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1.
2.
Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phenolic compound which is present at high levels in wine and has been recently proposed as a potential cancer chemopreventive and chemoterapeutic agent. In this study, we evaluated the antiproliferative activity of resveratrol on a panel of cell lines of various histogenetic origin, including normal rat fibroblasts and mouse mammary epithelial cells compared to human breast, colon and prostate cancer cells. The concentration of resveratrol inhibiting cell growth by 50% (IC(50)) ranged from about 20 to 100 microM. At such concentration, we were unable to detect a significant increase in the apoptotic index in most of the cell lines analyzed.We also studied the effects of resveratrol on cell cycle distribution. The most striking effect was a reduction in the percentage of cells in the G2/M phase which was most frequently associated with an increase of cells in the S phase of the cell cycle. We also found that resveratrol is able to prevent the increase in reactive oxygen species (ROS) following exposure to oxidative agents (i.e. tobacco-smoke condensate (TAR) and H(2)O(2)). Resveratrol also reduced nuclear DNA fragmentation, as assessed by single cell gel electrophoresis (comet test). Taken together our results suggest that resveratrol can act as an antimutagenic/anticarcinogenic agent by preventing oxidative DNA damage which plays a pivotal role in the carcinogenic activity of many genotoxic agents.  相似文献   

3.
This study aims to evaluate and compare the antiproliferative and proapoptotic effects of resveratrol (trans-3,4',5-trihydoxystilbene) with two of its naturally occurring oligomers, epsilon-viniferin (a dimer) and miyabenol C (a trimer). Proliferation assays performed on myeloid and lymphoid cell lines show that the three compounds inhibit cell growth of all cell types tested, with miyabenol C being the most efficient (IC50 ranging from 10.8 to 29.4 muM). Further analysis performed on the multiple myeloma cell line U266 shows that all compounds modify cell cycle distribution probably via actions on different targets. Whereas cells treated with resveratrol accumulate in S phase, cells treated with epsilon-viniferin and miyabenol C accumulate in G2/M and G0/G1, respectively. Miyabenol C is also the most efficient at inducing cell death in U266 cells. All compounds induce apoptosis of U266 cells via mechanisms entirely dependent on caspase activation and associated with mitochondrial membrane potential disruption. Compounds do not act directly on the mitochondrial membrane, but could induce activation of upstream caspases such as caspase 8 and/or caspase 2, depending on the compound. In no case did upstream caspase 8 activation involve Fas/FasL interaction. Taken together, these results show that epsilon-viniferin and, more importantly, miyabenol C represent potent antitumor agents that require further investigation, either alone or in combination with resveratrol.  相似文献   

4.
The objective of this project was to identify some possible mechanisms by which two common phytochemicals, resveratrol and beta-sitosterol, inhibit the growth of human prostate cancer PC-3 cells. These mechanisms include the effect of the phytochemicals on apoptosis, cell cycle progression, prostaglandin synthesis and the production of reactive oxygen species (ROS). Prostaglandins have been known to play a role in regulating cell growth and apoptosis. PC-3 cells were supplemented with 50 microM resveratrol or 16 microM beta-sitosterol alone or in combination for up to 5 days. Phytochemical supplementation resulted in inhibition in cell growth. beta-Sitosterol was more potent than resveratrol and the combination of the two resulted in greater inhibition than supplementation with either alone. Long-term supplementation with resveratrol or beta-sitosterol elevated basal prostaglandin release but beta-sitosterol was much more potent than resveratrol in this regard. beta-Sitosterol was more effective than resveratrol in inducing apoptosis and the combination had an intermediate effect after 1 day of supplementation. Cells supplemented with resveratrol were arrested at the G1 phase and at the G2/M phase in the case of beta-sitosterol while the combination resulted in cell arrest at the two phases of the cell cycle. beta-Sitosterol increased ROS production while resveratrol decreased ROS production. The combination of the two phytochemicals resulted in an intermediate level of ROS. The observed changes in prostaglandin levels and ROS production by these two phytochemicals may suggest their mediation in the growth inhibition. The reduction in ROS level and increase by resveratrol supplementation in PC-3 cells reflects the antioxidant properties of resveratrol. It was concluded that these phytochemicals may induce the inhibition of tumor growth by stimulating apoptosis and arresting cells at different locations in the cell cycle and the mechanism may involve alterations in ROS and prostaglandin production.  相似文献   

5.
The current study investigated the relationship of the cell cycle phase (as G(0)/G(1), S, and G(2)/M) and cytotoxicity (as sub-G(1) DNA) to determine whether alterations in cell replication were associated with organophosphate (OP) compound induced cytotoxicity. Results demonstrated that, overall, OP compound--induced cell cycle changes were variable and depended on the OP compound, exposure concentration, and temporal relationship to cytotoxicity. Noncytotoxic OP compound treatments substantially decreased the percentage of cells in S phase of the cell cycle when compared to controls. A corresponding increase was seen in the percent of cells in G(0)/G(1) phase of the cell cycle. In the precytotoxic interval of exposure, most cytotoxic OP compound treatments substantially decreased the percentage of cells in G(2)/M phase of the cell cycle. Corresponding increases were seen primarily in G(0)/G(1) phase cells. Effects on cells in S stage of the cell cycle varied with the OP compound. In the during cytotoxic interval of exposure, most cytotoxic OP compound treatments substantially increased the percentage of cells in S phase of the cell cycle. A corresponding decrease in the percent of cells in G(0)/G(1) stage of the cell cycle was observed. Furthermore, treatments either increased or decreased the percentage of cells in G(2)/M phase of the cell cycle when compared to controls, with decreases more likely with the most cytotoxic OP compound exposures. Overall, the in vitro data suggest that exposure to OP compounds can alter the cell cycle status of SH-SY5Y neuroblastoma cells depending on compound, concentration, and interval from initial exposure. Changes in cell cycle, however, did not differentiate between OP compounds that are known for their ability to acutely inhibit acetylcholinesterase versus those inducing type I and type II delayed neurotoxicity.  相似文献   

6.
Kuo PL  Chiang LC  Lin CC 《Life sciences》2002,72(1):23-34
Resveratrol, a phytoalexin found in many plants, has been reported to possess a wide range of pharmacological properties and is one of the promising chemopreventive agents for cancer. Here, we examined the antiproliferation effect of resveratrol in two human liver cancer cell lines, Hep G2 and Hep 3B. Our results showed that resveratrol inhibited cell growth in p53-positive Hep G2 cells only. This anticancer effect was a result of cellular apoptotic death induced by resveratrol via the p53-dependent pathway. Here we demonstrated that the resveratrol-treated cells were arrested in G1 phase and were associated with the increase of p21 expression. In addition, we also illustrated that the resveratrol-treated cells had enhanced Bax expression but they were not involved in Fas/APO-1 apoptotic signal pathway. In contrast, the p53-negative Hep 3B cells treated with resveratrol did not show the antiproliferation effect neither did they show significant changes in p21 nor Fas/APO-1 levels. In summary, our study demonstrated that the resveratrol effectively inhibited cell growth and induced programmed cell death in Hepatoma cells on a molecular basis. Furthermore, these results implied that resveratrol might also be a new potent chemopreventive drug candidate for liver cancer as it played an important role to trigger p53-mediated molecules involved in the mechanism of p53-dependent apoptotic signal pathway.  相似文献   

7.
Resveratrol, a naturally occurring polyphenolic compound, has been reported to exert anticancer activity by affecting diverse molecular targets. In this study, we examined the effects and the underlying mechanisms of resveratrol on gastric cancer. We found that resveratrol inhibited the proliferation of gastric cancer cells in a dose-dependent manner. At the concentration of 25 and 50 µM, resveratrol inhibited the cell viability and diminished the clonogenic potential of gastric cancer cells. Resveratrol treatment arrested gastric cancer cells in the G1 phase and led to senescence instead of apoptosis. Regulators of the cell cycle and senescence pathways, including cyclin D1, cyclin-dependent kinase (CDK4 and 6), p21 and p16, were dysregulated by resveratrol treatment. The inhibitory effects of resveratrol on gastric cancer were also verified in vivo using a nude mice xenograft model. Resveratrol (40 mg/kg/d) exerted inhibitory activities on gastric cancer development and significantly decreased the fractions of Ki67-positive cells in the tumor specimens from the nude mice. After resveratrol treatment, the induction of senescence and the changes in the expression of the regulators involved in the cell cycle and senescence pathways were similar to what we observed in vitro. However, the depletion of Sirtuin (Sirt)1 reversed the above-described effects of resveratrol both in vitro and in vivo. Our data suggest that resveratrol inhibits gastric cancer in a Sirt1-dependent manner and provide detailed evidence for the possibility of applying resveratrol in gastric cancer prevention and therapy.  相似文献   

8.
Resveratrol is a phytoalexin, that belongs to a family of naturally occurring stilbenes. It has been reported that resveratrol can inhibit chemical carcinogenesis in experimental animals and although the mechanisms involved are unknown, an anti-mutagen mechanism has been proposed. We have explored this hypothesis using mutagenicity assays based on bacterial (Salmonella typhimurium) and eukaryotic cells (Chinese hamster V79 cells). We found resveratrol to be potent in both systems, blocking the mutagenicity of the food-derived heterocyclic amines (HA) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) at micromolar concentrations. Furthermore, in cells capable of activating 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine to cytotoxic derivatives, resveratrol was able to attenuate cytotoxicity. Paradoxically, in cells lacking the ability to activate PhIP, resveratrol itself was toxic and co-incubation with PhIP reduced this toxicity. Our data confirm the potent anti-mutagenic activity of resveratrol and support its potential as a chemopreventative.  相似文献   

9.
Resveratrol (3,4′,5-trans-trihydroxystilbene) is a phytoalexin with emerging lines of evidence supporting its beneficial effects on cardiovascular systems and inhibition of carcinogenesis. It has also been reported that certain methylated resveratrol derivatives are more effective than resveratrol in the prevention/treatment of cancer. However, little is known about the impact of resveratrol and its derivatives on the development of Parkinson's disease. In this study, we compared the neuroprotective effects of resveratrol with four methylated (fully or partially) resveratrol derivatives against parkinsonian mimetic 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. Release of lactate dehydrogenase and activity of caspase-3 triggered by 6-OHDA were significantly reduced by resveratrol and one of the methylated derivatives, pinostilbene (3,4′-dihydroxy-5-methoxystilbene), in a dose-dependent manner. In addition, pinostilbene exerted a potent neuroprotective effect with a wider effective concentration range than resveratrol. By using high-performance liquid chromatography, we found that uptake of pinostilbene into SH-SY5Y cells was significantly higher than that of resveratrol. Enhanced bioavailability may thus be a major factor contributing to the neuroprotective activity of pinostilbene. Moreover, Western blot analysis demonstrated that pinostilbene markedly attenuated the phosphorylation of JNK and c-Jun triggered by 6-OHDA. Besides, mammalian target of rapamycin kinase may be an intracellular target accounting for the neuroprotective effects of pinostilbene. Our findings demonstrate the potential of methylated stilbenes in neuroprotection and provide important information for further research in this field.  相似文献   

10.
Aesculus hippocastanum (the horse chestnut) seed extract has a wide variety of biochemical and pharmacological effects including anti-inflammatory, antianalgesic, and antipyretic activities. The main active compound of this plant is escin. It is known that several medicinal herbs with anti-inflammatory properties have been found to have a role in the prevention and treatment of cancer. In the present study, the cytotoxic effects of escin in the C6 glioma and A549 cell lines were analyzed by MTT. Apoptotic effects of escin on both cell lines were evaluated by Annexin V binding capacity with flow cytometric analysis. Structural and ultrastructural changes were also evaluated using transmission electron microscopy. The results indicated that escin has potent antiproliferative effects against C6 glioma and A549 cells. These effects are both dose and time dependent. Taken together, escin possesses cell cycle arrest on G0/G1 phase and selective apoptotic activity on A549 cells as indicated by increased Annexin V-binding capacity, bax protein expression, caspase-3 activity and morphological changes obtained from micrographs by transmission electron microscopy.  相似文献   

11.
In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC50=2.25 µM) and U239 (IC50=5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC50=0.76 µM) in LPS stimulated PMBC and showed nearly no toxicity to this normal human cell line. The TR-FRET assay showed compound 10a having potent inhibitory activity against CRBN (IC50=4.83 µM), and the docking study confirmed a nice fitting of 10a into the active sites of CRBN. Further biology studies revealed compound 10a can increase the apoptotic events, arrest the NCI-H929 cells at G0/G1 cell cycle, and induce the ubiquitination degradation of IKZF1 and IKZF3 proteins by CRL4CRBN. These preliminary results suggested that compound 10a could serve as a potential antitumor drug and worthy of further investigation.  相似文献   

12.
The forward chemogenomics strategy allowed us to identify a potent cytotoxic thiazolidine compound as an apoptosis-inducing agent. Chemical structures were designed around a thiazolidine ring, a structure already noted for its anticancer properties. Initially, we evaluated these novel compounds on liver, breast, colon and endometrial cancer cell lines. The compound 3 (ALC67) showed the strongest cytotoxic activity (IC(50) ~5μM). Cell cycle analysis with ALC67 on liver cells revealed SubG1/G1 arrest bearing apoptosis. Furthermore we demonstrated that cytotoxicity of this compound was due to the activation of caspase-9 involved apoptotic pathway, which is death receptor independent.  相似文献   

13.
In this work, the effects of a pair of positional isomer of ganoderic acids (GAs), namely ganoderic acid Mf (GA-Mf) and ganoderic acid S (GA-S) purified from the fermented mycelia of Ganoderma lucidum, on induction of cell apoptosis and the apoptotic pathway in HeLa cells were investigated. The results demonstrate that both isomers decreased cell population growth on various human carcinoma cell lines by MTT assay, while GA-Mf had better selectivity between normal and cancer cells. The flow cytometry analysis indicated that treatment of HeLa cells with GA-S caused cell cycle arrest in the S phase, while GA-Mf caused cell cycle arrest in the G1 phase. Compared with GA-S, GA-Mf had more potent increase in the number of early and late apoptotic cells. Treatment of HeLa cells with each isomer decreased the mitochondria membrane potential and caused the release of cytochrome c from mitochondria into the cytosol. In addition, stimulation of caspase-3 and caspase-9 activity was observed. The Bax/Bcl-2 ratio was also increased in GA-treated HeLa cells. The results demonstrated that both isomers GA-Mf and GA-S induced apoptosis of human HeLa cells through a mitochondria mediated pathway, but they had the different cell cycle arrest specificity. The findings will be helpful to the development of useful cancer chemopreventive compounds from G. lucidum.  相似文献   

14.
The distribution of Ehrlich ascites tumor cells in the cell cycle was studied by flow cytometry following treatment with α-methyl ornithine (αMO) or methylglyoxal-bis(guanylhydrazone) (MeGAG). αMO and MeGAG are potent inhibitors of ornithine decarboxylase (putrescine synthesis) and S-adenosyl-methionine decarboxylase (spermidine and spermine synthesis), respectively. The data show that these polyamine synthesis inhibitors produce significant cell cycle perturbations resulting in an accumulation of cells in S and G2. This fact suggests that a normal polyamine complement is essential for the progression through these phases of the cell cycle.  相似文献   

15.
Lee EJ  Min HY  Joo Park H  Chung HJ  Kim S  Nam Han Y  Lee SK 《Life sciences》2004,75(23):2829-2839
Stilbenoids, including resveratrol (3,5,4'-trihydroxy-trans-stilbene) which is a naturally occurring phytoalexin abundant in grapes and several plants, have been shown to be active in inhibiting proliferation and inducing apoptosis in human cancer cell lines. Using resveratrol as the prototype, we have synthesized various analogs and evaluated their growth inhibitory effects in cultured human cancer cells. In the present study, we show that one of the stilbenoids, 3,4,5-trimethoxy-4'-bromo-cis-stilbene (BCS), was more effective than its corresponding trans-isomer and resveratrol on the inhibition of cancer cell growth. Prompted by the strong growth inhibitory activity of BCS (IC50; 0.03 microM) compared to its trans-isomer (IC50; 6.36 microM) and resveratrol (IC50; 33.0 microM) in cultured human lung cancer cells (A549), we investigated its mechanism of action. BCS induced arrest at the G2/M phase cell cycle in the early time and subsequently increased in the sub-G1 phase DNA contents in a time-dependent manner, indicating induction of apoptosis. Morphological observation with round-up shape and DNA fragmentation was also revealed the apoptotic phenomena. BCS treatment elevated the expression levels of the pro-apoptotic protein p53, the cyclin-dependent kinase inhibitor p21, and the release of cytochrome c in the cytosol. The down-regulation of checkpoint protein cyclin B1 by BCS was well correlated with the cell cycle arrest at G2/M. These data suggest the potential of BCS to serve as a cancer chemotherapeutic or chemopreventive agent by virtue of arresting the cell cycle and induction of apoptosis of human lung cancer cells.  相似文献   

16.
Pterostilbene, a methoxylated analogue of resveratrol, is a natural compound primarily found in blueberries and several types of grapes. However, little is known about the effect of pterostilbene on the proliferation of hepatoma cells and its modes of actions. This study was undertaken to characterize its ability to suppress the proliferation of hepatoma AH109A cells and the possible mechanism(s) involved. Pterostilbene showed a significant and dose-dependent effect on the anti-proliferative activity against AH109A cells. Pterostilbene exerted little or no effect on the proliferation of rat L6 myoblasts and rat skin fibroblasts. Pterostilbene-loaded rat sera could significantly inhibit the proliferation of AH109A cells, which suggests that pterostilbene could be absorbed through gastrointestinal tract and retain its anti-proliferative activity. Pterostilbene arrested the cell cycle of AH109A cells at G0/G1 phase and reduced the protein expression of cyclin-dependent kinase 4 and cyclin-dependent kinase 6 dose-dependently. We also found that pterostilbene could significantly increase the intracellular peroxide level of AH109A cells, which may be involved in its anti-proliferative activity.  相似文献   

17.
A series of bisindole-pyrrolobenzodiazepine conjugates (5a-f) linked through different alkane spacers was prepared and evaluated for their anticancer activity. All compounds exhibited significant anticancer potency and the most potent compounds 5b and 5e were taken up for detailed studies on MCF-7 cell line. Cell cycle effects were examined apart from investigating the inhibition of tubulin polymerization for compounds 2a, 2b, 5b and 5e at 2μM. FACS analysis showed that at higher concentrations (4 and 8μM) there was an increase of sub-G1 phase cells and decrease of G2/M phase cells, thus indicating that compounds 5b and 5e are effective in causing apoptosis in MCF-7 cells. It was also observed that compounds 5b and 5e showed the down regulation of histone deacetylase protein levels such as HDAC1, 2, 3, 8 and increase in the levels of p21, followed by apoptotic cell death. The apoptotic nature of these compounds was further evidenced by increased expression of cleaved-PARP and active caspase-7 in MCF-7 cells.  相似文献   

18.
An accumulating body of evidence suggests that resveratrol can inhibit carcinogenesis through antiproliferative and apoptotic effects. One proposed mechanism for this is the modulation of genes, for example, Ras and p53, frequently associated with human cancer. To test the effect of resveratrol on gene expression, we used the WR-21 cell line because it contains a mutated human c-Ha-ras gene. Cells at > or =70% confluency were incubated with media alone or with increasing concentrations of trans-resveratrol (0.1-1000 microM) for 24 h. Resveratrol (30-100 microM) decreased cellular proliferation by 80% (bromodeoxyuridine incorporation) and increased apoptosis by 60% (TUNEL). Cells were then treated with media alone or with 50-microM resveratrol for 24 h. RNA was isolated for nylon-based macroarray analyses and protein for immunoblotting. Resveratrol increased (+) and decreased (-) gene expression associated with apoptosis (Birc5+, Cash+, Mcl-1+, Mdm2+, Rpa-like+), cellular proliferation (Ctsd+, Mdm2+, Egr1+, ODC+) and cell cycle (cyclin D+, cyclin g+, Gadd45a-, Mad2l-, Mdm2+). Resveratrol consistently increased by > or =6-fold Mdm2 expression and other downstream p53 effectors, but not p53 itself at 24 h. Subsequent cell cycle analysis indicated a significant accumulation of cells in G2/M, and a decrease in G1/G0 suggesting a G2/M blockade. Further RT-PCR and Western blot analyses indicated no differential changes in Ras mRNA expression or p21(ras) protein levels, respectively. These results suggest that resveratrol potently inhibits cellular proliferation, increases apoptosis, alters cell cycle dynamics and modulates associated gene expression. Furthermore, these effects appear mediated, in part, by p53 without direct modulation of mutant c-Ha-ras expression.  相似文献   

19.
20.
Resveratrol is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Sulforaphane belongs to the family of isothiocyanates and is highly enriched in cruciferous vegetables. Our previous study showed that resveratrol, when used at high concentrations, inhibited cell proliferation, caused the cell cycle arrest and induced apoptotic cell death in glioma cells. In the current study, we tested the effect of combination treatment with resveratrol and sulforaphane, when both were used at low concentrations, on cell proliferation, migration and death in human U251 glioma cells. Our study shows that combination treatment with resveratrol and sulforaphane inhibits cell proliferation and migration, reduces cell viability, induces lactate dehydrogenase release, decreases pro-survival Akt phosphorylation and increases caspase-3 activation. The use of combination of bioactive food components, such as resveratrol and sulforaphane, may be a viable approach for the treatment of glioma.  相似文献   

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