Uptake of resveratrol and role of resveratrol-targeting protein, quinone reductase 2, in normally cultured human prostate cells
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Resveratrol 是拥护对许多人的癌症类型举办 chemopreventive 活动的饮食的多酚。我们首先报导 resveratrol 显著地减少雄激素依赖者和荷尔蒙倔强的前列腺癌症房间的增长。然而，特别地关于它的举起， subcellular 分发和细胞内部的目标，在上皮的正常前列腺和 stromal 房间的 resveratrol 的效果没被调查。在前列腺房间在可接近性和 resveratrol 的细胞的布置上推进知识，[ 3H ] resveratrol ，进 subcellular 分隔空间的房间摘录的分别，西方的污点分析， resveratrol 亲密关系列层析和流动 cytometry 被用来在通常有教养的前列腺 stromal ( PrSCs )和上皮的房间( PrECs )学习举起和 resveratrol 的细胞内部的分发。为有 resveratrol 的 2 天的 PrSCs 和 PrECs 的预告的处理调制了它的举起并且有选择地增加了它的分发到膜和细胞器分隔空间。Resveratrol 亲密关系列层析研究显示出以前识别的指向 resveratrol 蛋白质的微分表示， quinone reductase 2 (QR2 ) ，在 PrSCs 和 PrECs。比较对待 resveratrol 、未经治疗的 PrSCs 的流动 cytometric 分析在在房间周期的 S 和 G2/M-phases 的 G1 阶段和伴随物增加显示出大减少。这些结果建议 resveratrol 由影响房间周期阶段分发压制 PrSC 增长，它可以由 QR2 包含参予。Cite
Abstract Various natural products have been proposed to both increase health at the organismic level, and delay the onset of cellular aging. Of particular interest is resveratrol, a phytoalexin that has been demonstrated to have cardioprotective effects and to slow the progression of a variety of illnesses, including various types of cancers. More recently, resveratrol has been demonstrated to increase the maximum lifespan of model organisms, such as C. elegans, D. melanogaster and N. furzeri. However, the potential health benefits of resveratrol and other similar compounds on the human immune response have not been adequately addressed. We have, therefore, initiated research to determine the in vitro effects of the nutraceuticals resveratrol, and its analogs (polydatin and acetyl-resveratrol), as well as curcumin on a variety of human T cell functions. In this study we evaluated the effect of these compounds on proliferative potential, telomerase activity, expression of costimulatory and memory surface markers and sirtuin gene expression profiles of both human CD4 and CD8 T cells. Our data show that these compounds stimulated strong dose-dependent anti-inflammatory responses, and upregulated surface protein markers associated with the suppression of T cell activity. Our preliminary results suggest that these compounds may function to down-modulate ongoing CD4 and CD8 immune activity, while, nevertheless, poising the T cells for a subsequent immune response.
Sirtuin 1
Phytoalexin
Hydroxytyrosol
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Since resveratrol (3,4',5 tri-hydroxystilbene), which has been shown to inhibit multistage carcinogenesis, is not a potent cytotoxic compound, several studies were undertaken to obtain synthetic analogues of resveratrol with potent activity. We previously reported that a resveratrol derivative HS-1793 exhibits stronger antitumor effects than resveratrol in several cancer cell types. The present study was undertaken to reveal precise mechanism by which HS-1793 induces cell death. The induction of CCAAT/enhancer-binding protein-homologous protein (CHOP) and glucose-regulated protein (GRP)-78, and ER stress-specific XBP1 splicing were found in HT29 human colon carcinoma cells treated with resveratrol. Conversely, these manifestations were not observed in HT29 cells treated with HS-1793. Inhibition of caspase-4 activity by z-LEVD-fmk significantly reduced the induction of apoptosis by resveratrol but not by HS-1793. These findings suggest that HS-1793, contrary to resveratrol, does not induce ER stress-mediated apoptosis. Importantly, we observed that HS-1793 but not resveratrol decreased phosphorylated Akt level. We also demonstrated that HS-1793, compared to resveratrol, exerted more effective apoptosis inducing activity in Akt-activated cells. Taken together, the stronger antitumor activity of HS-1793 originates, at least in part, from its ability for Akt inactivation.
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Resveratrol (RES) (trans-3, 5,-4′-trihydroxystilebene) is a multi-biofunctional compound found in a variety of plants such as grapes and mulberries. Studies of nanoencapsulated resveratrol have indicated that this compound can inhibit the growth of cancer cells and free radicals. The aim of this study was to isolate resveratrol from Vitis vinifera, develop and evaluate resveratrol nanostructured lipid carriers (NLCs) and/or resveratrol encapsulated chitosan-coated nanostructured lipid carriers (CSNLCs) using low-viscous chitosan for anticancer therapy. In addition, our study was carried out to examine the prophylactic potential of RES, NLC, and CSNLC on paraquat-induced injury in rat hepatocytes. In this study we isolated resveratrol and encapsulated NLCs in phosphate-buffered saline solution using a phase inversion method. In addition, CSNLCs were prepared by ionic gelation method of NLCs using chitosan. NLCs and CSNLCs were then characterized for their particle size, zeta potential, morphology, and entrapment efficiency. Furthermore, NLCs and CSNLCs were evaluated for their cytotoxic effect on Hep-G2, human HCT-116 (colorectal cancer cell line), lymphoblastic leukemia (1301), and human MCF-7 (Michigan Cancer Foundation-7) cells as well as their effect on caspase-3 and death receptor (DR-4). In addition, incubation of hepatocytes with paraquat resulted in increased formation of TBARS (thiobarbituric acid reactive substances) with a parallel increase in lactate dehydrogenase (LDH) leakage at 1 h after incubation. Time-dependent depletion of cellular glutathione (GSH) was observed starting 2 h after incubation with paraquat. The mean particle size of NLC and CSNLC were 67.0 and 98.41 nm, zeta potential were (−) 24.8 and (+) 31.6 mV, entrapment efficiency were 74.15% and 85.46%, respectively, with the observed shapes of nanoparticle being spherical. The treatment of Hep-G2, human HCT-116, lymphoblastic leukemia (1301), and human MCF-7 cells with NLC led to high inhibition in the cell proliferation as concluded by the low IC50 values 27.7, 17.43, 35.39, and 47.66 μg/mL, respectively, whereas CSNLC had high cytotoxic effect on Hep-G2, human HCT-116, lymphoblastic leukemia (1301), and human MCF-7 cells with low IC50 values 13.29, 10.56, 16.79 and 22.60 μg/mL, respectively. Both NLC and CSNLC possess apoptotic properties through activation of the caspase-3 and death receptor (DR-4). In addition, incubation of hepatocytes with RES, NLC, and CSNLC markedly protected against paraquat-induced formation of TBARS, increase in LDH leakage, and prevented GSH depletion. The most effective doses for ethyl acetate, ethanolic, and aqueous extracts were 7.5, 10, and 12.5 μg, respectively. The results presented here may suggest that nanoencapsulated resveratrol isolated from the stems of V. vinifera to obtain NLC and CSNLC possess anticancer and apoptotic effects on cell proliferation, and therefore, can be used as new approach of pharmaceutical drugs. In addition, the results clearly suggest that the RES, NLC, and CSNLC exerted protective effect against cytotoxicity induced by paraquat. On the contrary, the effect decreased in order of CSNLC, NLC, and RES.
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Resveratrol is a dietary polyphenol espoused to have chemopreventive activity against a variety of human cancer types.We first reported that resveratrol significantly decreases the proliferation of both androgen-dependent and hormone-refractory prostate cancer cells.However, the effects of resveratrol in normal prostate epithelial and stromal cells, particularly with regard to its uptake, subcellular distribution and intracellular targets, have not been investigated.To advance the knowledge on accessibility and cellular disposition of resveratrol in prostate cells, [ 3 H] resveratrol, fractionation of cell extracts into subcellular compartments, Western blot analysis, resveratrol affinity column chromatography and flow cytometry were used to study the uptake and intracellular distribution of resveratrol in normally cultured prostate stromal (PrSCs) and epithelial cells (PrECs).Pretreatment of both PrSCs and PrECs for 2 days with resveratrol modulated its uptake and selectively increased its distribution to the membrane and organelle compartments.Resveratrol affinity column chromatography studies showed differential expression of a previously identified resveratrol-targeting protein, quinone reductase 2 (QR2), in PrSCs and PrECs.Flow cytometric analysis comparing resveratrol-treated and untreated PrSCs showed a large decrease in G 1 -phase and a concomitant increase in S and G 2 /M-phases of the cell cycle.These results suggest that resveratrol suppresses PrSC proliferation by affecting cell cycle phase distribution, which may involve the participation by QR2.
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Resveratrol has been shown to possess antioxidant and anticancer activities, but little is known on the effect of resveratrol derivatives. Recently we have isolated resveratrol and its dimers and trimers from peony (Paeonia lactiflora) seeds, and reported their strong antioxidant and cytotoxic activity. In the present study, we have evaluated cellular effects of resveratrol derivatives; viniferin, gnetin H, and suffruticosol B on the proliferation and apoptosis in HL-60 cells in vitro. All resveratrol and its derivatives reduced viability of HL-60 cells in a dose-dependent manner with their IC50 values of 20-90 µM. Ascending orders of IC50 values were suffruticosol B, gnetin H, viniferin and resveratrol respectively. HL-60 cells treated with the four stilbenes exhibited the distinct morphological changes characteristics of cell apoptosis such as chromatin condensation, apoptotic bodies, and DNA fragmentations. A time-dependent histogram of the cellular DNA analyzed by flow cytometry revealed a rapid increase in subdiploid cells and a concomitant decrease in diploid cells exposed to 100 µM resveratrol for 0-24 h. Cells treated with 25 µM of resveratrol, viniferin, gnetin H, and suffruticosol B for 24 h resulted in increment of sub-G1 population by 51, 5, 11 and 59%, respectively. Treatment of cells with 0-20 µM resveratrol for 5 h produced a concentration-dependent decrease in cytochrome P450 (CYP) 1B1 mRNA levels. Suffruticosol B also suppressed CYP1B1 gene expression. These results demonstrated that resveratrol oligomers also strongly suppressed HL-60 cell proliferation, and induced DNA damage. In addition, CYP1B1 gene supression may suggest an involvement in the resveratrol-induced apoptosis in HL-60 cells.
Paeonia lactiflora
Viability assay
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The chemopreventive potential of resveratrol is marred by its low bioavailability. Studies of modified resveratrol may reveal features that affect its bioefficacy and bioavailability. We compared the anti-proliferative and gene regulatory activities of resveratrol with trimethoxy-resveratrol and triacetyl-resveratrol using cultured human prostate cancer (CaP) cells. LNCaP cells were incubated with resveratrol and its analogues. Changes in proliferation, colony formation, cell cycle, apoptosis and prostate specific antigen (PSA) PSA were determined. DNA damage was assayed by phosphorylated-histone H2AX changes. Expression of total and serine-15-phosphorylated p53 and p53-inducible cell cycle regulatory protein p21 and ribonucleotide reductase subunit p53R2 involved in DNA repair were measured by immunobloting and reverse transcription–polymerase chain reaction. Exposure to resveratrol or triacetyl-resveratrol activated p53, increased p21 and p53R2 and decreased PSA expression in LNCaP cells. These changes were attenuated by the p53 inhibitor pifithrin-α. However, LNCaP cells exposed to trimethoxy-resveratrol showed induction of apoptosis, reduction in G 1 and prolongation of the SG 2 M phases. Resveratrol and analogues were also studied in CWR22Rv1 (containing mutated p53) and p53-null PC-3 cells. CWR22Rv1 cells exposed to resveratrol and triacetyl-resveratrol showed a G 1 S block, concomitant with increased p53 and p21 expression; however, identically treated PC-3 cells showed attenuated progression through the SG 2 M phases. Trimethoxy-resveratrol did not affect CWR22Rv1 cell cycle but reduced and expanded PC-3 cells in the G 1 and SG 2 M phases, respectively. These results suggest that triacetyl-resveratrol and trimethoxy-resveratrol are active against different stage CaP cells, using overlapping and distinct mechanisms.
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Resveratrol, a chemopreventive agent, is rapidly metabolized in the intestine and liver via glucuronidation. Thus, the pharmacokinetics of resveratrol limits its efficacy. To improve efficacy, the activity of resveratrol was investigated in the context of sphingolipid metabolism in human gastric cancer cells. Diverse sphingolipid metabolites, including dihydroceramides (DHCer), were tested for their ability to induce resveratrol cytotoxicity. Exposure to resveratrol (100 μM) for 24 hr induced cell death and cell cycle arrest in gastric cancer cells. Exposure to the combination of resveratrol and dimethylsphingosine (DMS) increased cytotoxicity, demonstrating that sphingolipid metabolites intensify resveratrol activity. Specifically, DHCer accumulated in a resveratrol concentration-dependent manner in SNU-1 and HT-29 cells, but not in SNU-668 cells. LC-MS/MS analysis showed that specific DHCer species containing C24:0, C16:0, C24:1, and C22:0 fatty acids chain were increased by up to 30-fold by resveratrol, indicating that resveratrol may partially inhibit DHCer desaturase. Indeed, resveratrol mildly inhibited DHCer desaturase activity compared to the specific inhibitor GT-11 or to retinamide (4-HPR); however, in SNU-1 cells resveratrol alone exhibited a typical cell cycle arrest pattern, which GT-11 did not alter, indicating that inhibition of DHCer desaturase is not essential to the cytotoxicity induced by the combination of resveratrol and sphingolipid metabolites. Resveratrol-induced p53 expression strongly correlated with the enhancement of cytotoxicity observed upon combination of resveratrol with DMS or 4-HPR. Taken together, these results show that DHCer accumulation is a novel lipid biomarker of resveratrol-induced cytotoxicity in human gastric cancer cells.
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Resveratrol has been reported to inhibit or induce DNA damage, depending upon the type of cell and the experimental conditions. Dietary resveratrol is present in the body predominantly as metabolites and limited data is available concerning the activities of these metabolic products. In the present study, physiologically obtainable levels of the resveratrol metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide and resveratrol-3-O-sulfate were evaluated for their ability to protect Jurkat T cells against DNA damage induced by the topoisomerase I inhibitors camptothecin and topotecan. The cells were pretreated for 24 h with 10 µM resveratrol aglycone or each resveratrol metabolite prior to the induction of DNA damage with camptothecin or topotecan. In separate experiments, the cells were co-treated with resveratrol or its metabolites, and a topoisomerase I inhibitor. The detection of histone 2AX phosphorylation and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) were used to determine DNA damage, and apoptosis was measured using an antibody against cleaved poly ADP-ribose polymerase. It was identified that pretreatment of the cells with resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduced the mean fluorescence intensity of staining for DNA strand breaks following treatment with camptothecin, while the percentage of cells undergoing apoptosis was unchanged. However, pretreatment of the cells with resveratrol aglycone increased the DNA damage and apoptosis induced by the drugs. These results suggest that the glucuronide metabolites of resveratrol partially protected the cells from DNA damage, but did not influence the induction of cell death by camptothecin and topotecan. These data suggest that resveratrol aglycone treatment may be beneficial for treating types of cancer that have direct contact with resveratrol prior to its metabolism, including gastrointestinal cancers, which are routinely treated with topoisomerase I inhibitors.
Camptothecin
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