Antiproliferative effect of synthetic resveratrol on human breast epithelial cells.

Mgbonyebi, O. P.; Russo, José; Russo, Irma H.

doi:10.3892/ijo.12.4.865

Cited by 149 publications

(164 citation statements)

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“…7 Moreover, LNCaP prostatecarcinoma cells downregulated androgen receptor in one study 25 but not in another. 26 Breast-carcinoma cells have been variably demonstrated to be growth-stimulated by (estrogen-mimicking) resveratrol, 6 to be growth-inhibited by resveratrol regardless of the expression of estrogen receptor 27 or to suffer Fas-mediated apo- ptosis. 24 Still others have described that resveratrol causes apoptosis independently of Fas signaling.…”

Section: Epithelial Differentiation At Early Times During Resveratrolmentioning

confidence: 99%

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

et al. 2001

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Resveratrol, a polyphenol present in wine and grapes, can inhibit tumor cell growth in vitro and tumorigenesis in vivo. Some of its effects have been linked to activation of the p53 tumor suppressor; however, p53 is frequently mutated in tumors, particularly in the common and often therapy-resistant colon cancers. Using the human wild-type p53-expressing HCT116 colon carcinoma cell line and HCT116 cells with both p53 alleles inactivated by homologous recombination, we show in the current study that resveratrol at concentrations comparable to those found in some foods can induce apoptosis independently of p53. The cell death is primarily mitochondria-mediated and not receptor-mediated. No cells survived in cultures continuously exposed to 100 M resveratrol for 120 hr. When compared with 5-FU, resveratrol stimulated p53 accumulation and activity only weakly and with delayed kinetics and neither the increased levels nor the activity affected apoptosis detectably. The apoptosis agonist Bax was overproduced in response to resveratrol regardless of p53 status, yet the kinetics of Bax expression were influenced by p53. Remarkably, apoptosis was preceded by mitochondrial proliferation and signs of epithelial differentiation. Thus, resveratrol triggers a p53-independent apoptotic pathway in HCT116 cells that may be linked to differentiation. The antifungal phytoalexin resveratrol (3,5,4Ј-trihydroxy-transstilbene) is a constituent of many plant species and present at particularly high levels in grapes and wine. 1 As a polyphenol, it is not only a potent inhibitor of radical formation (ED 50 27 M) but acts as a pleiotropic effector molecule to inhibit initiation, promotion and progression of malignant transformation. Resveratrol inhibits the cyclooxygenase (ED 50 15 M) and hydroperoxidase (ED 50 3.7 M) activities of COX-1 and the hydroperoxidase activity of COX-2 (ED 50 85 M). 2 Furthermore, it functions as an inhibitor of platelet aggregation, a modulator of lipid and lipoprotein metabolism 3 and an effective blocker of ribonucleotide reductase (ED 50 100 M) that provides deoxyribonucleotides for DNA synthesis. 4 It also inhibits DNA polymerase 5 and mimics estradiol. 6 Several of these activities constitute the basis for the chemopreventive action of resveratrol, exemplified by its antimutagenic activity in the Ames assay, inhibition of tumorigenesis in a 2-stage murine skin-cancer model 2 and inhibition of cell proliferation in vitro. 7,8 The presence of the functional wild-type form of the p53 tumor suppressor correlates with the sensitivity of mouse tumors and at least some human tumors to therapeutic agents. 9 -11 p53 is stabilized and activated as a transcription factor in response to a variety of cellular stresses, 12 the result being either cell-cycle arrest, mostly through transcriptional activation of the p21 WAF/Cip1 inhibitor of cyclin-dependent kinases, or apoptosis, depending on the cell context. Apoptosis often involves changes to mitochondria. 13 One of the major predictive parameters indicating commitment...

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Section: Epithelial Differentiation At Early Times During Resveratrolmentioning

confidence: 99%

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

et al. 2001

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“…Resveratrol (RSVL), a phytoalexin in grapes, berries and peanuts, has been shown to interfere with tumor initiation, promotion and progression in di¡erent systems [2,3]. At the molecular level, these e¡ects were related to inhibition of ribonucleotide reductase with cellular arrest in the S-phase or the S/G2 phase transition [4,5].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol inhibits MAPK activity and nuclear translocation in coronary artery smooth muscle: reversal of endothelin‐1 stimulatory effects

1999

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In porcine coronary arteries, short-term treatment with resveratrol (RSVL) substantially inhibited MAPK activity (IC 50 = 37 W WM); and immunoblot analyses revealed consistent reduction in the phosphorylation of ERK-1/-2, JNK-1 and p38, at active sites. Endothelin-1 (ET-1), a primary antecedent in coronary heart diseases, enhanced MAPK activity, phosphorylation and nuclear translocation in a concentration-responsive but RSVL-sensitive manner. RSVL had no effect on basal or forskolin-stimulated cAMP levels, a known downregulator of the MAPK cascade. Likewise, inhibition of MAPK by RSVL was not reversed by the estrogen receptor blockers tamoxifen and ICI-182,780. Conversely, RSVL remarkably attenuated basal and ET-1-evoked protein tyrosine phosphorylation. Because MAPKs promote smooth muscle proliferation and contraction, their current inhibition may contribute to the putative protection by RSVL against coronary heart diseases. These effects apparently do not involve interaction with estrogen receptors.z 1999 Federation of European Biochemical Societies.

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“…Particularly, by acting as antioxidant, anti-mutagen as well as by inducing phase II drug-metabolizing enzymes, trans-resveratrol inhibits the initiation phase of tumorigenesis; concomitantly, it mediates the anti-inflammatory response and induces cell differentiation, thereby inhibiting tumor promotion and progression, respectively [28]. Subsequently, other groups reported the anti-proliferative and pro-apoptotic activity of trans-resveratrol in several tumor cell lines [2,27,41,56], suggesting that it can function by modulating and interacting with a broad range of cellular targets, ranging from cell surface receptors [5,7] to caspases [43]; from mitochondria [8] and mitochondria-associated proteins [43,50,60], to intracellular protein kinases, such as protein kinase B (PKB)/Akt, PKC, MAP kinases [34,57,58,62,65] and transcription factors (e.g. p53, pRb, c-Jun and NF-jB) [30,37,45,59].…”

Section: Introductionmentioning

confidence: 99%

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

et al. 2007

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Polyphenols represent a large class of plantderived molecules with a general chemical structure that act as potent free radical scavengers. They have long been recognized to possess several therapeutic activities ranging from anti-thrombotic to antioxidant. Moreover, the capability of polyphenols to act as reducing or oxidizing molecules depends on the presence of environmental metals and on the concentrations used. In this work we demonstrated that the stilbene trans-resveratrol was able to commit human breast cancer MCF-7 cells to apoptosis. Mainly, we evidenced a pivotal role of the mitochondria in this phenomenon as cytochrome c release into the cytosol was found after the treatment. We further showed that trans-resveratrol was able to affect cellular redox state. In particular, it induced an early production of ROS and lipid oxidation, and only later compromised the GSH/GSSG ratio. This mode of action was mirrored by a temporally different activation of JNK and p38 MAPK , with the former rapidly induced and the latter weakly activated at long intervals. The results obtained demonstrate a pro-apoptotic activity for trans-resveratrol, and suggest a preferential activation of different classes of MAP kinases in response to different oxidative stimuli (ROS versus GSH/GSSG alteration).

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Antiproliferative effect of synthetic resveratrol on human breast epithelial cells.

Cited by 149 publications

References 0 publications

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

Resveratrol inhibits MAPK activity and nuclear translocation in coronary artery smooth muscle: reversal of endothelin‐1 stimulatory effects

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

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