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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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Development and validation of a rapid UPLC/MS method for the simultaneous determination of I3C, DIM, and related metabolites and its application to pharmacokinetics studies

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Journal of Chinese Pharmaceutical Sciences 2016年第7期25卷 477-488页

作者： Yury Gomez Hu Wang ah-ng tony kong Graduate Program in Pharmaceutical Science Ernest Mario School of Pharmacy Rutgers The State University of New Jersey Department of Pharmaceutics Ernest Mario School of Pharmacy Rutgers The State University of New Jersey

Indole-3-carbinol(I3C) and diindolylmethane(DIM) are naturally derived dietary phytochemicals with promising anti-cancer properties that have been demonstrated both in vitro and in vivo. Using reversed-phase ultra-performance liquid chromatography(UPLC) coupled with mass spectrometry(MS), a rapid, specific, and high throughput method was developed and validated for the quantification and identification of I3 C, DIM, and other I3 C metabolites in plasma. Samples containing I3 C or DIM and the internal standard 4-methoxy indole(IS) were extracted using a liquid-liquid extraction technique. The mean recovery was 96.21% for I3 C and 108.5% for DIM. Separation was achieved using a Waters Acquity UPLC HSS T3, 1.8 μm, 2.1 mm×150 mm column and acetonitrile–water gradient elution. The flow rate was 0.3 m L/min and the run time was 9 min. The limits of detection and quantification for I3 C and DIM were 15 ng/m L and 25 ng/m L, respectively. Calibration curves for I3 C and DIM were linear(r2>0.99) over a concentration range of 0.025–20 μg/m L. Precision, accuracy, and stability analysis fulfilled the CDER guidelines criteria. The method was successfully applied to the determination of the pharmacokinetic parameters of I3 C or DIM after oral, intravenous, or intraperitoneal administration to Sprague Dawley rats. The method described here is superior over existing analytical methods for I3 C and its metabolites in terms of sensitivity, speed, and separation.

关键词： UPLC/MS Indole-3-Carbinol Diindolylmethane Pharmacokinetics Single-dose administration Sprague-Dawley Rats

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

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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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Cancers chemoprevention by dietary phytochemicals and traditional Chinese medicines: epigenetics and cellular signaling pathways

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Journal of Chinese Pharmaceutical Sciences 2016年第4期25卷 233-234页

作者： ah-ng tony kong Siwang Yu Department of Pharmaceutics Earnest Mario School of Pharmacy Rutgers The State University of New Jersey School of Pharmaceutical Sciences Peking University Health Science Center

The incidence and mortality of cancer have been increasing alarmingly in China and *** other chronic diseases such as metabolic,cardiovascular,and neuropathies,most cancers,especially metastatic ones,are still essenti... 详细信息

关键词： epigenetics medicines dietary cardiovascular metastatic spite mortality carcinogenesis incidence alterations

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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： Human prostate cancer Microarray Biological network Biomarker

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Mechanisms of prostate carcinogenesis and its prevention by a γ-tocopherolrich mixture of tocopherols in TRAMP mice

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Journal of Chinese Pharmaceutical Sciences 2016年第3期25卷 170-177页

作者： Ying Huang Zhengyuan Su Tienyuan Wu Constance Lay-Lay Saw ah-ng tony kong Department of Pharmaceutics Earnest Mario School of Pharmacy Rutgers The State University of New Jersey

Tocopherols belong to a subgroup of the vitamin E family. Dietary feeding of a γ-tocopherol-rich mixture of tocopherols(γ-Tm T) inhibits prostate tumorigenesis in TRAMP mice. In this study, we aimed to investigate mechanisms of prostate carcinogenesis in TRAMP mice by identifying differentially expressed pathways and effects of γ-Tm T on these pathways. Eight-week-old TRAMP and age-matched C57BL/6 mice were administered either 600 mg/kg of γ-Tm T or a control vehicle via oral gavage. Twelve hours after dosing, prostate tissues were collected for RNA extraction. Whole genome mouse microarrays were used to examine gene expression profiles. The expression of the selected genes were validated using quantitative PCR. Thousands of genes and various pathways were altered in the prostates of TRAMP mice. Compared to C57BL/6 mice, TRAMP mice exhibited enhanced proliferation, suppressed expression of antioxidant and phase II detoxification enzymes, and metabolic reprogramming in the prostate. γ-Tm T differentially regulated the gene expression profiles of TRAMP and C57BL/6 mice, with only a small percentage of genes overlapping. γ-Tm T inhibited genes involved in proliferation and glucose metabolism and induced several antioxidant/phase II detoxification genes in TRAMP mice. γ-Tm T modulates multiple aberrant pathways in the prostate of TRAMP mice, which might represent important mechanisms for prostate cancer prevention.

关键词： Tocopherol Vitamin E Prostate cancer Proliferation Antioxidant Glucose metabolism

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Prostate cancer and chemoprevention by natural dietary phytochemicals

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Journal of Chinese Pharmaceutical Sciences 2016年第9期25卷 633-650页

作者： Asia Abed Al-Mahmood Limin Shu Hyuck Kim Christina Ramirez Douglas Pung Yue Guo Wenji Li ah-ng tony kong Graduate Program in Pharmaceutical Sciences Ernest Mario School of PharmacyRutgersThe State University of New JerseyPiseatawayNJ08854USA Department of Pharmaceuties Ernest Mario School of PharmacyRutgersThe State University of New JerseyPiseatawayNJ08854USA Center for Cancer Prevention Research Ernest Mario School of PharmacyRutgersThe State University of New JerseyPiscatawayNJ08854USA Graduate Program in Cellular and Molecular Pharmacology RutgersThe State University of New JerseyPiscatawayNJ 08854USA

Prostate cancer is the second leading cancer among men in the United States. Several studies have correlated the development of prostate cancer with diet and life-style. Therefore, a balanced diet and improved life style might inhibit prostate cancer progression. Cancer chemoprevention has emerged as an important factor in controlling cancer development through natural or synthetic compounds. Oxidative stress is among the factors contributing to prostate cancer development. The transcription factor nuclear factor(erythroid-derived 2)-like 2(Nrf2) controls detoxifying antioxidant enzymes expression by binding to the antioxidant response element(ARE) in the promoter of these genes to activate their expression. Many natural products can fight oxidative stress and protects cells from DNA damage by activating the Nrf2/ARE pathway. High consumption of fruits and vegetables can reduce disease incidence and invasive tumors. In this review, the roles of important fruit and vegetable phytochemicals in regulating prostate cancer progression and tumor growth are discussed.

关键词： Prostate cancer Phytochemicals Chemoprevention Nuclear factor(erythroid-derived 2)-like 2 Oxidative stress Antioxidant response element

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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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食用植物成分和中药用于癌症化学预防:Nrf2,表观基因组学,癌症干细胞(英文)

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化学进展 2013年第9期25卷 1526-1543页

作者：苏正元舒利民 Jong Hun Lee Franciso Fuentes 王虎吴天元余四旺 ah-ng tony kong Center for Cancer Prevention Research Department of PharmaceuticsErnest-Mario School ofPharmacyRutgersthe State University of New Jersey160 Frelinghuysen RoadPiscatawayNJ 08854USA Departamento de Agricultura del Desierto y Biotecnologia Universidad Arturo PratCasilla 121IquiqueChile 北京大学医学部药学院化学生物学系中国北京100190

癌症是世界范围内的首要致死原因之一。现代诊断和治疗技术的革新改善了癌症患者的治疗和护理,但晚期癌症的治疗仍然是一个巨大的挑战。因此,亟需新的创造性的策略来防治癌症。几个世纪以来,草药曾被用于防治癌症等疾病。科研资助机构,... 详细信息

癌症是世界范围内的首要致死原因之一。现代诊断和治疗技术的革新改善了癌症患者的治疗和护理,但晚期癌症的治疗仍然是一个巨大的挑战。因此,亟需新的创造性的策略来防治癌症。几个世纪以来,草药曾被用于防治癌症等疾病。科研资助机构,例如美国的国家癌症研究所(NCI),在近期加强了对利用天然植物成分和非毒性药物如非甾体抗炎药(NSAIDs)预防或减缓癌症发生研究的支持。本文综述了利用来源于蔬果、绿茶和中药的生物活性成分来预防癌症方面的研究,尤其是重点讨论了在Nrf2、表观基因组学和癌症干细胞等方面的影响。

关键词：癌症化学预防 Nrf2 表观基因组学食植成分植物成分中药

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