animal carcinogen-esis *** compounds typically generate"cellular stress"and modulategene expression of phase Ⅱ detoxifying/antioxidant ***,reac-tive oxygen species,and reactive nitrogen species are known to act as secondmessengers in the modulation of many cellular signaling pathways leading togene expression changes and pharmacological ***-sensitive tran-scription factors such as nuclear factor-E2-related factor 2 (Nrf2),AP-1,NF-κB,tocite a few examples,sense and transduce changes in the cellular redox status andmodulate gene expression responses to oxidative and electrophilic stresses,pre-sumably via sulfhydryl modification of critical cysteine residues found on theseproteins and/or other upstream redox-sensitive molecular *** the currentreview,we will explore dietary cancer chemopreventive phytochemicals,discussthe link between oxidative/electrophilic stresses and the redox circuitry,and con-sider different redox-sensitive transcription *** will also discuss thekelch-l

关键词： redox Nrf2 Keapl NES NLS gene expression profiles

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Pharmacometrics of nutraceutical sulforaphane and its implications in prostate cancer prevention

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Journal of Chinese Pharmaceutical Sciences 2016年第1期25卷 12-22页

作者： sujit nair Ah-Ng Tony Kong Amrita Cancer Discovery Biology Laboratory Amrita Vishwa Vidyapeetham University Center for Cancer Chemoprevention Research and Department of Pharmaceutics Rutgers The State University of New Jersey

Sulforaphane(SFN), found in broccoli and other cruciferous vegetables, has a beneficial effect in chemoprevention of prostate cancer, whose incidence and associated mortality have gradually increased worldwide. There is great enthusiasm for bench-to-bedside development of SFN as a potent chemopreventive agent, possibly alone or as an adjunct to existing chemotherapy regimens, in the oncology care setting to reduce toxicity of chemotherapeutics and potentially enhance their cancer cell-kill efficacy. In this review, we appreciate existing knowledge on SFN using a pharmacometrics approach, which is fast becoming a gold standard in discovery research and validation of New Chemical Entities and New Biological Entities in pharmaceutical industry. We discuss the epistemology of SFN target engagement and quantitative systems pharmacology with due emphasis on mechanistic pharmacology, pharmacodynamics, pharmacogenomics and metabolism of SFN. In addition, we explore the quantitative freeway to SFN translational medicine by assessing the preclinical and clinical PK/metabolism aspects of SFN that form the cornerstone of SFN pharmacometric evaluation, as well as the promise of SFN in prostate cancer. Taken together, we share perspectives on the exciting developments in translational cancer chemoprevention, with emphasis on the pharmacometric aspects, of the nutraceutical SFN which is currently in clinical trials, and suggest that the pharmacometric approach holds great promise in the SFN translational pharmacology paradigm for prostate cancer.

关键词： Pharmacometrics Pharmacokinetics Quantitative systems pharmacology Target engagement Metabolism Pharmacogenomics Chemoprevention Sulforaphane Isothiocyanate Prostate cancer

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Differential signaling regulatory networks governing hormone refractory prostate cancers

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Journal of Chinese Pharmaceutical Sciences 2014年第8期23卷 511-524页

作者： sujit nair Celine Liew Tin Oo Khor Li Cai Ah-Ng Kong Amrita Cancer Discovery Biology Laboratory and Amrita School of Pharmacy Amrita Vishwa Vidyapeetham UniversityPonekkara P.O. Kochi-682041 Kerala India Department of Pharmaceutics Rutgers The State University of New Jersey Piscataway NJ-08854 USA Department of Pharmacy National University of Singapore Singapore-117543 Republic of Singapore Department of Biomedical Engineering Rutgers The State University of New Jersey Piscataway NJ-08854 USA

To understand the organization of the biological networks that might potentially govern the pathogenesis of hormone refractory prostate cancer(HRPC), we investigated the transcriptional circuitry and signaling in androgen-dependent 22Rv1 and MDA PCa 2b cells, androgen- and estrogen-dependent LNCaP cells, and androgen-independent DU 145 and PC-3 prostate cancer(PCa) cell lines. We used microarray analyses, quantitative real-time PCR, pathway prediction analyses, and determination of Transcription Factor Binding Site(TFBS) signatures to dissect HRPC regulatory networks. We generated graphical representations of global topology and local network motifs that might be important in prostate carcinogenesis. Many important putative biomarker ‘target hubs' were identified in the current study including AP-1, NF-?B, EGFR, ERK1/2, JNK, p38 MAPK, TGF beta, VEGF, PDGF, CD44, Akt, PI3 K, NOTCH1, CASP1, MMP2 and AR. Our results suggest that complex cellular events including autoregulation, feedback loops and cross-talk might govern progression from early lesion to clinically diagnosed PCa, as well as metastatic potential of pre-existent high-grade prostate intraepithelial neoplasia(HG-PIN) and/or advancement to HRPC. The identification of TFBS signatures for TCF/LEF, SOX9 and ELK1 in the regulatory elements suggests additional biomarkers for the potential development of chemopreventive/therapeutic strategies against PCa. Taken together, in this study, we have identified putative biomarker ‘target hubs' in the architecture of PCa signaling networks, and investigated TFBS signatures that might enhance our understanding of key regulatory nodes in the progression and pathogenesis of HRPC.

关键词： Prostate cancer, Signaling network, Target hub, Regulatory , Biomarker, Transcription Factor Binding Site

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Elucidation of regulatory interaction networks underlying human prostate adenocarcinoma

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Journal of Chinese Pharmaceutical Sciences 2015年第1期24卷 12-27页

作者： sujit nair Celine Liew Tin-Oo Khor Li Cai Ah-Ng Tony Kong Amrita Cancer Discovery Biology Laboratory and Amrita School of Pharmacy Amrita Vishwa Vidyapeetham University Ponekkara P.O. Kochi-682041 Kerala India Department of Pharmaceutics Rutgers The State University of New Jersey Piscataway NJ-08854 USA Department of Pharmacy National University of Singapore 18 Science Drive 4 Singapore--117543 Department of Biomedical Engineering Rutgers the State University of New Jersey Piscataway NJ-08854 USA

The incidence of prostate cancer is rising in the Asia-Pacific region as well as other countries. Androgen-ablation therapy is clinically useful in the androgen-dependent phenotype however, many patients progress to hormone refractory prostate cancer that is difficult to treat and needs newer interventions that are more effective. The objective of this study was to determine functionally-relevant biological networks, to appreciate the potential crosstalk between signaling members, and to identify biomarker signatures in prostate cancer. We used microarray analyses to identify key genes that were upregulated or down regulated at least five-fold in human prostate cancer and constructed canonical interaction networks that are important in prostate cancer through metabolomics analyses. Our prostate cancer network architecture revealed several key biomarkers including ERK1/2, JNK, p38, MEK, PI3 K, NFκB, AP-1, 14-3-3, VEGF, PDGF, Rb, WNT8 A, WNT10 A, CD44, ESR2, FSH and LH. Furthermore, the top ten transcription factors identified by TFBS-association signature analysis in the regulatory elements of co-regulated biomarkers were delineated, which may crosstalk with upstream or downstream genes elicited in our network architecture. Taken together, our results demonstrate that the regulatory interaction networks in prostate cancer provide a universal view of crosstalk between important biomarkers, i.e., key players in the pathogenesis of this disease. This will facilitate more rapid screening of functional biomarkers in early/intermediate drug discovery.

关键词：前列腺癌微阵列生物学网生物标记

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Nrf2-mediated antioxidant and detoxifying enzyme induction by a combination of curcumin and sulforaphaneNrf2-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 Hep G2-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. Hep G2-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-1) 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 μM) and SFN(12.5 μM) significantly induced the expression of HO-1 and UGT1A1 proteins. Through the use of chemical inhibitors of mR NA 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 Hep G2-C8 cells. Thus, CUR and SFN at low concentrations augment therapeutic effects in Hep G2-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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