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PubMed1996

Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells.

Flavopiridol (NSC 649890, L86-8275), a potent inhibitor of cyclin-dependent kinase 1/p34cdc2 phosphorylation and kinase activity, is currently undergoing Phase I clinical testing as a potential antineoplastic agent. Previous studies have suggested that flavopiridol is cytostatic but not cytotoxic when applied to exponentially growing cells. In the present study, various human tumor cell lines were assayed for trypan blue exclusion and ability to form colonies after exposure to flavopiridol under a variety of growth conditions. When log phase A549 non-small cell lung cancer cells were examined 72 h after the start of a 24-h flavopiridol exposure, as many as 90% of the cells accumulated trypan blue. A 24-h exposure to 250-300 nM resulted in trypan blue uptake in 50% of A549 cells at 72 h and a 50% reduction in colony formation. Similar results were observed in HCT8 ileocecal adenocarcinoma, T98G glioblastoma, MCF-7 breast adenocarcinoma, and HL-60 leukemia cells. With A549 cells, identical results were obtained in actively growing logarithmic phase cells and growth-arrested confluent cells. Treatment with the DNA synthesis inhibitor aphidicolin only minimally affected the cytotoxicity of flavopiridol. In contrast, the RNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole or the protein synthesis inhibitor cycloheximide reduced the cytotoxicity of flavopiridol. These results suggest that: (a) flavopiridol is not only cytostatic, but also cytotoxic to a variety of human tumor cell lines; (b) flavopiridol is equally active against cycling and noncycling A549 cells; and (c) RNA and protein synthesis appear to play a role in flavopiridol-induced cytotoxicity.

Antineoplastic Agents↗
PubMedDate not supplied

Antioxidant activity of flavones from Scutellaria baicalensis in lecithin liposomes.

The antioxidant effect of a trihydroxyflavone extract from Scutellaria baicalensis on oxidation induced by ultraviolet light, was studied with phosphatidylcholine liposome membrane. Also, as standards, the antioxidative activity of baicalin, wogonin, baicalein and butylated hydroxytoluene (BHT) was investigated. Comparison of the protective effects of the compounds studied against photoinduced lipid peroxidation in lecithin liposome membranes showed that: (1) the inhibitory effect of those compounds (at 1.2 mol% antioxidant content in liposomes) on TBA reactive materials from lipid peroxidation decreased in the order of baicalin > BHT approximately equal to Scutellaria baicalensis. These were found much greater than wogonin and baicalein; (2) the depressed effect of those compounds (at 1.1 mol% compounds content in liposomes) on the production of conjugated dienes (proportional to oxidation index) could be classified as follows: Scutellaria baicalensis approximately equal to baicalin > BHT, these three were found more active much greater than baicalein and wogonin. Results obtained by ESR measurement confirm that Scutellaria baicalensis extract and the BHT compound significantly depressed the effect of liposome oxidation. It was found that the new trihydroxyflavones of Scutellaria baicalensis, ensured a very satisfactory concentration-dependent protection of the liposome membrane against UV-induced oxidation. These findings suggest that some of the beneficial effects of the extract of the Scutellaria baicalensis can be mediated in certain diseases (for example in skin diseases) by their ability to scavenge free radicals and by their protective effect on lipid peroxidation caused by sunlight irradiation.

Antioxidants↗
PubMed2003

Relaxant effects of flavonoids in isolated guinea pig trachea and their structure-activity relationships.

The structure-activity relationships between flavonoids and their tracheal relaxant action are little known. In the present study, 26 natural and synthetic flavonoids, divided into the five classes of flavones, flavonols, flavanones, isoflavones, and chalcones, were tested, and their IC (50) values were determined. The IC (50) values of these five classes indicated that flavones were more potent than flavonols. Flavones were also more potent than flavanones suggesting that the presence of a double bond between C-2 and C-3 is important. However, flavones were similar to isoflavones in potency. Chalcones, a class with an open C-ring, appeared to be the least potent among these five classes. Introduction of a hydroxy group at position C-6 of flavones increases their relaxant activities. So does adding a hydroxy group at position C-7 of flavones. It appears that the optimal number of hydroxy groups introduced to the A-ring of flavones is one. As more hydroxy groups are introduced to positions at C-5, C-6, and/or C-7 of flavones, the IC (50) values increase. It seems that flavones or flavonols with a pyrogallol moiety either in the A- or B-ring, respectively, have no activity. It appears that flavonols with ortho-hydroxy groups in the B-ring are more potent than those with meta-hydroxy groups. The activity of 6-hydroxyflavone disappears if the C-6 hydroxy group of the A-ring is methoxylated. If the C-4' hydroxy group of the B ring is methoxylated, the relaxant effect of these flavones is also attenuated or disappears. Therefore, the hydroxy group on either the A- or B-ring of flavones and flavonols being methylated resulted in lower potency of the tracheal relaxant effects. However, when all hydroxy groups on both the A- and B-rings of flavones or flavonols are methoxylated this results in higher potency. Therefore, the influence of methoxylation in flavones may be similar to that in flavonols. However, if the C-3 hydroxy group on the C-ring of flavonols, but not flavones which lack this hydroxy group, is methoxylated, the relaxant effects may increase. Glycosylation of the hydroxy group at position C-7 of flavones or flavanones attenuates the relaxant effects.

Animals↗
PubMed1984

In vitro and in vivo activation of oxidative drug metabolism by flavonoids.

Several naturally occurring and synthetic flavonoids were studied for their effects on the metabolism of zoxazolamine to 6-hydroxyzoxazolamine. Flavone, nobiletin, tangeretin and 7,8-benzoflavone (50-250 microM) stimulated the metabolism of zoxazolamine by liver microsomes obtained from 5-day-old rats. Evidence was obtained indicating that flavone changed the apparent Km and Vmax values for zoxazolamine hydroxylation. The i.p. administration of 5 mumol of flavone, nobiletin, tangeretin or 7,8-benzoflavone concurrently with 740 nmol of zoxazolamine immediately stimulated the total body metabolism of zoxazolamine to 6-hydroxyzoxazolamine. The magnitude of the flavone-mediated increases in zoxazolamine hydroxylation in vivo was dependent on the dose of flavone and the dose of zoxazolamine administered. The i.p. administration of 5 mumol of flavone caused a 3- to 5-fold stimulation in the in vivo metabolism of 740 to 3000 nmol of zoxazolamine, but flavone had little or no stimulatory effect when 74 nmol of zoxazolamine were administered. Flavone stimulated zoxazolamine metabolism both in vitro and in vivo when control or phenobarbital-treated rats were used, but flavone inhibited the in vitro and in vivo hydroxylation of zoxazolamine when rats induced with 5,6-benzoflavone were studied. Although flavone activated zoxazolamine metabolism in vivo in neonatal rats, flavone did not activate the in vivo metabolism of benzo(a)pyrene. The in vitro addition of the hydroxylated flavonoids apigenin, chrysin, fisetin, morin and quercetin inhibited the hydroxylation of zoxazolamine by liver microsomes from neonatal rats, but studies with quercetin and apigenin indicated that these flavonoids had no effect on the in vivo metabolism of zoxazolamine.

Animals↗
PubMed2006

The mitogen-activated protein kinase kinase (mek) inhibitor PD98059 elevates primary cultured rat hepatocyte glutathione levels independent of inhibiting mek.

The antioxidant activity of flavonoids, directly through scavenging oxidizing species and indirectly through modulating drug-metabolizing enzyme activities, is associated with chemopreventive and chemotherapeutic effects. However, little published information is available concerning the effect of flavonoids on glutathione (GSH) homeostasis. We previously demonstrated that PD98059 (2'-amino-3'-methoxyflavone), a flavone derivative and selective mitogen-activated protein kinase kinase (MEK) 1 inhibitor, enhanced the insulin-mediated increase in GSH levels. To determine whether the PD98059-mediated increase in GSH levels was associated with MEK inhibition, primary cultured rat hepatocytes were treated with PD98059, the MEK inhibitor U0126, which is not a flavone derivative, or flavone. PD98059 increased GSH levels in a concentration-dependent manner in hepatocytes cultured in the presence or absence of insulin. In contrast, GSH levels were not affected by U0126 at concentrations sufficient to inhibit insulin-mediated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Flavone, however, markedly increased GSH levels without inhibition of ERK1/2 phosphorylation. The concentration of GSH in the culture medium was also elevated by PD98059 or flavone, suggesting that the cellular GSH elevation could not be accounted for by the inhibition of GSH efflux into medium. Interestingly, PD98059 and flavone increased cellular cysteine levels, which may be responsible for the PD98059- and flavone-mediated elevation of GSH levels. These results provide evidence that PD98059 and flavone produce dramatic changes in GSH homeostasis in hepatocytes, through a mechanism(s) unrelated to MEK inhibition. Moreover, the current study implies that flavonoid-induced chemopreventive and chemotherapeutic effects may be mediated by regulation of redox state through the stimulation of GSH synthesis.

Animals↗
PubMed2005

Analysis of antioxidant compounds in sweet orange peel by HPLC-diode array detection-electrospray ionization mass spectrometry.

HPLC-diode array detection-electrospray ionization mass spectrometry was used to determine qualitatively and quantitatively the flavonoid content of several fractions and residues of extracts of Greek navel sweet orange peel (Citrus sinensis) from the region of southern Greece (Leonidi-Tripoli). The main groups of flavonoids found according to HPLC retention times, spectral data and literature references were polymethoxylated flavones, C-glycosylated flavones, O-glycosylated flavones, O-glycosylated flavanones, flavonols and phenolic acids and their derivatives. The ethyl acetate fraction which has been shown in previous work to possess the best radical scavenging activity among the others was found to contain C-glycosylated flavones, polymethoxylated flavones, O-glycosylated flavones, O-glycosylated flavanones, two phenolic acid derivatives and two unknown compounds, all in low concentrations. The group of C-glycosylated flavones was reported for the first time in the peel of Navel sweet orange. The C-glycosylated flavones found according to their spectral characteristics and literature were 6-C-beta-glucosyldiosmin, 6,8-di-C-glucopyranosylapigenin, 6,8-di-C-beta-glucosyldiosmin and two unknown. The results suggest that the ethyl acetate fraction of navel Citrus sinensis peel consists of significant antioxidant compounds and can be used as a food additive of natural origin or a pharmaceutical supplement using as a source of peel the byproducts of the orange juice industry.

Acetates↗
PubMed1995

Identification of 3'-methoxy-4'-nitroflavone as a pure aryl hydrocarbon (Ah) receptor antagonist and evidence for more than one form of the nuclear Ah receptor in MCF-7 human breast cancer cells.

The competitive binding of 3'-methoxy-4'-nitro, 4'-amino-3'-methoxy, 4'-methoxy-3'-nitro, and 3'-amino-4'-methoxyflavone (compounds 1 to 4, respectively) to the rat cytosolic aryl hydrocarbon (Ah) receptor gave IC50 values of 2.27, 86.1, 872, and 19.4 nM. Flavones 3 and 4 were characterized as Ah receptor agonists in MCF-7 human breast cancer cells and induced CYP1A1 gene expression, whereas the 3-methoxy-substituted flavones (1 and 2) were inactive. All four compounds inhibited induction of ethoxyresorufin O-deethylase (EROD) activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells; moreover, in vitro studies with TCDD-induced rat liver microsomes showed that flavones 1 to 4 inhibited EROD activity in the presence or absence of NADPH. In MCF-7 cells cotreated with flavones 1 or 2 (0.01 to 10 microM) plus TCDD or [3H]TCDD, there was a concentration-dependent inhibition of TCDD-induced CYP1A1 mRNA levels and formation of radiolabeled nuclear Ah receptor complex. Velocity sedimentation analysis of nuclear extracts from MCF-7 cells treated with [3H]TCDD plus 1 or 10 microM concentrations of flavones 1 and 2 showed that an early eluting specifically bound nuclear Ah receptor complex was present. However, under these same conditions the flavones inhibited TCDD-induced CYP1A1 gene expression. The apparent molecular mass of this nuclear complex was 190 kDa as determined by cross-linking to a 32P-labeled bromodeoxyuridine-substituted consensus dioxin-responsive element. Similar cross-linking results were obtained using the nuclear extract from MCF-7 cells treated with [3H]TCDD alone. The results of this study suggest that there are at least two forms of the nuclear Ah receptor complex in MCF-7 cells; the major transcriptionally active form binds [3H]TCDD and flavones 1 or 2 inhibit nuclear uptake of this receptor complex. The other form of the nuclear Ah receptor complex appears to be transcriptionally inactive and ligand binding with [3H]TCDD is not competitively inhibited by flavones 1 and 2.

Animals↗
PubMed1988

Effects of Ginkgo biloba constituents related to protection against brain damage caused by hypoxia.

The purpose of the present study was to approach the compound(s) responsible for the beneficial effects of an extract of Ginkgo biloba leaves (EGB) on animals subjected to hypoxia. In this first approach we compared the effects of the flavone and the non-flavone fraction of EGB with those of the whole extract on mice in lethal hypoxia (3.5% O2), on brain energy metabolism of artificially ventilated rats inspiring 7% O2, and on local cerebral blood flow (LCBF) of normoxic rats. The latter two experimental settings should also extend the knowledge about the underlying mechanisms of the antihypoxidotic actions. EGB as well as its non-flavone fraction considerably prolonged the survival time of mice under lethal hypoxia. EGB retarded the breakdown of brain energy metabolism in the hypoxic artificially ventilated rat. A corresponding effect was exerted by the non-flavone fraction while the flavone fraction even worsened the metabolic state. The non-flavone fraction increased LCBF in the majority of 35 examined brain regions; a similar effect could be seen after EGB-treatment, while the flavone fraction caused only minor alterations of LCBF. We conclude that the non-flavone fraction of EGB carries the antihypoxidotic activity. Metabolic effects are suggested to cause this activity. Further studies are necessary to elucidate the effective compound within this fraction.

Animals↗
PubMed2004

Fractionation of orange peel phenols in ultrafiltered molasses and mass balance studies of their antioxidant levels.

Orange peel molasses, a byproduct of juice production, contains high concentrations of phenols, including numerous flavanone and flavone glycosides, polymethoxylated flavones, hydroxycinnamates, and other miscellaneous phenolic glycosides and amines. Extensive fractionation of these phenols was achieved by adsorption, ion exchange, and size exclusion chromatography. Size exclusion chromatography effectively separated the different classes of flavonoids in ultrafiltered molasses, including the polymethoxylated flavones, flavanone-O-trisaccharides, flavanone- and flavone-O-disaccharides, and, finally, flavone-C-glycosides. Mass spectral analysis of the early-eluting flavonoid fractions off the size exclusion column revealed a broad collection of minor-occurring flavone glycosides, which included, in part, glycosides of limocitrin, limocitrol, and chrysoeriol. Most hydroxycinnamates in the molasses were recovered by ion exchange chromatography, which also facilitated the recovery of fractions containing many other miscellaneous phenols. Total antioxidant levels and total phenolic contents were measured for the separate categories of phenols in the molasses. Inhibition of the superoxide anion reduction of nitroblue tetrazolium showed that a significant amount of the total antioxidant activity in orange peel molasses was attributable to minor-occurring flavones. The miscellaneous phenolic-containing fractions, in which a large portion of the total phenolic content in molasses occurred, also constituted a major portion of the total antioxidants in ultrafiltered molasses.

Antioxidants↗
PubMed2000

Antimutagens in gaiyou (Artemisia argyi levl. et vant.).

Antimutagens from gaiyou (Artemisia argyi Levl. et Vant., Compositae) were examined. The methanol extract prepared from aerial parts of this plant strongly reduced the mutagenicity of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), when Salmonella typhimurium TA98 was used in the presence of the rat liver microsomal fraction. The antimutagens were purified chromatographically while monitoring the antimutagenic activity against Trp-P-2 with a modified Ames test employing a plate method. This purification resulted in the isolation of four strong antimutagens, 5,7-dihydroxy-6,3',4'-trimethoxyflavone (eupatilin), 5, 7,4'-trihydroxy-6,3'-dimethoxyflavone (jaceosidin), 5,7, 4'-trihydroxyflavone (apigenin) and 5,7, 4'-trihydroxy-3'-methoxyflavone (chrysoeriol) from the methanol extract. These antimutagenic flavones exhibited strong antimutagenic activity against not only Trp-P-2 but also against other heterocyclic amines, such as 3-amino-1,4-dimethyl-5H-pyrido[4, 3-b]indole (Trp-P-1), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA(alpha)C) in S. typhimurium TA98. In contrast, they did not exhibit antimutagenic activity against benzo[a]pyrene (B[a]P), 4-nitroquinoline-1-oxide (4-NQO), 2-aminofluorene (2-AF), 2-nitrofluorene (2-NF) or furylfuramide (AF-2) in S. typhimurium TA98, or B[a]P, 4-NQO, 2-NF, AF-2, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or sodium azide (SA) in Salmonella typhimurium TA100, whereas they decreased the mutagenicity caused by aflatoxin B(1) (AFB(1)) and 2-aminoanthracene (2-AA) in both of these tester strains. Regarding the structure-activity relationship, the tested flavones had distinct differences in the intensities of their antimutagenic activities according to the differences of their substitution patterns. Namely, the intensity of antimutagenic activities against Trp-P-2 decreased in the order of: 5,7,3',4'-tetrasubstituted flavones (IC(50): <0.1 mmol/plate), 5,7,4'-trisubstituted flavones (IC(50): 0.120-0.260 mmol/plate), 5,6,7,3',4'-pentasubstituted flavones (IC(50): 0.440-0. 772 mmol/plate). The four isolated flavones were also studied regarding their antimutagenic mechanisms with preincubation methods of the modified Ames test and emission spectroscopic analysis. The results suggested that all isolated flavones were desmutagens which directly inactivated Trp-P-2 or inhibited its metabolic activation.

Antimutagenic Agents↗
PubMed2002

Protection of flavonoids against lipid peroxidation: the structure activity relationship revisited.

The inhibition of the lipid peroxidation, induced by iron and ascorbate in rat liver microsomes, by phenols and flavones was studied. The activity of phenol was enhanced by electron donating substituents, denoted by the Hammett sigma (sigma). The concentration of the substituted phenols giving 50% inhibition (IC50) of lipid peroxidation gave a good correlation with the sigma of the substituent (ln(1/IC50) = -8.92sigma + 5.80 (R = 0.94, p < 0.05)). In flavones two pharmacophores for the protection against lipid peroxidation were pinpointed: (i) a catechol moiety as ring B and (ii) an OH-group at the 3 position with electron donating groups at the 5 and/or 7 position in the AC-ring. An example of a flavone with the latter pharmacophore is galangin (3,5,7-trihydroxyflavone) where the reactivity of the 3-OH-group is enhanced by the electron donating effect of the 5- and 7-OH-groups. This is comparable to the effect of electron donating substituents on the activity of phenol. The prooxidant activity of flavones has been related to a low half peak oxidation potential (Ep/2). All flavones with a catechol as ring B have very low Ep/2, suggesting that they display a prominent prooxidant activity. In contrast, the Ep/2 varies within the group of flavones with a 3-OH, e.g. TUM 8436 (5,7,3',4'-tetra-O-methyl-quercetin) has a relatively high Ep/2 and is an excellent protector against lipid peroxidation. Apparently amongst the flavones with the pharmacophore in the AC-ring there are good antioxidants that are expected to display no or limited prooxidant properties.

Animals↗