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Journal Article

Suppression of 7,12-Dimethylbenz(a)anthracene-induced Mammary Carcinogenesis in Rats by Resveratrol Role of Nuclear Factor-κB, Cyclooxygenase 2, and Matrix Metalloprotease 9

01 Sep 2002-Cancer Research (American Association for Cancer Research)-Vol. 62, Iss: 17, pp 4945-4954
TL;DR: Results suggest that resveratrol suppresses DMBA-induced mammary carcinogenesis, which correlates with down-regulation of NF-kappaB, cyclooxygenase-2, and matrix metalloprotease-9 expression.
Abstract: We have reported recently that resveratrol ( trans -3,4′,5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, fruits, and root extracts of the weed Polygonum cuspidatum , is a potent inhibitor of nuclear factor (NF)-κB activation. Because NF-κB suppression has been linked with chemoprevention, this prompted us to investigate the chemopreventive potential of resveratrol by testing it against mammary carcinogenesis induced by 7,12-dimethylbenz( a )anthracene (DMBA) in female Sprague Dawley rats. Dietary administration of resveratrol (10 ppm) had no effect on body weight gain and tumor volume but produced striking reductions in the incidence (45%; P P in situ (7 of 7), whereas treatment with resveratrol suppressed DMBA-induced ductal carcinoma. Immunohistochemistry and Western blot analysis revealed that resveratrol suppressed the DMBA-induced cyclooxygenase-2 and matrix metalloprotease-9 expression in the breast tumor. Gel shift analysis showed suppression of DMBA-induced NF-κB activation by resveratrol. Treatment of human breast cancer MCF-7 cells with resveratrol also suppressed the NF-κB activation and inhibited proliferation at S-G 2 -M phase. Overall, our results suggest that resveratrol suppresses DMBA-induced mammary carcinogenesis, which correlates with down-regulation of NF-κB, cyclooxygenase-2, and matrix metalloprotease-9 expression.
Citations
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Journal ArticleDOI
TL;DR: Attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.
Abstract: Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.

2,804 citations

Journal ArticleDOI
TL;DR: Evidence is presented that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways and the active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases.

1,653 citations

Journal ArticleDOI
TL;DR: The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans.
Abstract: The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.

1,577 citations


Cites background from "Suppression of 7,12-Dimethylbenz(a)..."

  • ...This includes effects on tumors of the colon (Tessitore et al., 2000) and esophagus (Li et al., 2002), i.e., tissues immediately accessible to orally administered drug, and, surprisingly, the mammary glands (Banerjee et al., 2002)....

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  • ...…in some laboratory animals suggest that resveratrol may have sufficient bioavailability to produce chemopreventive effects (Tessitore et al., 2000; Banerjee et al., 2002; Li et al., 2002), it appears clear that this may not be the case in humans, unless other factors are taken into consideration....

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Journal ArticleDOI
TL;DR: The NF-kappaB proteins themselves and proteins regulated by it have been linked to cellular transformation, proliferation, apoptosis suppression, invasion, angiogenesis, and metastasis as mentioned in this paper.

1,537 citations

Journal Article
TL;DR: In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression.
Abstract: Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

1,377 citations

References
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Journal ArticleDOI
TL;DR: This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr with little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose.

225,085 citations


"Suppression of 7,12-Dimethylbenz(a)..." refers methods in this paper

  • ...The protein concentration was measured by the method of Bradford (35) with BSA as the standard....

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  • ...The protein content was measured by the method of Bradford (36)....

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Journal ArticleDOI
10 Jan 1997-Science
TL;DR: It is suggested that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
Abstract: Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

4,786 citations


"Suppression of 7,12-Dimethylbenz(a)..." refers background in this paper

  • ...(8) have shown that resveratrol induces quinone reductase activity, a phase II enzyme, in cultured mouse hepatoma cells....

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