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PubMed1983

Intracellular SITS injection dye-uncouples mammalian oligodendrocytes in culture.

When the blue fluorescing dye SITS (4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulfonic acid disodium salt) is injected into one of a pair of electrically and dye-coupled oligodendrocytes it does not cross the intercellular junctions but remains in the injected cell. Moreover, the fluorescent dye Lucifer Yellow CH (LY), which normally crosses these intercellular junctions after injection, does not diffuse into a SITS-injected cell. Thus, intracellular SITS injection leads to dye-uncoupling. SITS injection does not eliminate electrical-coupling.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1986

Subcellular and organ distribution of cholesterol epoxide hydrolase in the rat.

The subcellular and organ distributions of microsomal epoxide hydrolases measured with cis-stilbene oxide and cholesterol 5,6 alpha-epoxide as substrates have been investigated. These two enzyme activities were found to have essentially the same subcellular distribution, with the highest total and specific activities localized in rough and smooth endoplasmic reticulum. Among the tissues studied (i.e., liver, kidney, lung, testis, spleen, brain and intestinal epithelium), the highest specific activities were recovered in liver microsomes, where the activities were at least 5-fold greater than in any of the other microsomal preparations.

Animals↗
PubMed1986

DIDS, an anion transport blocker, modulates ivermectin-induced enhancement of benzodiazepine receptor binding in rat brain.

Ivermectin enhancement of [3H]diazepam binding was abolished by pretreatment of membranes with 0.05% Triton X-100, whereas GABA-induced enhancement was not changed after this treatment. Ivermectin enhancement was neither affected by picrotoxinin nor dependent on the chloride ion. 4,4'-Diisothiocyano-2,2'-disulfonic acid stilbene (DIDS) dose-dependently reduced [3H]diazepam binding enhanced by 10(-6) M ivermectin, without affecting the basal specific binding. The effects of DIDS were derived from reduction of increased binding affinity of benzodiazepine receptors by ivermectin, but were not dependent on chloride ion in the assay medium. DIDS inhibited GABA- and pentobarbital- but not chloride ion-induced enhancement of [3H]diazepam binding.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMedDate not supplied

Chiral HPLC versus chiral SFC: evaluation of long-term stability and selectivity of Chiralcel OD using various eluents.

The long-term stability of Chiralcel OD columns under varying HPLC and SFC conditions was evaluated. Two new columns from the same supplier lot were procured, and one was installed in an HPLC system, and the other was installed in an SFC system. Enantiomeric mixtures of trans-stilbene oxide and carbobenzyloxy phenylalaninol were repeatedly injected in both systems over several days. For HPLC, hexane was the primary solvent used, along with IPA, EtOH, MeOH/IPA, or EtOH/TFA modifier. Carbon dioxide was the primary SFC solvent, together with the similar modifiers as the HPLC. Column performance was monitored by measuring resolution, theoretical plate number, and alpha between enantiomeric peaks. It was observed that, when the eluent strengths were adjusted to provide comparable retention times, the Chiralcel OD gave superior enantiomeric resolution when used in the SFC than the HPLC. Equilibration in between solvents was faster with SFC. The columns were demonstrated to be quite stable in both systems.

Alanine↗
PubMed2005

Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells.

Resveratrol (3,4',5-trihydroxy stilbene), a phytoalexin found in the skin and seeds of grapes, has been reported to possess anti-inflammatory, anticarcinogenic, and antioxidant activities. In this work, we assessed the ability of resveratrol to upregulate heme oxygenase-1 (HO-1) gene expression via activation of NF-E2-related factor 2 (Nrf2) in cultured PC12 cells. Nrf2 is a transcription factor involved in the cellular protection against oxidative stress through antioxidant response element (ARE)-directed induction of several phase 2 detoxifying and antioxidant enzymes, such as HO-1. Here, we report that resveratrol induces HO-1 expression via the ARE-mediated transcriptional activation of Nrf2. Moreover, PC12 cells treated with resveratrol exhibited transient activation of Akt/protein kinase B and extracellular signal-regulated protein kinase 1/2 (ERK1/2). LY294002 and U0126, pharmacological inhibitors of phosphatidylinositol 3-kinase and MEK1/2 which are upstream of Akt and ERK1/2, respectively, attenuated resveratrol-induced HO-1 expression and exhibited antioxidant effects. Taken together, the above findings suggest that resveratrol augments cellular antioxidant defense capacity through induction of HO-1 via Nrf2-ARE signaling, thereby protecting PC12 cells from oxidative stress.

Animals↗
PubMed2006

Inhibitory effects of cis- and trans-isomers of 3,5-dihydroxystilbene on the activity of mushroom tyrosinase.

The effects of cis- and trans-isomers of 3,5-dihydroxystilbene on the activity of mushroom tyrosinase have been studied. The results show that both cis- and trans-isomers of 3,5-dihydroxystilbene can inhibit the diphenolase activity of the enzyme and the inhibition type was reversible. The IC(50) values were estimated as 0.405+/-0.013 and 0.705+/-0.017 mM, respectively. Kinetic analysis showed that the inhibition of cis-3,5-dihydroxystilbene and trans-3,5-dihydroxystilbene on the diphenolase activity of the enzyme belonged to competitive type, and the inhibition constants (K(I)) were determined to be 0.232+/-0.015 and 0.395+/-0.020 mM, respectively. In this investigation, the inhibitory effects of cis-3,5-dihydroxystilbene and trans-3,5-dihydroxystilbene on the diphenolase activity of mushroom tyrosinase were compared. The inhibitory capacity of cis-isomer was stronger than that of corresponding trans-isomer. Nevertheless, the trans-3,5-dihydroxystilbene was used more frequently than its corresponding cis-form compound. This research may offer some references for designing and synthesizing some novel and effective tyrosinase inhibitors. Furthermore, it may improve the use of stilbenes on the field of food preservation and depigmentation.

Agaricales↗
PubMed2006

Resveratrol induces apoptosis of human malignant B cells by activation of caspase-3 and p38 MAP kinase pathways.

Red wine polyphenol, trans-resveratrol (trans-3,4',5-trihydroxy stilbene), has potent chemopreventive effects against various tumors. In this study, we found for the first time that resveratrol rapidly induces S phase cell cycle arrest of human malignant B cells including myeloma cells in dose- and time-dependent manners, followed by S phase cell cycle arrest through ATM/Chk pathway. Resveratrol-induced apoptosis occurs in association with the activation of caspase-3 and the loss of mitochondrial transmembrane potentials. In addition, resveratrol induces the phosphorylation of p38 MAP kinase, and specific inhibition of p38 MAP kinase abolishes the resveratrol-induced apoptosis, indicating that activation of the p38 MAP kinase pathway is required for inducing apoptosis in malignant B cells. These results suggest that resveratrol may have potential as a novel therapeutic agent for the patients with B cell malignancies including multiple myeloma.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Relative effects of phenolic constituents from Yucca schidigera Roezl. bark on Kaposi's sarcoma cell proliferation, migration, and PAF synthesis.

Yuccaols (A, B, C) are phenolic constituents isolated from Yucca schidigera bark characterized by unusual spirostructures made up of a C15 unit and a stilbenic portion closely related to resveratrol. These novel compounds are of particular interest for their antioxidant and anti-inflammatory properties. However, their effects on cell proliferation, migration, and platelet-activating factor (PAF) biosynthesis remain unknown. PAF, a potent mediator of inflammation, is known to promote angiogenesis and in vitro migration of endothelial cells and Kaposi's sarcoma (KS) cells. The objective of our study was to determine the effect of Yuccaols and resveratrol on the vascular endothelial growth factor (VEGF)-induced proliferation, migration, and PAF biosynthesis in KS cells. The results indicated that Yuccaols (25 microM) were more effective than resveratrol (25 microM) in inhibiting the VEGF-induced KS cell proliferation. Western blot analysis revealed that Yuccaols reduced the VEGF-induced phosphorylation of p38 and p42/44, thus indicating a possible interference with the mechanism underlying the VEGF-stimulated cell proliferation. Furthermore, Yuccaols completely inhibited the VEGF-stimulated PAF biosynthesis catalyzed by the acetyl-CoA:lyso-PAF acetyltransferase and enhanced its degradation through the PAF-dependent CoA-independent transacetylase (250% of control). In addition, Yuccaol C abrogated the PAF-induced cell motility whereas Yuccaol A and Yuccaol B reduced the cell migration from 7.6 microm/h to 6.1 microm/h and 5.6 microm/h, respectively. These results indicate that the anti-inflammatory properties attributed to Yucca schidigera can be ascribed to both resveratrol and Yuccaols and provide the first evidences of the anti-tumor and anti-invasive properties of these novel phenolic compounds.

Antineoplastic Agents↗
PubMed2005

Pterostilbene and 3'-hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR-ABL-expressing leukemia cells.

Pterostilbene and 3,5-hydroxypterostilbene are the natural 3,5-dimethoxy analogs of trans-resveratrol and piceatannol, two compounds which can induce apoptosis in tumor cells. In previous studies we demonstrated the importance of a 3,5-dimethoxy motif in conferring pro-apoptotic activity to stilbene based compounds so we now wanted to evaluate the ability of pterostilbene and 3,5-hydroxypterostilbene in inducing apoptosis in sensitive and resistant leukemia cells. When tested in sensitive cell lines, HL60 and HUT78, 3'-hydroxypterostilbene was 50-97 times more potent than trans-resveratrol in inducing apoptosis, while pterostilbene appeared barely active. However, both compounds, but not trans-resveratrol and piceatannol, were able to induce apoptosis in the two Fas-ligand resistant lymphoma cell lines, HUT78B1 and HUT78B3, and the multi drug-resistant leukemia cell lines HL60-R and K562-ADR (a Bcr-Abl-expressing cell line resistant to imatinib mesylate). Of note, pterostilbene-induced apoptosis was not inhibited by the pancaspase-inhibitor Z-VAD-fmk, suggesting that this compound acts through a caspase-independent pathway. On the contrary, 3'-hydroxypterostilbene seemed to trigger apoptosis through the intrinsic apoptotic pathway: indeed, it caused a marked disruption of the mitochondrial membrane potential delta psi and its apoptotic effects were inhibited by Z-VAD-fmk and the caspase-9-inhibitor Z-LEHD-fmk. Moreover, pterostilbene and 3'-hydroxypterostilbene, when used at concentrations that elicit significant apoptotic effects in tumor cell lines, did not show any cytotoxicity in normal hemopoietic stem cells. In conclusion, our data show that pterostilbene and particularly 3'-hydroxypterostilbene are interesting antitumor natural compounds that may be useful in the treatment of resistant hematological malignancies, including imatinib, non-responsive neoplasms.

Apoptosis↗
PubMed2005

Chemo-enzymatic synthesis and cell-growth inhibition activity of resveratrol analogues.

The stilbenoid resveratrol (1) was subjected to regioselective acetylation catalysed by Candida antarctica lipase (CAL) to obtain 4'-acetylresveratrol (2). CAL biocatalysed regioselective alcoholysis of 3,5,4'-triacetylresveratrol (3), 3,5,4'-tributanoylresveratrol (6), and 3, 4, 5'-trioctanoylresveratrol (9) afforded derivatives 4, 5, 7, 8, 10, and 11. Further resveratrol analogues (12-18) were obtained through methylation and hydrogenation reactions, whereas the 3,4,4'-trimethoxystilbene (19) was obtained by complete synthesis. Resveratrol and its lipophylic analogues were subjected to cell-growth inhibition bioassays towards DU-145 human prostate cancer cells. Compounds 2-19 showed cell-growth inhibition activity comparable to or higher than resveratrol (GI(50)=24.09 microM), displaying low or very low toxicity against non-tumorigenic human fibroblast cells. Comparison of the trimethoxy stilbenes 12 (GI(50)=2.92 microM) and 19 (GI(50)=25.39 microM) indicates that the position of the substituents is important for the activity. The marked activity of methyl ethers 12, 13, and 18 in comparison with that of the corresponding esters suggests that the different chemical reactivity, rather than steric factors, strongly influences the activity.

Anticarcinogenic Agents↗
PubMed2004

A mechanistic study on the nuclease activities of some hydroxystilbenes.

The nuclease activities of a series of hydroxystilbeneoids have been studied so as to establish a structure-activity correlation and deduce the mechanistic pathway of the process. Although the test compounds could nick plasmid DNA, only three of these including resveratrol produced double strand breaks in DNA. Amongst these new stilbenes, compound 2e containing a partially methylated catechol and a C-4 hydroxy moieties was equally potent as resveratrol. The activities of the unprotected catechol-derivatives were less than those of the resorcinol-derivatives, which were, however, compensated by partial methylation of the former. The presence of Cu(2+) and O(2) and the participation of a Cu(+)-oxo intermediate were obligatory in the process which did not require addition of any external reducing agent. Overall, the differential nuclease activities of the compounds could be explained primarily with their superoxide anion generation abilities, and to a lesser extent with their DNA binding and Cu(2+) reducing capacities. The amount of superoxide anion produced by the compounds depended strongly on their Cu(+)-complexation abilities, which again, was decided by the pattern and nature of the oxygenated substituents in the aromatic rings.

Catechols↗
PubMed2005

Structural basis for DNA-cleaving activity of resveratrol in the presence of Cu(II).

Resveratrol (1, 3,5,4'-trihydroxy-trans-stilbene), a polyphenol found in grapes and other food products, is known as an antioxidant and cancer chemopreventive agent. However, 1 was shown to induce genotoxicity through a high frequency of micronucleus and sister chromatid exchange in vitro and DNA-cleaving activity in the presence of Cu(II). The present study was designed to explore the structure-activity relationship of 1 in DNA strand scission and to characterize the substrate specificity for Cu(II) and DNA binding. When pBR322DNA was incubated with 1 or its analogues differing in the number and positions of hydroxyl groups in the presence of Cu(II), the ability of 4-hydroxystilbene analogues to induce DNA strand scission is much stronger than that of 3-hydroxy analogues. The high binding affinity with both Cu(II) and DNA was also observed by 4-hydroxystilbene analogues. The reduction of Cu(II) which is essential for activation of molecular oxygen proceeded by addition of 1 to the solution of the Cu(II)-DNA complex, while such reduction was not observed with the addition of isoresveratrol, in which the 4-hydroxy group of 1 is changed to the 3-position. The results show that the 4-hydroxystilbene structure of 1 is a major determinant of generation of reactive oxygen species that was responsible for DNA strand scission.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Chemical transformations of oxyresveratrol (trans-2,4,3',5'-tetrahydroxystilbene) into a potent tyrosinase inhibitor and a strong cytotoxic agent.

From oxyresveratrol (trans-2,4,3',5'-tetrahydroxystilbene 1), seven derivatives were prepared, including trans-2-methoxy-4,3',5'-trihydroxystilbene (2), trans-2,3'-dimethoxy-4,5'-dihydroxystilbene (3), trans-4,3'-dimethoxy-2,5'-dihydroxystilbene (4), trans-2,4,3',5'-tetramethoxystilbene (5) and cis-2,4,3',5'-tetramethoxystilbene (6), 2,4,3',5'-tetrahydroxybibenzyl (7), and 2,4,3',5'-tetramethoxybibenzyl (8). The tetrahydroxybibenzyl 7, a hydrogenation product of 1, exhibited more potent tyrosinase inhibitory activity than the parent compound, without cytotoxicity. A kinetic study revealed that 7 was a reversible and non-competitive inhibitor of mushroom tyrosinase with l-dopa as the substrate. Analysis of the K(i) values indicated that 7 has a slightly higher affinity to the enzyme than 1. Compound 6, a tetra-O-methylated analogue of 1 with cis-configuration, was deprived of inhibitory effect on the enzyme tyrosinase, but showed very strong cytotoxicity against the human cancer cells KB, BC, and NCI-H187, with potency comparable to those of the anticancer agents ellipticine and doxorubicin. Data on the tyrosinase inhibitory activity and cytotoxicity of 1-8 indicated that O methylation on stilbene 1 destroyed anti-tyrosinase activity but generated cytotoxicity. Thus, facile preparations of a potent tyrosinase inhibitor (7) and a strong cytotoxic agent (6) from the natural product 1 were achieved through simple chemical reactions.

Cell Line, Tumor↗
PubMed2006

Syntheses of hydroxy substituted 2-phenyl-naphthalenes as inhibitors of tyrosinase.

Oxyresveratrol and resveratrol, with hydroxy substituted trans-stilbene structure, exert potent inhibitory effects on cyclooxygenase, rat liver mitochondrial ATPase activity, and tyrosinase. As the isosteres of oxyresveratrol, a new family of hydroxyl substituted phenyl-naphthalenes were synthesized to show excellent inhibition of mushroom tyrosinase. Compound 10, which is isostere of resveratrol, showed IC50 value of 16.52 microM in mushroom tyrosinase activity. As compared to this, the reference compound, resveratrol, showed IC50 value of 55.61 microM. Compound 4, which is isostere of oxyresveratrol, showed IC50 value of 0.49 microM. Among the other three derivatives, compound 13 showed IC50 value of 0.034 microM.

Agaricales↗
PubMed2004

Effects of resveratrol on the expression of a panel of genes interacting with the BRCA1 oncosuppressor in human breast cell lines.

BACKGROUND: trans-Resveratrol, or 3,5,4'trihydroxy-trans-stilbene, is a polyphenolic compound that seems to provide a protective effect against several types of cancer, notably breast cancer. Through its phytoestrogenic properties it regulates the expression of hormone-dependent genes, such as the oncosuppressor BRCA1, in breast cells. This gene is involved in the majority of hereditary breast cancer, as well as sporadic cancers. METHODS: We used three human breast tumor cell lines (HBL100, MCF7 and MBA-MB-231) and one breast cell line (MCF10a) derived from a fibrocystic disease to study in vitro the effect of resveratrol on the transcription of a group of genes whose proteins interact in different pathways with BRCA1. BRCA1, BRCA2, ER alpha, ER beta, p53, p21(waf1/cip1), CBP/P300, RAD51, pS2 and Ki67 mRNA were quantified using real-time quantitative RT-PCR with an ABI 7700 apparatus. RESULTS: Resveratrol modulated the expression of these genes in a pattern dependent on the status of alpha and beta estrogen receptors. These results show that resveratrol regulates gene expression via the estrogen receptor pathway and also an undetermined pathway. CONCLUSION: Thus, resveratrol seems to have an effect on breast tumor cell lines, on a fibrocystic cell line by affecting several factors regulating the function of BRCA1.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Piceatannol stimulates osteoblast differentiation that may be mediated by increased bone morphogenetic protein-2 production.

Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene) is a polyphenol present in grapes and wine. By means of alkaline phosphatase activity and osteocalcin enzyme-linked immunosorbent assay (ELISA), we have shown that piceatannol exhibits a significant induction of differentiation in immortalized fetal osteoblasts (hFOB), and osteosarcoma cells (MG-63). Alkaline phosphatase and osteocalcin are phenotypic markers for early-stage differentiated osteoblasts and terminally differentiated osteoblasts, respectively, our results indicate that piceatannol stimulate osteoblast differentiation at various stages (from maturation to terminally differentiated osteoblasts). Induction of differentiation by piceatannol was associated with increased bone morphogenetic protein-2 (BMP-2) production. Addition of purified BMP-2 protein did not increase the upregulation of alkaline phosphatase activity and osteocalcin secretion by piceatannol, whereas the BMP-2 antagonist noggin blocked piceatannol and BMP-2-mediated alkaline phosphatase activity, and osteocalcin secretion enhancement, indicating that BMP-2 production is required in piceatannol-mediated osteoblast maturation and differentiation. In conclusion, piceatannol increased BMP-2 synthesis, and this effect may contribute to its action on the induction of osteoblasts maturation and differentiation, followed by an increase of bone mass. Decreases in new bone formation, followed by estrogen deficiency or various pathologic factors, may contribute to the mechanisms involved in postmenopausal osteoporosis.

Alkaline Phosphatase↗
PubMed2005

Synergistic action of resveratrol, an ingredient of wine, with Ara-C and tiazofurin in HL-60 human promyelocytic leukemia cells.

OBJECTIVE: Resveratrol, a naturally occurring stilbene derivative, is a potent free-radical scavenger causing a number of biochemical and antineoplastic effects. It was shown to induce differentiation and apoptosis in leukemia cells. Resveratrol was also identified as an inhibitor of ribonucleotide reductase (RR), a key enzyme of DNA synthesis. We report about the biochemical effects of resveratrol on the concentration of deoxyribonucleoside triphosphates (dNTPs), the products of RR, and on the incorporation of 14C-labeled cytidine into the DNA of HL-60 human promyelocytic leukemia cells. MATERIALS AND METHODS: Incorporation of 14C-labeled cytidine into the DNA of resveratrol-treated HL-60 cells was measured. Concentration of dNTPs was determined by a HPLC method. Cytotoxic effects of resveratrol, Ara-C, and tiazofurin were analyzed using growth inhibition and clonogenic assays. Induction of apoptosis was studied using a Hoechst/propidium iodide staining method. RESULTS: We found that resveratrol effectively inhibited incorporation of 14C-labeled cytidine into DNA. Furthermore, incubation of HL-60 cells with resveratrol significantly decreased intracellular dCTP, dTTP, dATP, and dGTP concentrations. Based on these results, we investigated the combination effects of resveratrol with Ara-C or tiazofurin, both antimetabolites, which are known to exhibit synergistic effects in combination with other inhibitors of RR. In growth inhibition, apoptosis, and clonogenic assays, resveratrol acted synergistically with both Ara-C and tiazofurin in HL-60 cells. CONCLUSIONS: We conclude that resveratrol could become a viable candidate as one compound in the combination chemotherapy of leukemia and therefore deserves further testing.

Antineoplastic Agents↗
PubMed2006

Cytotoxic and biochemical effects of 3,3',4,4',5,5'-hexahydroxystilbene, a novel resveratrol analog in HL-60 human promyelocytic leukemia cells.

OBJECTIVE: Resveratrol (3,4',5,-trihydroxystilbene, RV), an ingredient of wine, is an inhibitor of the proliferation-linked enzyme ribonucleotide reductase (RR) and shows a broad spectrum of cytotoxic effects against human cancer cells. In order to enhance these effects, we introduced additional hydroxyl moieties into the molecule. In the present study, the activity of a novel RV analog, 3,3',4,4',5,5'-hexahydroxystilbene (M8), was investigated in HL-60 human promyelocytic leukemia cells. METHODS: Cytotoxicity of M8 alone or in combination with Ara-C was assessed employing growth inhibition assays. Effects of M8 on nucleoside triphosphates (NTPs) and deoxynucleoside triphosphates (dNTPs) were examined by HPLC. The apoptotic potential of M8 and RV was compared using a specific double-staining method and inhibition of TNF-alpha-induced activation of NF-kappaB was studied. Cell-cycle distribution was analyzed by FACS. RESULTS: Addition of ascorbic acid decreased the IC(50) value of M8 from 6.25 microM to 2 microM. M8 depleted dATP and dTTP pools to 41% and 21% of control values, whereas dCTP pools increased to 199% of untreated controls. In addition, TTP, ATP, CTP, and GTP concentrations were decreased while UTP concentrations increased. M8 induced apoptosis at concentrations significantly lower than RV and could remarkably inhibit the activation of NF-kappaB. M8 arrested cells in the S phase of the cell cycle while depleting cells in the G2-M phase and exhibited synergistic combination effects when applied simultaneously with Ara-C. CONCLUSION: Due to these promising results, this novel polyhydroxylated stilbene derivative might become an additional option for the treatment of leukemia and therefore deserves further preclinical and in vivo testing.

Antineoplastic Combined Chemotherapy Protocols↗