Green Tea Polyphenols and Cancer Chemoprevention: Multiple Mechanisms and Endpoints for Phase II Trials

Moyers, Susan; Kumar, Nagi B.

doi:10.1301/nr.2004.may.204-211

Cited by 41 publications

(26 citation statements)

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“…It was reported previously that EGCG had remarkable chemopreventive and chemotherapeutic properties, due mainly to its ability to induce apoptosis (3,4,(31)(32)(33). In this study, we found that the protein tyrosine phosphatase SHP-2 serves as a negative regulator for EGCG-induced apoptosis because its inactivation renders cells sensitive to EGCG.…”

Section: Discussionmentioning

confidence: 50%

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

Amin¹,

Thakur²,

Paul³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Green tea polyphenol, epigallocatechin-3-gallate (EGCG) differentially regulates the cellular growth of cancer cells in a p53-dependent manner through apoptosis and/or cell cycle arrest. In an effort to further elucidate the mechanism of differential growth regulation by EGCG, we have investigated the role of the tyrosine phosphatase, SHP-2. Comparing the responses of mouse embryonic fibroblasts (MEFs), expressing either WT or functionally inactive/truncated SHP-2, we find that inactivation of SHP-2 remarkably sensitizes cells to EGCG-mediated killing. MEFs lacking functional SHP-2 undergo massive apoptosis upon treatment with EGCG. By comparing gene expression profiles, we have identified a set of transcriptional targets of p53 that are differentially modulated in cells undergoing apoptosis. Western blot and real-time PCR analyses of a select group of genes further confirm that the expression is SHP-2-dependent. Similar observations were made in MEFs lacking p53, confirming that the expression of these ''p53 target genes'' is p53-independent. In addition, EGCG treatment induced the expression of p73 mRNA and protein in both cell types, but not p63. Inactivation of p73 in cells expressing nonfunctional SHP-2 markedly inhibited apoptosis and p53 target gene expression. Although phosphorylation of JNK is differentially regulated by SHP2, it was found to be dispensable for EGCG-induced apoptosis and p53 target gene expression. Our results have identified SHP-2 as a negative regulator of EGCG-inducedapoptosis and have identified a subset of p53 target genes whose expression is paradoxically not mediated by p53 but by one of its family members, p73.green tea ͉ MAPK pathway ͉ mouse embryonic fibroblasts ͉ transcriptional activation

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Section: Discussionmentioning

confidence: 50%

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

Amin¹,

Thakur²,

Paul³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…SAR studies on catechins and related compounds have mainly focused on the structural requirements for radical scavenger and antioxidant activity [32][33][34][35]. However, polyphenols may affect many biological activities not only through their antioxidant effect, but also by interacting with specifi c molecular targets in the cell machinery.…”

Section: Discussionmentioning

confidence: 99%

A structure-activity study for the inhibition of metalloproteinase-9 activity and gene expression by analogues of gallocatechin-3-gallate

Dell’Agli

Bellosta

Rizzi

et al. 2005

Cell. Mol. Life Sci.

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Catechins are able to modulate the gelatinolytic activity of matrix metalloproteinase-9 (MMP-9) by reducing its release from macrophages. Gallocatechins decrease MMP-9 secretion by lowering MMP-9 promoter activity and mRNA levels. The effect appears to be dependent on some structural and stereochemical requirements. In this study, the relationship between chemical structure and activity was studied by testing the effect of analogues of (+/-)-gallocatechin-3-gallate (+/-)-GCG, selectively deprived of hydroxyl groups, on MMP-9 activity, transcription, and secretion. Our results indicate that (+/-)-GCG and (+/-)-catechin-3-gallate are characterized by a substitution pattern compatible with direct inhibition of MMP-9 activity. Conversely, when transcription was the target, (+/-)-trans-3-flavanol-3-benzoate, lacking all the hydroxyl groups, was the most effective both in lowering MMP-9 promoter activity and consequently protein secretion, and in inhibiting nuclear-factor-kappaB-driven transcription. Our results suggest that the structural requirements for enzyme inhibition are different from those necessary for targeting gene expression.

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“…19) Flavonoids possess multi-bioactivity such as antihyperuricemic, anti-inflammatory and antioxidant activities. [13][14][15][16] In fact positive healthy effects of flavonoids have also been reported in several diseases, such as cardiovascular diseases and cancer. 17,18) Moreover, the hypouricemic and XOD inhibitory actions of flavonoids have been confirmed in this study.…”

Section: Fig 1 Effects Of Flavonoids On Liver Uric Acid Levelsmentioning

confidence: 99%

Hypouricemic Action of Selected Flavonoids in Mice: Structure-Activity Relationships

Zhou

et al. 2007

Biological & Pharmaceutical Bulletin

154

104

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Gout occurs in individuals who have high serum uric acid levels, in response to precipitation of monosodium urate monohydrate crystals in various tissues, followed by an inflammatory response. 1) The essence of the prevention and treatment of gout is antihyperuricemic therapy, either by uricosuric drugs or by xanthine oxidase (XOD) inhibitors. Allopurinol, an XOD inhibitor which is structurally related to xanthine, binds tightly to the active site of XOD thus causes inhibition on XOD. Allopurinol is used to treat gout for more than 40 years and remains a cornerstone in the therapy of primary and secondary hyperuricemia. 2-7) However, the most common adverse effects of allopurinol are gastrointestinal distress, hypersensitivity reactions, 8) and renal toxicity. 9) Thus, new alternatives with an increased therapeutic activity and less side effects are desired.Dietary flavonoids have been attracted attention because of their potential beneficial effects on human health. The structural components common to these molecules include two benzene rings on either side of a 3-carbon ring (Table 1). 10) Multiple combinations of hydroxyl groups, sugars, oxygens, and methyl groups attached to these structures create the various classes of flavonoids: flavanols, flavanones, flavones, flavanonol, flavan-3-ols (catechins), anthocyanins, and isoflavones. 11) Flavonoids are well known to possess antiviral, antiallergic, antiplatelet, antiinflammatory, antitumor and antioxidant activities. 12-15) Catechin and its derivatives, oligomeric proanthocyanidins, quercetin and quercetin chalcone, Ginkgo flavone glycosides, silymarin, and others can be utilized in preventative and treatment protocols for cardiovascular disease, cancer, inflammatory conditions, asthma, periodontal disease, liver disease, cataracts and macular degeneration. 16,17) Hyperuricemia is a risk factor for the disorder metabolic syndrome and increased cardiovascular disease, and the mechanisms involve inflammation and generation of oxidative stress in the vasculature. 18) Thus, the antiinflammatory and antioxidant activities of flavonoids might bring benefit for hyperuricemia and its complications. In addition, the flavonoids have increasingly aroused interest recently for their hypouricemic action in hyperuricemic animal models. [19][20][21] In the present study, we have explored hypouricemic actions from 15 flavonoids including quercetin, morin, myricetin, kaempferol, icariin, apigenin, luteolin, baicalin, silibinin, naringenin, formonoetin, genistein, puerarin, daidzin and naringin dihydrochalcone in a hyperuricemic animal model induced by potassium oxonate. We have also studied the effects of six most active compounds on serum and liver uric acid levels in normal mice. The effects on liver XOD activities were further examined in animals. MATERIALS AND METHODSMaterials Quercetin, morin, myricetin, kaempferol, icariin, apigenin, luteolin, baicalin, silibinin, naringenin, formonoetin, genistein, puerarin, daidzin and naringin dihydrochalcone were obtained commerci...

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Green Tea Polyphenols and Cancer Chemoprevention: Multiple Mechanisms and Endpoints for Phase II Trials

Cited by 41 publications

References 0 publications

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

A structure-activity study for the inhibition of metalloproteinase-9 activity and gene expression by analogues of gallocatechin-3-gallate

Hypouricemic Action of Selected Flavonoids in Mice: Structure-Activity Relationships

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