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Sci Rep.2012;2:314. doi: 10.1038/srep00314. Epub 2012 Mar 15.

Stilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activity.

Hagiwara K1, Kosaka N, Yoshioka Y, Takahashi RU, Takeshita F, Ochiya T.

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It is well known that natural products are a rich source of compounds for applications in medicine, pharmacy, and biology. However, the exact molecular mechanisms of natural agents in human health have not been clearly defined. Here, we demonstrate for the first time that the polyphenolic phytoalexin resveratrol promotes expression and activity of Argonaute2 (Ago2), a central RNA interference (RNAi) component, which thereby inhibits breast cancer stem-like cell characteristics by increasing the expression of a number of tumour-suppressive miRNAs, including miR-16, -141, -143, and -200c. Most importantly, resveratrol-induced Ago2 resulted in a long-term gene silencing response. We also found that pterostilbene, which is a natural dimethylated resveratrol analogue, is capable of mediating Ago2-dependent anti-cancer activity in a manner mechanistically similar to that of resveratrol. These findings suggest that the dietary intake of natural products contributes to the prevention and treatment of diseases by regulating the RNAi pathway.

PMID: 22423322

BMC Med Genomics.2008 Mar 20;1:7. doi: 10.1186/1755-8794-1-7.

Identification of molecular pathways affected by pterostilbene, a natural dimethylether analog of resveratrol.

Pan Z1,Agarwal AK, Xu T, Feng Q, Baerson SR, Duke SO, Rimando AM.

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BACKGROUND:  Pterostilbene, a naturally occurring phenolic compound produced by agronomically important plant genera such as Vitis and Vacciunium, is a phytoalexin exhibiting potent antifungal activity. Additionally, recent studies have demonstrated several important pharmacological properties associated with pterostilbene. Despite this, a systematic study of the effects of pterostilbene on eukaryotic cells at the molecular level has not been previously reported. Thus, the aim of the present study was to identify the cellular pathways affected by pterostilbene by performing transcript profiling studies, employing the model yeast Saccharomyces cerevisiae.

METHODS:  S. cerevisiae strain S288C was exposed to pterostilbene at the IC50 concentration (70 muM) for one generation (3 h). Transcript profiling experiments were performed on three biological replicate samples using the Affymetrix GeneChip Yeast Genome S98 Array. The data were analyzed using the statistical methods available in the GeneSifter microarray data analysis system. To validate the results, eleven differentially expressed genes were further examined by quantitative real-time RT-PCR, and S. cerevisiae mutant strains with deletions in these genes were analyzed for altered sensitivity to pterostilbene.

RESULTS:  Transcript profiling studies revealed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, drug detoxification, and transcription factor activity were significantly up-regulated. Additional analyses revealed that a large number of genes involved in lipid metabolism were also affected by pterostilbene treatment.

CONCLUSION:  Using transcript profiling, we have identified the cellular pathways targeted by pterostilbene, an analog of resveratrol. The observed response in lipid metabolism genes is consistent with its known hypolipidemic properties, and the induction of mitochondrial genes is consistent with its demonstrated role in apoptosis in human cancer cell lines. Furthermore, our data show that pterostilbene has a significant effect on methionine metabolism, a previously unreported effect for this compound.

PMID: 18366703

J Gastrointest Surg.2012 Jun;16(6):1136-43. doi: 10.1007/s11605-012-1869-7. Epub 2012 Mar 27.

Genomic analysis of pterostilbene predicts its antiproliferative effects against pancreatic cancer in vitro and in vivo.

McCormack DE1,Mannal P, McDonald D, Tighe S, Hanson J, McFadden D.

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BACKGROUND:  To investigate the inhibitory role of pterostilbene in pancreatic cancer, we conducted a genomic analysis of pterostilbene-treated pancreatic cancer cells. We also investigated the effect of pterostilbene upon the carcinogenic markers, manganese superoxide dismutase, cytochrome C, Smac/DIABLO, and STAT3 phosphorylation in vitro. The antiproliferative effects of pterostilbene were further evaluated in an in vivo model.

METHODS:  Pancreatic cancer cells were treated with pterostilbene and evaluated with DNA microarray analysis. Pterostilbene-treated cells were analyzed for cytochrome C, Smac/DIABLO, manganese superoxide dismutase (MnSOD)/antioxidant activity, and STAT3 phosphorylation using ELISA. Data were statistically analyzed using ANOVA. Pterostilbene was then administered to nude mice for 8 weeks, and tumor growth rates were recorded and statistically analyzed.

RESULTS:  Microarray analysis of pterostilbene-treated cells revealed upregulation of pro-apoptosis genes. In vitro, pterostilbene treatment altered levels of phosphorylated STAT3, MnSOD/antioxidant activity, cytochrome C, and Smac/DIABLO. In nude mice, oral pterostilbene inhibited tumor growth rates.

CONCLUSION:  Pterostilbene alters gene expression in pancreatic cancer and increases the antiproliferative markers cytochrome C, Smac/DIABLO, and MnSOD/antioxidant activity. It was also shown to inhibit phosphorylated STAT3, a marker of accelerated tumorigenesis, and decrease pancreatic tumor growth in vivo. Further studies are warranted to elucidate the effects of pterostilbene in humans.

PMID: 22450950

Mol Nutr Food Res.2013 May;57(5):886-95. doi: 10.1002/mnfr.201200715. Epub 2013 Feb 18.

Invadopodia-associated proteins blockade as a novel mechanism for 6-shogaol and pterostilbene to reduce breast cancer cell motility and invasion.

Hong BH1,Wu CH, Yeh CT, Yen GC.

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SCOPE:  Invadopodia are actin-rich membrane protrusions of tumor cells that are thought to initiate the local migration and invasion during cancer metastasis. The blockade of invadopodia-associated proteins has been reported as a promising approach for prevention of tumor metastasis. The aim of this study was to investigate the modulatory effects of 6-shogaol and pterostilbene on invadopodia in aggressive breast cancer cells.

METHODS AND RESULTS: By wound-healing, transwell, and gelatin zymography assays, we found that 6-shogaol and pterostilbene effectively attenuated the motility and invasion of MDA-MB-231 cells, and suppressed the activities of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Further investigation into the underlying molecular mechanisms revealed that the levels of key modulators of invadopodium maturation, including c-Src kinase, cortactin, and membrane type 1-matrix metalloproteinase (MT1-MMP) decreased when cells were treated with 6-shogaol or pterostilbene.

CONCLUSION:  These data suggest that the repression of these factors might affect the maturation of invadopodia, inhibiting the metastasis of MDA-MB-231 cells. In conclusion, the present study demonstrates for the first time that 6-shogaol and pterostilbene can inhibit invadopodium formation and MMP activity in highly invasive breast cancer cells. We suggest that these compounds may be clinically useful in chemopreventive treatments for metastatic breast cancer.

© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID: 23417847

Chem Biol Interact.2013 Nov 25;206(2):175-85. doi: 10.1016/j.cbi.2013.09.013. Epub 2013 Sep 25.

Scavenging of hydroxyl radical by resveratrol and related natural stilbenes after hydrogen peroxide attack on DNA.

Rossi M1,Caruso F, Antonioletti R, Viglianti A, Traversi G, Leone S, Basso E, Cozzi R.

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Resveratrol (3,5,4′-trihydroxystilbene) is of interest due to its role in prevention and therapy of degenerative diseases as cancer and aging. However, depending on its concentration and cell type studied, resveratrol activity appears conflicting. It exerts antioxidant action, as a scavenger of free radicals and as promoter of antioxidant enzyme activity, but resveratrol acts also as a pro-oxidant. Here we present experimental and theoretical studies for resveratrol and two methoxy-derivatives found in plants, pterostilbene and 3,5,4′-trimethoxystilbene. We show that both methoxy-derivatives induce less DNA damage than resveratrol. The protective effects of the three molecules against oxidative DNA damage induced by hydrogen peroxide treatment were analyzed on mammalian cells in vitro. Our data show for the first time that methoxylated derivatives of resveratrol are very efficient in reducing DNA damage: using the same concentration of the three molecules we obtain a relative reduction of 85.5% (pterostilbene), 43.7% (trimethoxystilbene) and 21.1% (resveratrol). Analysis of the crystal structures of pterostilbene and 3,5,4′-trimethoxystilbene, compared to resveratrol, show fewer intermolecular interactions and a lack of planarity, due to packing forces, which is confirmed by density functional theory (DFT) calculations. We also describe the results of DFT calculations (including water solvent effects) in which the three stilbene species scavenge the hydroxyl radical (associated with the H2O2 insult).

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS: DNA protection; Hydrogen peroxide; Hydroxyl radical; Pterostilbene; Resveratrol

PMID: 24075811

Curr Pharm Biotechnol.2014;14(12):1027-35.

Pterostilbene as a potential novel telomerase inhibitor: molecular docking studies and its in vitro evaluation.

Tippani R,Prakhya LJ, Porika M, Sirisha K, Abbagani S, Thammidala C1.

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Pterostilbene is a naturally occurring dimethyl ether analog of resveratrol identified in several plant species. Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. Molecular docking studies were performed on pterostilbene with the crystal structure of telomerase (3DU6). Pterostilbene was evaluated for its in vitro cytotoxicity in breast (MCF7) and lung cancer (NCI H-460) cell lines, antimitotic activity in green grams and telomerase activity. Curcumin was used as a standard. Docking results indicated good interaction between pterostilbene and the active site of telomerase and the docked energy of pterostilbene was -7.10 kcal/mol. Pterostilbene showed strong inhibitory effect on in vitro telomerase activity and cell growth in both the cell lines tested in a dose dependent manner. Cancer cells treated with 80 µM pterostilbene exhibited significant telomerase inhibition, after 72 hours (MCF-7 and NCI H-460; 81.52% and 74.69% reduction, respectively, compared to control). The IC50 of pterostilbene for anti-proliferative activity in MCF7 and NCI H-460 cell lines were found to be 30.0 and 47.2 µM, respectively. The best antimitotic activity was obtained with 80 μM of pterostilbene (100% reduction in water imbibition). All the above results were comparable to that of curcumin. The drug-related properties of pterostilbene were calculated using Molinspiration, Osiris Property Explorer and ACD/Chemsketch softwares. Pterostilbene obeyed Lipinski’s Rule of Five indicating its therapeutic potential in humans. It was found that the telomerase inhibitory activity exhibited by pterostilbene was dependent of the cell viability and has the potential to be a new drug candidate against breast and lung cancers.

PMID: 24433502

Bioorg Med Chem Lett.2014 Feb 15;24(4):1176-9. doi: 10.1016/j.bmcl.2013.12.115. Epub 2014 Jan 7.

Urokinase-type plasminogen activator expression and Rac1/WAVE-2/Arp2/3 pathway are blocked by pterostilbene to suppress cell migration and invasion in MDA-MB-231 cells.

Ko HS1,Kim JS1, Cho SM1, Lee HJ1, Ahn KS1, Kim SH1, Lee EO2.

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Breast cancer is the most common malignancy among females, and cancer invasion and metastasis are the leading causes of cancer death in breast cancer patients. Pterostilbene, a naturally occurring dimethylether analogue of resveratrol, has been demonstrated to possess anti-cancer effects. However, inhibitory effects of pterostilbene on cell migration and invasion and its underlying mechanisms are not fully understood. In this study, we investigated the anti-invasive mechanisms of pterostilbene in human breast cancer cell line MDA-MB-231 cells. Pterostilbeneeffectively inhibited serum-induced migration and invasion without affecting the viability of breast cancer cells. The mRNA expression and activity of urokinase-type plasminogen activator (uPA) were markedly reduced by pterostilbene treatment. Moreover, pterostilbene attenuated nuclear factor κB (NF-κB) transcriptional activity and DNA binding of NF-κB on uPA promoter. In addition, pterostilbene significantly impaired the activity of Rac1 and the expression of WASP-family verprolin-homologous protein-2 (WAVE-2) and actin-related protein 2/3 (Arp2/3). Overall, these results suggest that pterostilbene caused considerable suppression of cell migration and invasion through blocking NF-κB-mediated uPA expression and Rac1/WAVE/Arp2/3 pathway.

Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

KEYWORDS: Arp2/3; Invasion; MDA-MB-231 cells; Migration; NF-κB; Pterostilbene; Rac1; WAVE; uPA

PMID: 24440300

J Pharmacol Sci.2014;126(3):216-29. Epub 2014 Oct 21.

Involvement of the Nrf2 pathway in the regulation of pterostilbene-induced apoptosis in HeLa cells via ER stress.

Zhang B1, Wang XQ, Chen HY, Liu BH.

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Among the various cancer cell lines, HeLa cells were found to be sensitive to pterostilbene (Pte), a compound that is enriched in small fruits such as grapes and berries. However, the mechanism involved in the cytotoxicity of Pte has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the pro-apoptotic profiles of Pte and evaluated the level of redox stress-triggered ER stress during HeLa cell apoptosis. The data showed a strong dose-response relationship between Pte exposure and the characteristics of HeLa apoptosis in terms of changes in apoptotic morphology, DNA fragmentation, and activated caspases in the intrinsic apoptotic pathway. During drug exposure, alterations in the intracellular redox homeostasis that favor oxidation were necessary to cause ER stress-related apoptosis, as demonstrated by enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P < 0.05) was found with regard to the unique expression levels of Nrf2/ARE downstream target genes in HeLa cells undergoing late apoptosis, levels that were restored with anti-oxidant application with the Pte treatment. Our research demonstrated that Pte trigged ER stress by redox homeostasis imbalance, which was negatively regulated by a following activation of Nrf2.

PMID: 25341683

Int Immunopharmacol.2015 Sep;28(1):10-21. doi: 10.1016/j.intimp.2015.05.003. Epub 2015 May 13.

Understanding the mode of action of a pterostilbene derivative as anti-inflammatory agent.

Nikhil K1,Sharan S1, Palla SR2, Sondhi SM2, Peddinti RK2, Roy P3.

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Inflammatory response plays an important role not only in the normal physiology, but also in the pathology of certain diseases such as cancers. In our previous study, we found a novel derivative of pterostilbene(PTER), to be an effective inducer of apoptosis in human breast and prostate cancer cells affecting various cellular targets. Herein, we further attempted to investigate its anti-inflammatory potential followed by its probable mode of action. The newly developed compound was tested for its anti-inflammatory actions in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages and carrageenan-induced rat paw edema models. Our data showed that the derivative inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as the downstream products like nitric oxide (NO) and PGE2, at much lower doses as compared to PTER. This effect was found to be associated with the inhibition of phosphorylation/degradation of IκB-α and nuclear translocation of the p-NFκB p65. Moreover, inhibition of mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) was also observed. In addition, the newly developed compound also reduced the paw edema, the tissue content of NO, PGE2 and expression of iNOS and COX-2 proteins within the tissues after λ-carrageenan stimulation. Taken together, our findings provide the possibility that the PTER derivative might have enhanced cancer chemopreventive potential based on its stronger anti-NFκB and anti-inflammatory activities as compared to its natural counterpart, i.e., PTER. Thus, this compound can be used towards the development of an effective anti-inflammatory agent.

Copyright © 2015 Elsevier B.V. All rights reserved.

KEYWORDS:  Anti-inflammatory; Carrageenan; Lipopolysaccharide; NFκB; Pterostilbenederivative; RAW 264.7 macrophage

PMID: 25981112

Mol Carcinog.2017 Mar;56(3):1117-1126. doi: 10.1002/mc.22578. Epub 2016 Oct 24.

The resveratrol analogue trimethoxystilbene inhibits cancer cell growth by inducing multipolar cell mitosis.

Traversi G1,Fiore M2, Percario Z1, Degrassi F2, Cozzi R1.

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Natural compounds are extensively studied for their potential use in traditional and non-traditional medicine. Several natural and synthetic Resveratrol analogues have shown interesting biological activities in the field of cancerchemoprevention. In the present study, we have focused on the ability of Resveratrol and two methoxylated derivatives (Trimethoxystilbene and Pterostilbene) to inhibit human cancercell growth particularly analyzing their ability to interfere with tubulin dynamics at mitosis. We show that Trimethoxystilbene, differently from Resveratrol and Pterostilbene, alters microtubule polymerization dynamics in HeLa cells specifically inducing multipolar spindles and mitotic arrest coupled to a reduction of cell growth and an increase in apoptotic death by mitotic catastrophe. This work demonstrates that the structural modification of Rsv causes substantial changes in the mechanism of action of the derivatives. The presence of three extra methyl groups renders Trimethoxy very efficient in impairing cell proliferation by inducing mitotic catastrophe in cancercells. © 2016 Wiley Periodicals, Inc.

© 2016 Wiley Periodicals, Inc.

KEYWORDS: apoptosis; cancercell growth; mitotic catastrophe; resveratrol analogues; tubulin polymerization

PMID: 27739192