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Evid Based Complement Alternat Med. 2009 Jul 16. [Epub ahead of print]

Suppression of Heregulin-{beta}1/HER2-Modulated Invasive and Aggressive Phenotype of Breast Carcinoma by Pterostilbene via Inhibition of Matrix Metalloproteinase-9, p38 Kinase Cascade and Akt Activation.

Pan MH, Lin YT, Lin CL, Wei CS, Ho CT, Chen WJ.

Department of Biomedical Sciences, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo N. Road, Taichung 402, Taiwan.

Invasive breast cancer is the major cause of death among females and its incidence is closely linked to HER2 (human epidermal growth factor receptor 2) overexpression. Pterostilbene, a natural analog of resveratrol, exerts its cancer chemopreventive activity similar to resveratrol by inhibiting cancer cell proliferation and inducing apoptosis. However, the anti-invasive effect of pterostilbene on HER2-bearing breast cancer has not been evaluated. Here, we used heregulin-beta1 (HRG-beta1), a ligand for HER3, to transactivate HER2 signaling.

We found that pterostilbene was able to suppress HRG-beta1-mediated cell invasion, motility and cell transformation of MCF-7 human breast carcinoma through down-regulation of matrix metalloproteinase-9 (MMP-9) activity and growth inhibition.

In parallel, pterostilbene also inhibited protein and mRNA expression of MMP-9 driven by HRG-beta1, suggesting that pterostilbene decreased HRG-beta1-mediated MMP-9 induction via transcriptional regulation. Examining the signaling pathways responsible for HRG-beta1-associated MMP-9 induction and growth inhibition, we observed that pterostilbene, as well as SB203580 (p38 kinase inhibitor), can abolish the phosphorylation of p38 mitogen-activated protein kinase (p38 kinase), a downstream HRG-beta1-responsive kinase responsible for MMP-9 induction. In addition, HRG-beta1-driven Akt phosphorylation required for cell proliferation was also suppressed by pterostilbene.

Taken together, our present results suggest that pterostilbene may serve as a chemopreventive agent to inhibit HRG-beta1/HER2-mediated aggressive and invasive phenotype of breast carcinoma through down-regulation of MMP-9, p38 kinase and Akt activation.


PMID: 19617202 [PubMed - as supplied by publisher] PMCID: PMC3136680

Neuroscientist. 2002 Dec;8(6):586-95.

Matrix metalloproteinases and neuroinflammation in multiple sclerosis.
Rosenberg GA.

Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA.

Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral proteases that are important in normal development, angiogenesis, wound repair, and a wide range of pathological processes. Growing evidence supports a key role of the MMPs in many neuroinflammatory conditions, including meningitis, encephalitis, brain tumors, cerebral ischemia, Guillain-Barré, and multiple sclerosis (MS).

The MMPs attack the basal lamina macromolecules that line the blood vessels, opening the blood-brain barrier (BBB).

They contribute to the remodeling of the blood vessels that causes hyalinosis and gliosis, and they attack myelin.

During the acute inflammatory phase of MS, they are involved in the injury to the blood vessels and may be important in the disruption of the myelin sheath and axons.

Normally under tight regulation, excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS. Because they are induced in immunologic and nonimmunologic forms of demyelination, they act as a final common pathway to exert a "bystander" effect.

Agents that block the action of the MMPs have been shown to reduce the damage to the BBB and lead to symptomatic improvement in several animal models of neuroinflammatory diseases, including experimental allergic encephalomyelitis. Such agents may eventually be useful in the control of excessive proteolysis that contributes to the pathology of MS and other neuroinflammatory conditions.

PMID: 12467380 [PubMed - indexed for MEDLINE]

J Agric Food Chem. 2012 Apr 13. [Epub ahead of print]

Piceatannol Suppresses Breast Cancer Cell Invasion through the Inhibition of MMP-9: Involvement of PI3K/AKT and NF-κB Pathways.

Ko HS, Lee HJ, Kim SH, Lee EO.

Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University , 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.

Cancer invasion and metastasis are the main causes of treatment failure and death in cancer patients.

Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene) is a natural analogue of resveratrol.

This study investigated the anti-invasive mechanisms of piceatannol in MDA-MB-231 cells. Piceatannol significantly reduced serum-induced cell invasion and migration as well as adhesion without affecting the viability of cells.

Furthermore, piceatannol markedly inhibited matrix metalloproteinase-9 (MMP-9) activity and expression at both protein and mRNA levels.

Piceatannol attenuated phosphoinisitide-3-kinase (PI3K) and phosphorylation of AKT and mammalian target of rapamycin (mTOR), whereas phosphatase and tensin homologue (PTEN) was increased. Moreover, piceatannol inhibited nuclear factor kappa B (NF-κB) transcriptional activity and DNA binding of NF-κB on MMP-9 promoter. In addition, piceatannol diminished NF-κB nuclear translocation through blocking the inhibitor of NF-κB alpha (IκBα) phosphorylation in the cytoplasm.

These results proposed piceatannol as a potential anti-invasive agent by inhibiting MMP-9 involved in PI3K/AKT and NF-κB pathways.

PMID: 22480333 [PubMed - as supplied by publisher]

jackD wrote:I do not think that Piceatannol is available as a supplement. I have very little on this stuff but I am looking...

• Piceatannol, a naturally occurring analog of resveratrol, was previously identified as the active ingredient in herbal preparations in folk medicine and as an inhibitor of p72Syk. We studied the effects of piceatannol on growth, proliferation, differentiation and cell cycle distribution profile of the human colon carcinoma cell line Caco-2. Growth of Caco-2 and HCT-116 cells was analyzed by crystal violet assay, which demonstrated dose- and time-dependent decreases in cell numbers. Treatment of Caco-2 cells with piceatannol reduced proliferation rate. No effect on differentiation was observed. Determination of cell cycle distribution by flow cytometry revealed an accumulation of cells in the S phase. Immunoblotting demonstrated that cyclin-dependent kinases (cdk) 2 and 6, as well as cdc2 were expressed at steady-state levels, whereas cyclin D1, cyclin B1 and cdk 4 were downregulated. The abundance of p27Kip1 was also reduced, whereas the protein level of cyclin E was enhanced. Cyclin A levels were enhanced only at concentrations up to 100 μmol/L. These changes also were observed in studies with HCT-116 cells. On the basis of our findings, piceatannol can be considered to be a promising chemopreventive or anticancer agent.

Neurobiol Aging. 2011 Oct 7. [Epub ahead of print]

Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer's disease.

Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, Shukitt-Hale B, Smith MA, Joseph JA, Casadesus G

Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA.

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD.

Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression.

Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene.

Copyright © 2011. Published by Elsevier Inc.


PMID: 21982274 [PubMed - as supplied by publisher]

J Surg Res. 2012 Apr 29. [Epub ahead of print]

Pterostilbene induces mitochondrially derived apoptosis in breast cancer cells in vitro.

Moon D, McCormack D, McDonald D, McFadden D.

Division of Surgical Research, University of Vermont, 111 Colchester Avenue, Fletcher House 311, MCHV Campus, Burlington, Vermont.


Abstract

BACKGROUND:

The ability of a breast cancer cell to evade apoptosis has a key role in tumor progression and sensitivity to treatment. High levels of Bcl-2-associated X protein (Bax) in tumor cells have been found to promote apoptosis and sensitize cells to anti-cancer therapies. Bcl-2-associated X protein redistribution to the mitochondrial membrane results in the release of proapoptotic factors including cytochrome C, second-mitochondrial-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI (Smac/DIABLO), and Ca(2+). We aimed to explore this pathway in cancerous breast cell lines treated with the naturally occurring antioxidant 3,5-dimethoxy-4-hydroxystilbene (pterostilbene).

METHODS:

We used whole cell lysates +/- Bax SiRNA from the cell lines MCF-7 and MDA-MB-231 in an enzyme-linked immunosorbent assay to quantify Bax, cytochrome C, Smac/DIABLO expression, and manganese superoxide dismutase (MnSOD) activity after treatment with pterostilbene. We quantified cell death using histone-related DNA complexes from cytosolic and mitochondrial fractions and used methylthiazol tetrazolium assay to analyze cell proliferation, in the presence of Bax-silencing or scrambled RNA. We measured changes in cytosolic calcium using the ratiometric calcium-sensitive dye fura-2-AM using an inverted ratiometric monochromator microscope.

RESULTS:

Treatment of MCF-7 and MDA-MB-231 (MDA) cells with pterostilbene caused concentration-dependent increases in intracellular Bax at all doses tested. RNA silencing of Bax resulted in reduced rates of apoptosis in both cells types and increased cell survival when treated with pterostilbene. We observed an increase in cytochrome C in MDA cells after treatment with pterostilbene. The MCF-7 cells showed a net increase in cytosolic cytochrome C, with a corresponding reduction in mitochondrial cytochrome C after treatment with 50 and 75 μmol/L pterostilbene. We observed this again in Smac/DIABLO expression in both cell types. In MCF-7 cells, pterostilbene treatment caused an increase in cytosolic but a decrease in mitochondrial Smac/DIABLO protein concentrations. Pterostilbene significantly increase MnSOD activity in MDA-MB-231 cells. Finally, pterostilbene resulted in significant increases in cytosolic calcium concentrations.

CONCLUSIONS:

The natural dietary compound pterostilbene has an anti-proliferative effect and induces apoptosis in breast cancer cells in vitro via Bax activation and overexpression, resulting in increased MnSOD, Smac/DIABLO, and cytochrome C activity and cytosolic Ca(2+) overload.
]Copyright © 2012 Elsevier Inc. All rights reserved.

PMID: 22572619 [PubMed - as supplied by publisher]

Supplement Facts

Serving Size 2 TABLETS

Servings Per Container 30

Amount Per Serving

COCOA EXTRACT POWDER(SEED) 300 Mg

GREEN TEA EXTRACT 250 Mg

Quercetin 200 Mg

CURCUMIN PHYTOSOME (CUCUMA LONGA EXTRACT) (ROOT) 150 Mg

RESVERATROL (POLYGONUM CUSPIDATUM)(RADIX AND RHIZOME) EXTRACT 100 Mg

PTEROSTILBENE (PTEROCARPUS MARSUPIUM) EXTRACT(AERIAL PARTS) 50 Mg

BIOPERINE BLACK PEPPER EXTRACT 5 Mg

Neurobiol Aging. 2012 Sep;33(9):2062-71. Epub 2011 Oct 7.

Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer's disease.

Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, Shukitt-Hale B, Smith MA, Joseph JA, Casadesus G.

Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA.

Abstract

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare.

As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD.

Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression.

Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene.

Copyright © 2012 Elsevier Inc. All rights reserved.


PMID: 21982274 [PubMed - in process]