[Rich66]

(CD133/CSC, prolif/apop,VEGF,CyclinD1, glycolysis, w/antiestrogens, NOT w/quercetin, low dose bad/Hi dose good, w/Cyclo,w/Gem ,w/Vit E & Selenium, absorption issues, increased NK, w/Vit D, decreased cathepsin D at hi dose, DMU-212 analog superior,FGF inhib?)


How to pick the best brand of Resveratrol supplements
http://www.seopressreleases.com/pick...pplements/7991

TRANS-Resveratrol, not cis-resveratrol:

Resveratrol is composed of two principal isomers, trans-resveratrol and cis-resveratrol. Only the trans-isomer has been associated with health benefits. The cis isomer actually acts to nullify the effects of trans-resveratrol. Unless the seller states on the label that the product consists entirely of the trans-resveratrol form it is highly likely that it contains either some or all of cis-resveratrol, which is, by an order of magnitude, the less costly form of resveratrol.

AVOID QUERCETIN w/ resveratrol:

Quercetin is a potent antioxidant in its own right, however it should not be combined with resveratrol or even taken within at least 8 hours of taking a resveratrol supplement. The reason, which was only recently discovered, is that quercetin blocks the metabolites of resveratrol from entering your blood stream. Quercetin also down regulates sirtuins, precisely the opposite effect of resveratol. Until a few years ago it was assumed that adding quercetin was a good thing since the importance of the metabolites was not understood.

Since low levels may be detrimental, consider:

Potent(ial) source: http://www.longevinex.com/
Cardio article suggests this formulation is more potent than standard:
http://in.sys-con.com/node/1299322

Liposomal liquid claims IV levels orally:
http://www.nanoliposomals.com/More_on_RESVERATROL.html

PEGysomal (liquid) Resveratrol: http://www.life-enhancement.com/prod...p?SID=1&id=565

when taken orally resveratrol has very low bioavailability, and even the small portion that enters the bloodstream is rapidly metabolized. Until now! This PEGylated liposomal formulation enters the bloodstream via transmucosal absorption, thus providing enhanced bioavailability. As well, it is designed to help sustain blood levels, achieve higher-potency responses, increase circulatory half-life, and enhance site-specific actions.* Also, PEGysomal Resveratrol can more readily cross the blood-brain barrier.*

Arch Biochem Biophys. 2009 Jun 15;486(2):95-102.
Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms.


TEXT PURCHASE

Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL.
Departments of Dermatology, Columbia University Medical Center, Irving Cancer Research Center, New York, NY 10032, USA.
Plant-derived polyphenolic compounds, such as the stilbene resveratrol (trans-3,4',5-trihydroxystilbene), have been identified as potent anti-cancer agents. Extensive in vitro studies revealed multiple intracellular targets of resveratrol, which affect cell growth, inflammation, apoptosis, angiogenesis, and invasion and metastasis. These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases ATM/ATR; transcription factors NF-kappaB, AP-1, c-Jun, and c-Fos; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators, Bax, Bak, PUMA, Noxa, TRAIL, APAF, survivin, Akt, Bcl2 and Bcl-X(L). In addition to its well-documented anti-oxidant properties, there is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. This review summarizes in vitro mechanistic data available for resveratrol and discusses new potential anti-cancer targets and the antiproliferative mechanisms of resveratrol.

PMID: 19514131 [PubMed - indexed for MEDLINE]



J Nutr Biochem. 2009 Oct 2. [Epub ahead of print]
Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells.

Sakamoto T, Horiguchi H, Oguma E, Kayama F.
Division of Environmental Medicine, Center for Community Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke City, Tochigi 329-0498, Japan.
Phytoestrogens have attracted attention as being safer alternatives to hormone replacement therapy (HRT) and as chemopreventive reagents for breast cancer because dietary soy isoflavone intake has been correlated with reduction in risk. To identify safe and effective phytoestrogen candidates for HRT and breast cancer prevention, we investigated the effects of daidzein, genistein, coumestrol, resveratrol and glycitein on cell growth, cell cycle, cyclin D1 expression, apoptosis, Bcl-2/Bax expression ratio and p53-dependent or NF-kappaB-dependent transcriptional activity in MCF-7 breast cancer cells. Phytoestrogens, except for glycitein, significantly enhanced estrogen-response-element-dependent transcriptional activity up to a level similar to that of 17beta-estradiol (E(2)). E(2) increased cell growth significantly, coumestrol increased cell growth moderately, and resveratrol and glycitein reduced cell growth. Phytoestrogens, except for glycitein, stimulated the promotion of cells to G(1)/S transition in cell cycle analysis, similar to E(2). This stimulation was accompanied by transient up-regulation of cyclin D1. While genistein, resveratrol and glycitein all increased apoptosis and reduced the Bcl-2/Bax ratio, resveratrol reduced this ratio more than either genistein or glycitein. Moreover, resveratrol significantly enhanced p53-dependent transcriptional activity, but slightly reduced NF-kappaB-dependent transcriptional activity. On knockdown analysis, genistein, resveratrol and glycitein all reduced the Bcl-2/Bax ratio in the presence of apoptosis-inducing stimuli, and estrogen receptor (ER) alpha silencing had no effect on these reductions. In contrast, in the absence of apoptosis-inducing stimuli, only resveratrol reduced the ratio, and ERalpha silencing abolished this reduction. Thus, resveratrol might be the most promising candidate for HRT and chemoprevention of breast cancer due to its estrogenic activity and high antitumor activity.

PMID: 19800779 [PubMed - as supplied by publisher]





Toxicology. 2008 Jun 27;248(2-3):130-5. Epub 2008 Mar 29.
A positive feedback pathway of estrogen biosynthesis in breast cancer cells is contained by resveratrol.

Wang Y, Ye L, Leung LK.
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Cytochrome P450 (CYP) 19 enzyme or aromatase catalyses the rate-determining step of estrogen synthesis. The transcriptional control of CYP19 gene is highly specific in different cell types, for instance, Promoter I.3/II is commonly used for regulation in breast cancer cells. Recently, a positive feedback pathway for estrogen synthesis has been identified in ER alpha expressing SK-BR-3 cells. CYP19 mRNA abundance and activity are increased in this pathway and the promoter usage is switched from Promoter I.3/II to I.1 through a non-genomic process. In the present study, effect of the phytocompound resveratrol on this Promoter I.1-controlled expression of aromatase was investigated. Results indicated that resveratrol reduced the estradiol-induced mRNA abundance in SK-BR-3 cells expressing ER alpha. Luciferase reporter gene assays revealed that resveratrol could also repress the transcriptional control dictated by Promoter I.1. Since the ERE-driven luciferase activity was not repressed by resveratrol, the nuclear events of estrogen were unlikely to be suppressed by resveratrol. Instead the phytochemical reduced the amount of ERK activated by estradiol, which could be the pathway responsible for Promoter I.1 transactivation and the induced CYP19 expression. The present study illustrated that resveratrol impeded the non-genomic induction of estrogen on CYP19.

PMID: 18462857 [PubMed - indexed for MEDLINE]






Br J Cancer. 2004 Jul 5;91(1):178-85.
Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells.

Zhang S, Cao HJ, Davis FB, Tang HY, Davis PJ, Lin HY.
The Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA.
Resveratrol, a naturally occurring stilbene, induced apoptosis in human breast cancer MCF-7 cells. The mechanism of this effect was dependent on mitogen-activated protein kinase (MAPK, ERK1/2) activation and was associated with serine phosphorylation and acetylation of p53. Treatment of MCF-7 cells with resveratrol in the presence of 17beta-oestradiol (E(2)) further enhanced MAPK activation, but E(2) blocked resveratrol-induced apoptosis, as measured by nucleosome ELISA and DNA fragmentation assays. E(2) inhibited resveratrol-stimulated phosphorylation of serines 15, 20 and 392 of p53 and acetylation of p53 in a concentration- and time-dependent manner. These effects of E(2) on resveratrol action were blocked by ICI 182,780 (ICI) (Fulvestrant), an inhibitor of the nuclear oestrogen receptor-alpha (ER). ICI 182,780 did not block the actions of resveratrol, alone. Electrophoretic mobility studies of p53 binding to DNA and of p21 expression indicated that E(2) inhibited resveratrol-induced, p53-directed transcriptional activity. These results suggest that E(2) inhibits p53-dependent apoptosis in MCF-7 cells by interfering with post-translational modifications of p53 which are essential for p53-dependent DNA binding and consequent stimulation of apoptotic pathways. These studies provide insight into the complex pathways by which apoptosis is induced by resveratrol in E(2)-depleted and -repleted environments.

PMID: 15188005 [PubMed - indexed for MEDLINE]



Neoplasia. 2007 Feb;9(2):147-58.
Estrogen and resveratrol regulate Rac and Cdc42 signaling to the actin cytoskeleton of metastatic breast cancer cells.

Azios NG, Krishnamoorthy L, Harris M, Cubano LA, Cammer M, Dharmawardhane SF.
Department of Anatomy and Cell Biology, Universidad Central del Caribe, Bayamon, Puerto Rico.
Estrogen and structurally related molecules play critical roles in breast cancer. We reported that resveratrol (50 microM), an estrogen-like phytosterol from grapes, acts in an antiestrogenic manner in breast cancer cells to reduce cell migration and to induce a global and sustained extension of actin structures called filopodia. Herein, we report that resveratrol-induced filopodia formation is time-dependent and concentration-dependent. In contrast to resveratrol at 50 microM, resveratrol at 5 microM acts in a manner similar to estrogen by increasing lamellipodia, as well as cell migration and invasion.Because Rho GTPases regulate the extension of actin structures, we investigated a role for Rac and Cdc42 in estrogen and resveratrol signaling. Our results demonstrate that 50 microM resveratrol decreases Rac and Cdc42 activity, whereas estrogen and 5 microM resveratrol increase Rac activity in breast cancer cells. MDA-MB-231 cells expressing dominant-negative Cdc42 or dominant-negative Rac retain filopodia response to 50 microM resveratrol. Lamellipodia response to 5 microM resveratrol, estrogen, or epidermal growth factor is inhibited in cells expressing dominant-negative Rac, indicating that Rac regulates estrogen and resveratrol (5 microM) signaling to the actin cytoskeleton. These results indicate that signaling to the actin cytoskeleton by low and high concentrations of resveratrol may be differentially regulated by Rac and Cdc42.

PMID: 17356711 [PubMed - indexed for MEDLINE]




More dose-dependent effects..i.e. Low dose detrimental, High dose beneficial:


Growth Factors. 2006 Mar;24(1):79-87.
Insulin-like growth factor II mediates resveratrol stimulatory effect on cathepsin D in breast cancer cells.

Vyas S, Asmerom Y, De León DD.
Department of Anatomy, Loma Linda University, School of Medicine, CA 92350, USA.
Cathepsin D (CD) is an enzyme that promotes breast cancer. CD is stored intracellularly; however, we demonstrated that IGF-II promotes CD secretion in estrogen receptor positive (ER+) breast cancer cells. We also showed that resveratrol (RSV) stimulates IGF-II in ER(+) breast cancer cells. Thus, we designed this study to determine whether RSV regulates CD in MCF-7, T47D (ER+) breast cancer cells as well as in Hs578t (cancer) and MCF-10A (normal) ER - cell lines. RSV (10(- 6) M) increased CD and IGF-II secretion in ER+ but not ER - cells. RSV treatment (10(- 4) M) inhibited CD in ER+ but not in ER - cells. Transfection of ER - cells with proIGF-II increased CD secretion. RSV (10(- 6) M) modulates CD secretion through IGF-II while RSV (10(- 4) M) inhibits CD in ER+ but not ER - cells. Regulation of CD by RSV represents a novel mechanism by which RSV may protect against breast cancer.

PMID: 16393696 [PubMed - indexed for MEDLINE]








Antioxid Redox Signal. 2009 Nov;11(11):2851-97.
Resveratrol: its biologic targets and functional activity.

Pervaiz S, Holme AL.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore. phssp@nus.edu.sg
The polyphenolic phytoalexin resveratrol (RSV) and its analogues have received tremendous attention over the past couple of decades because of a number of reports highlighting their benefits in vitro and in vivo in a variety of human disease models, including cardio- and neuroprotection, immune regulation, and cancer chemoprevention. These studies have underscored the high degree of diversity in terms of the signaling networks and cellular effector mechanisms that are affected by RSV. The activity of RSV has been linked to cell-surface receptors, membrane signaling pathways, intracellular signal-transduction machinery, nuclear receptors, gene transcription, and metabolic pathways. The promise shown by RSV has prompted heightened interest in studies aimed at translating these observations to clinical settings. In this review, we present a comprehensive account of the basic chemistry of RSV, its bioavailability, and its multiple intracellular target proteins and signaling pathways.

PMID: 19432534 [PubMed - indexed for MEDLINE]





J Agric Food Chem. 2009 Nov 20. [Epub ahead of print]
Resveratrol Modulates Tumor Cell Proliferation and Protein Translation via SIRT1-Dependent AMPK Activation.

Lin JN, Lin VC, Rau KM, Shieh PC, Kuo DH, Shieh JC, Chen WJ, Tsai SC, Way TD.
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Pharmacy, China Medical University, Taichung, Taiwan.
Resveratrol functions as an agonist for estrogen receptor (ER)-mediated transcription. However, other researchers have reported that resveratrol decreases proliferation of breast cancer cells that are either ER-positive or ER-negative, which suggests that the interaction of resveratrol with the ER may not fully explain its inhibitory effect on proliferation. Similar to those effects associated with caloric restriction (CR), resveratrol has multiple beneficial activities, such as increased life span and delay in the onset of diseases associated with aging. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and antiproliferative properties of resveratrol has led us to hypothesize that resveratrol activity might have an important role in the activation of AMPK. Here, we show that resveratrol activated AMPK in both ER-positive and ER-negative breast cancer cells. Once activated, AMPK inhibited 4E-BP1 signaling and mRNA translation via mammalian target of rapamycin (mTOR). Moreover, we also found that AMPK activity mediated by resveratrol in cancer cells was due to inducing the expression of Sirtuin type 1 (SIRT1) via elevation in the cellular NAD(+)/NADH in ER-positive cells. To our knowledge, we demonstrate here for the first time that resveratrol induces the expression of SIRT1 protein in human cancer cells. These observations raise the possibility that SIRT1 functions as a novel upstream regulator for AMPK signaling and may additionally modulate tumor cell proliferation. Targeting SIRT1/AMPK signaling by resveratrol may have potential therapeutic implications for cancer and age-related diseases.

PMID: 19928762 [PubMed - as supplied by publisher]





Cancer Stem Cell harvesting and Resveratrol treatment patent 1/14/2010‏

http://www.freepatentsonline.com/20100010099.pdf





Int J Radiat Oncol Biol Phys. 2009 May 1;74(1):219-28.
Resveratrol-induced apoptosis and increased radiosensitivity in CD133-positive cells derived from atypical teratoid/rhabdoid tumor.

Kao CL, Huang PI, Tsai PH, Tsai ML, Lo JF, Lee YY, Chen YJ, Chen YW, Chiou SH.
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
PURPOSE: CD133 has recently been proposed as a marker for cancer stem-like cells (CSC) in brain tumors. The aim of the present study was to investigate the possible role of resveratrol (RV) in radiosensitivity of CD133-positive/-negative cells derived from atypical teratoid/rhabdoid tumors (AT/RT-CD133(+/-)). MATERIALS AND METHODS: AT/RT-CD133(+/-) were isolated and characterized by flow cytometry and quantitative real-time reverse transcription-polymerase chain reaction, and then treated with RV at different doses. Migratory ability, colony formation, apoptotic activity, and xenotransplantation were assessed for RV alone, ionizing radiation (IR) alone, and IR with RV conditions. RESULTS: AT/RT-CD133(+) displayed enhanced self-renewal and highly coexpressed "stem cell" genes and drug-resistant genes, in addition to showing significant resistance to chemotherapeutic agents and radiotherapy as compared with CD133(-) cells. After treatment with 200 microM RV, the in vitro proliferation rates and in vivo tumor restoration abilities of ATRT-CD133(+) were dramatically inhibited. Importantly, treatment with 150 microM RV can effectively inhibit the expression of drug-resistant genes in AT/RT-CD133(+), and further facilitate to the differentiation of CD133(+) into CD133(-). In addition, treatment with 150 microM RV could significantly enhance the radiosensitivity and IR-mediated apoptosis in RV-treated ATRT-CD133(+/-). Kaplan-Meier survival analysis indicated that the mean survival rate of mice with ATRT-CD133(+) that were treated with IR could be significantly improved when IR was combined with 150 microM RV treatment. CONCLUSIONS: AT/RT-CD133(+) exhibit CSC properties and are refractory to IR treatment. Our results suggest that RV treatment plays crucial roles in antiproliferative, proapoptotic, and radiosensitizing effects on treated-CD133(+/-); RV may therefore improve the clinical treatment of AT/RT.

PMID: 19362240 [PubMed - indexed for MEDLINE]





J Pharmacol Sci. 2009 Apr;109(4):473-85.
Caspase mediated enhanced apoptotic action of cyclophosphamide- and resveratrol-treated MCF-7 cells.

Singh N, Nigam M, Ranjan V, Sharma R, Balapure AK, Rath SK.
Genotoxicity Laboratory, Toxicology Division, Central Drug Research Institute, India. neetuaashi@yahoo.com
Cyclophosphamide (CPA) is a widely used chemotherapeutic drug for neoplasias. It is a DNA and protein alkylating agent having a broad spectrum of activity against a variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining resveratrol (RES) with CPA and aims to increase the understanding of the mechanism of cell killing. Interestingly, we found that RES significantly enhances the caspase-mediated cytotoxic activity of CPA on MCF-7 cells in vitro. RES at 50 microM decreases the IC(50) value of CPA from 10 to 5 mM. FACS data reveals CPA or RES alone mediated G0/G1 and S phase arrest, while the combination of these drugs released both the arrests and results in an increase in the sub G0/G1 peak. Additional analyses indicated the significant up-regulation (P = 0.001) of tumor suppressor p53 and p53-regulated pro-apoptotic Bax and Fas in MCF-7 cells following CPA treatment in combination with RES, which may contribute to the enhancement of the antitumor effect of CPA. Furthermore, downregulation of anti-apoptotic Bcl-2 (P = 0.001) was observed in MCF-7 cells treated with CPA with or without RES when compared to untreated MCF-7. These results suggest the possibility of a new combination chemotherapeutic regimen leading to improvements in the treatment of breast cancer.

PMID: 19372630 [PubMed - indexed for MEDLINE]





Int J Cancer. 2009 Nov 11. [Epub ahead of print]
Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer.

Harikumar KB, Kunnumakkara AB, Sethi G, Diagaradjane P, Anand P, Pandey MK, Gelovani J, Krishnan S, Guha S, Aggarwal BB.
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Gemcitabine, while a standard treatment of advanced pancreatic cancer (PaCa), alone is not very effective. New agents that are safe and effective are highly needed. Resveratrol is one such agent which is safe and multitargeted; and has been linked with suppression of survival, proliferation, invasion and angiogenesis of cancer. Whether resveratrol can sensitize PaCa to gemcitabine in vitro and in vivo was investigated. We established PaCa xenografts in nude mice, randomized into 4 groups, and treated with vehicle, gemcitabine, resveratrol and with combination. Modulation of NF-kappaB and markers of proliferation, angiogenesis and invasion were ascertained using electrophoretic mobility shift assay (EMSA), immunohistochemistry and western blot analysis. Resveratrol inhibited the proliferation of 4 different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expression of bcl-2, bcl-xL, COX-2, cyclin D1 MMP-9 and VEGF. In an orthotopic model of human PaCa, we found that resveratrol significantly suppressed the growth of the tumor (p < 0.001) and this effect was further enhanced by gemcitabine (p < 0.001). Both the markers of proliferation index Ki-67 and the micro vessel density CD31 were significantly downregulated in tumor tissue by the combination of gemcitabine and resveratrol (p < 0.001 vs. control; p < 0.01 vs. gemcitabine). As compared to vehicle control, resveratrol also suppressed the NF-kappaB activation and expression of cyclin D1, COX-2, ICAM-1, MMP-9 and survivin. Overall our results demonstrate that resveratrol can potentiate the effects of gemcitabine through suppression of markers of proliferation, invasion, angiogenesis and metastasis.

PMID: 19908231 [PubMed - as supplied by publisher]





Nutr Cancer. 2008;60(3):401-11.
Vitamin E analog alpha-TEA, methylseleninic acid, and trans-resveratrol in combination synergistically inhibit human breast cancer cell growth.

Snyder RM, Yu W, Jia L, Sanders BG, Kline K.
Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, Texas 78712-1097, USA.
Alpha-tocopherol ether-linked acetic acid analog [2,5,7,8-tetramethyl-2R-(4R, 8R-12-trimethyltridecyl) chroman-6-yloxyacetic acid (alpha-TEA)] is a novel form of vitamin E effective at killing cancer cells but not normal cells. alpha -TEA alone and together with methylseleninic acid (MSA) and trans-resveratrol (t-RES) were investigated for ability to induce apoptosis, DNA synthesis arrest, and cellular differentiation and inhibit colony formation in human MDA-MB-435-F-L breast cancer cells in culture. The 3 agents alone were effective in inhibiting cell growth by each of the 4 different assays, and 3-way combination treatments synergistically inhibited cell proliferation in each assay in comparison to individual treatments. Furthermore, combinations of alpha -TEA, t-RES, and MSA significantly enhanced levels of apoptosis in human breast (MDA-MB-231, MCF7, and T47D) and prostate (LnCaP, PC-3, and DU-145) cancer cell lines as well as in immortalized but nontumorigenic MCF10A cells but not primary cultures of human mammary epithelial cells. Western immunoblotting confirmed the induction of apoptosis in that the 3 agents induced poly(adenosine diphosphate-ribose) polymerase cleavage, with earlier detection and more complete cleavage seen in the combination treatment. Mechanistic studies showed combination treatments to inhibit cell proliferation via downregulation of cyclin D1 and induce apoptosis via activation of caspases 8 and 9 and downregulation of prosurvival proteins FLIP and survivin. In summary, the combination of alpha-TEA, MSA, and t-RES is more effective than single treatments for inhibiting cell proliferation, inducing cellular differentiation, and inducing cell death by apoptosis in human cancer cells in culture.

PMID: 18444175 [PubMed - indexed for MEDLINE]




J Nutr. 2010 Jan 20. [Epub ahead of print]
Multidrug Resistance Proteins Restrain the Intestinal Absorption of trans-Resveratrol in Rats.

Juan ME, González-Pons E, Planas JM.
Departament de Fisiologia (FarmÃ*cia) and Institut de Recerca en Nutrició i Seguretat AlimentÃ*ria, Universitat de Barcelona, Barcelona E-08028, Spain.
trans-Resveratrol, a natural antioxidant, has been described as a nutraceutic compound with important beneficial effects on health, but its low oral bioavailability hinders its therapeutic activity. Here, we studied the mechanisms of apical transport of trans-resveratrol in enterocytes and the role of ATP-binding cassette (ABC) transporters in the secretion of resveratrol glucuronide and sulfate resulting from the rapid intracellular metabolism. An intestinal perfusion method with recirculation in vivo was used in rats. Jejunal loops were perfused with increasing concentrations of trans-resveratrol and results showed that its uptake occurs by simple diffusion without the participation of a mediated transport. The apparent diffusion constant was 8.1 +/- 0.3 muL/(5 min.mg dry weight). The glycoprotein-P (Pgp, ABCB1), multidrug resistance-associated protein 2 (MRP2, ABCC2), and breast cancer resistance protein (BCRP, ABCG2) located in the apical membrane of enterocytes were investigated using specific inhibitors. The Pgp inhibitors verapamil (5 mumol/L) and cyclosporin A (5 mumol/L) did not affect the efflux of trans-resveratrol and its conjugates. The MRP2 inhibitors probenecid (2 mmol/L) and MK571 (10 mumol/L) reduced the efflux of glucuronide by 61 and 55%, respectively, and of sulfate by 43 and 28%, respectively. The BCRP inhibitor Ko143 (0.5 mumol/L) decreased the secretion of glucuronide by 64% and of sulfate by 46%. Our experiments identify MRP2 and BCRP as the 2 apical transporters involved in the efflux of resveratrol conjugates.

PMID: 20089784 [PubMed - as supplied by publisher]





J Cell Physiol. 2010 Jan 15. [Epub ahead of print]
Resveratrol enhances perforin expression and NK cell cytotoxicity through NKG2D-dependent pathways.

Lu CC, Chen JK.
Department of Physiology, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
In a previous report, we showed that the in vivo cytotoxic activity of the natural killer (NK) cells isolated from resveratrol-pretreated rats is significantly enhanced compared with that of the non-pretreated rats; however, the underlying mechanism remains unclear. In the present study, we use cultured NK92 cell line to examine the possible signaling pathways underlying the resveratrol-induced activation. Using cultured K562, HepG2, and A549 cells as targets, we show that resveratrol pretreatment increases NK cell cytotoxicity in a dose-dependent manner. The enhanced cytotoxic effect is accompanied by increases in JNK and ERK-1/2 MAP kinase activity and perforin expression. Moreover, the expression of NKG2D, an upstream signaling molecule of the MAP kinases pathway, is also enhanced. Resveratrol-enhanced perforin expression and cytotoxic activity are effectively inhibited by pretreatment with the inhibitors of JNK (SP600125), ERK-1/2 (PD98059), or by siRNAs against JNK-1 and ERK-2. However, the inhibitors or siRNA to p38 exhibits no effect. Since IL-2 has been shown to induce NKG2D expression and perforin release, we therefore, examined whether IL-2 and resveratrol act in parallel. We show that IL-2 also stimulates perforin expression, however, when treated together with resveratrol, they exhibit no additive effect. The results suggest that in NK92 cells, resveratrol may act via a similar or overlapping pathway as that of IL-2, to enhance perforin expression and cytotoxic activity. Data presented strongly indicate that resveratrol act via NKG2D-dependent JNK and ERK-1/2 pathways. J. Cell. Physiol. (c) 2010 Wiley-Liss, Inc.

PMID: 20082299 [PubMed - as supplied by publisher]





J Steroid Biochem Mol Biol. 2003 Feb;84(2-3):149-57.
Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25-dihydroxyvitamin D3 actions in human breast cancer cells.

Wietzke JA, Welsh J.
Department of Biological Sciences, University of Notre Dame, IN 46556, USA.
1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a steroid hormone derived from Vitamin D(3), is a negative growth regulator of breast cancer cells, and Vitamin D(3) analogs represent a novel treatment approach for human cancer. Elucidation of Vitamin D(3) receptor (VDR) regulation may reveal strategies to sensitize cancer cells to the effects of 1,25-dihydroxyvitamin D(3) and Vitamin D(3) analogs. We have previously characterized an estrogen responsive promoter region (800 bp upstream of exon 1c) in the human VDR gene, and the present studies examined regulation of this VDR promoter region by two phytoestrogens, resveratrol (present in red wine) and genistein (present in soy). We transiently transfected a VDR promoter luciferase construct into the estrogen receptor (ER) positive human breast cancer cell lines T47D and MCF-7, and treated with 0.4-4 microM resveratrol or 5-500 nM genistein. Both phytoestrogens up-regulated the transcription of the VDR promoter, as measured by reporter gene activity, approximately two-fold compared to vehicle treated cells. Co-treatment with the anti-estrogen tamoxifen (TAM) in T47D cells and transfection in an estrogen receptor negative breast cancer cell line demonstrated that the effects of phytoestrogens on the VDR promoter are dependent on estrogen receptor. Resveratrol and genistein also increased VDR protein expression as detected by Western blotting. Treatment with resveratrol had no effect on cell number or cell cycle profile, while treatment with genistein increased cell number. Because resveratrol could up-regulate VDR without increasing breast cancer cell growth, we hypothesized that resveratrol mediated increase in VDR expression would sensitize breast cancer cells to the effects of 1,25-dihydroxyvitamin D(3) and Vitamin D(3) analogs. In support of this hypothesis, both T47D and MCF-7 cells pre-treated with resveratrol exhibited increased VDR mediated transactivation of a Vitamin D(3) responsive promoter compared to cells pre-treated with vehicle. In addition, co-treatment with resveratrol enhanced the growth inhibitory effects of 1,25-dihydroxyvitamin D(3) and the Vitamin D(3) analog EB1089. These data support the concept that dietary factors, such as phytoestrogens, may impact on breast cancer cell sensitivity to Vitamin D(3) analogs through regulation of the VDR promoter.

PMID: 12710998 [PubMed - indexed for MEDLINE]



Cancer Chemother Pharmacol. 2008 Dec;63(1):27-35. Epub 2008 Feb 20.
Resveratrol analog trans 3,4,5,4'-tetramethoxystilbene (DMU-212) mediates anti-tumor effects via mechanism different from that of resveratrol.

Ma Z, Molavi O, Haddadi A, Lai R, Gossage RA, Lavasanifar A.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Comment in:

• Cancer Chemother Pharmacol. 2009 Feb;63(3):567.

PURPOSE: Resveratrol is a well-known chemopreventive and chemotherapeutic agent. Among all of the resveratrol analogs synthesized, 3,4,5,4'-tetramethoxystilbene (DMU-212) shows high activity and selectivity against various cancer cell types. The objective of this study is to investigate why DMU-212 has higher anti-tumor activity than resveratrol. METHODS: The effects of DMU-212 and resveratrol on cell viability, cell cycle, Stat3 activation, and microtubule dynamic were investigated and compared using MTT assay, cell cycle analysis, Western blot, tubulin polymerization assay, respectively, in MDA-MB-435 and MCF-7 human breast cancer cells. RESULTS: Compared to resveratrol, DMU-212 exerted a significantly higher growth inhibition in both cell lines. Further studies demonstrated that DMU-212 acted via different mechanisms from resveratrol. First, DMU-212 induced predominantly G2/M arrest whereas resveratrol induced G0/G1 arrest in both cell lines. Correlating with these findings, resveratrol induced more dramatic changes in the expression of Cyclin D1 compared to DMU-212. Second, DMU-212 induced apoptosis and reduced the expression of multiple anti-apoptotic proteins more appreciably than resveratrol. Third, while both agents inhibited Stat3 phosphorylation, treatments of DMU-212 but not resveratrol led to a significant increase in tubulin polymerization. The higher sensitivity to DMU-122 in MDA-MB-435 correlated with the more prominent effects seen in these parameters in this cell line, as compared to MCF7. CONCLUSION: Compared to resveratrol, the novel stilbene derivative, DMU-212, had higher anti-tumor effects, which are likely owing to its modulation of multiple cellular targets.

PMID: 18286288 [PubMed - indexed for MEDLINE]


The inventor of DMU-212:

LINK Private hell of Leicester scientist searching for cancer wonder drug
Saturday, February 13, 2010, 09:30