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PubMed2000

Structural determinants for activation and block of CFTR-mediated chloride currents by apigenin.

Apigenin (4',5,7-trihydroxyflavone) is an activator of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl(-) currents across epithelia at low concentrations and a blocker at high concentrations. We determined the roles of structural components of apigenin for both stimulation and block of Cl(-) currents across Calu-3 epithelia. The half-maximal binding affinity of apigenin for current stimulation (K(s)) was 9.1 +/- 1.3 microM, and the rank-order of molecular structures was 7-hydroxyl > pyrone = 4'-hydroxyl > 5-hydroxyl. Both the 7-hydroxyl and the 4'-hydroxyl served as H-bond acceptors, whereas the 5-hydroxyl was an H-bond donor. The half-maximal binding affinity of apigenin during current block was 74 +/- 11 microM. Blocked Cl(-) currents were structurally determined by 7-hydroxyl = 4'-hydroxyl > pyrone > 5-hydroxyl. Prestimulation of tissues with forskolin significantly affected activation kinetics and binding characteristics. After forskolin stimulation, K(s) was 4.1 +/- 0.9 microM, which was structurally determined by pyrone > all hydroxyls > single hydroxyls. In contrast, block of Cl(-) current by apigenin was not affected by forskolin stimulation. We conclude that apigenin binds to a stimulatory and an inhibitory binding site, which are distinguished by their affinities and the molecular interactions during binding.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2006

Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest.

BACKGROUND: Many chemotherapeutic agents have been used to treat pancreatic cancer without success. Apigenin, a naturally occurring flavonoid, has been shown to inhibit growth in some cancer cell lines but has not been studied in pancreatic cancer. We hypothesized that apigenin would inhibit pancreatic cancer cell growth in vitro. RESULTS: Apigenin caused both time- and concentration-dependent inhibition of DNA synthesis and cell proliferation in four pancreatic cancer cell lines. Apigenin induced G2/M phase cell cycle arrest. Apigenin reduced levels of cyclin A, cyclin B, phosphorylated forms of cdc2 and cdc25, which are all proteins required for G2/M transition. CONCLUSION: Apigenin inhibits growth of pancreatic cancer cells through suppression of cyclin B-associated cdc2 activity and G2/M arrest, and may be a valuable drug for the treatment or prevention of pancreatic cancer.

Apigenin↗
PubMed2001

Apigenin acts on the tumor cell invasion process and regulates protease production.

Apigenin is a widely distributed plant flavonoid and was proposed as an antitumor agent. In this study, we investigated the apigenin effects on the protease-mediated invasiveness in an estrogen-insensitive breast tumor cell line MDA-MB231. The results show that apigenin at 22.8-45.5 microM (2.5-10 micrograms/ml) strongly inhibited, in a dose-dependent manner, tumor cell invasion through Matrigel, cell migration, and cell proliferation. We show that apigenin treatment from 22.8 microM (2.5 micrograms/ml) led to a partial decrease in urokinase-plasminogen activator expression and to a total inhibition of phorbol 12-myristate 13-acetate-induced matrix metalloproteinase-9 secretion. We also demonstrate in the apigenin-treated cells a defective adhesion to Matrigel and a G2-M cell cycle arrest. Taken together, our results demonstrate that apigenin is a pleiotropic effector affecting protease-dependent invasiveness and associated processes and proliferation of tumor cells.

Antineoplastic Agents↗
PubMed2005

Biotransformation of chrysin and apigenin by Cunninghamella elegans.

Biotransformation of chrysin by Cunninghamella elegans NRRL 1392 produced apigenin, apigenin 7-sulfate, apigenin 7,4'-disulfate, and a new metabolite identified as chrysin 7-sulfate. On the other hand, fermentation of apigenin, using the same microorganism, yielded apigenin 7-sulfate and apigenin 7,4'-disulfate. The structures of the metabolites were established by spectral analysis, and acid and enzyme hydrolyses in addition to comparison with reference samples.

Apigenin↗
PubMed2006

Apigenin suppresses cancer cell growth through ERbeta.

Two flavonoids, genistein and apigenin, have been implicated as chemopreventive agents against prostate and breast cancers. However, the mechanisms behind their respective cancer-protective effects may vary significantly. The goal of this study was to determine whether the antiproliferative action of these flavonoids on prostate (DU-145) and breast (MDA-MB-231) cancer cells expressing only estrogen receptor (ER) beta is mediated by this ER subtype. It was found that both genistein and apigenin, although not 17beta-estradiol, exhibited antiproliferative effects and proapoptotic activities through caspase-3 activation in these two cell lines. In yeast transcription assays, both flavonoids displayed high specificity toward ERbeta transactivation, particularly at lower concentrations. However, in mammalian assay, apigenin was found to be more ERbeta-selective than genistein, which has equal potency in inducing transactivation through ERalpha and ERbeta. Small interfering RNA-mediated downregulation of ERbeta abrogated the antiproliferative effect of apigenin in both cancer cells but did not reverse that of genistein. Our data unveil, for the first time, that the anticancer action of apigenin is mediated, in part, by ERbeta. The differential use of ERalpha and ERbeta signaling for transaction between genistein and apigenin demonstrates the complexity of phytoestrogen action in the context of their anticancer properties.

Anticarcinogenic Agents↗
PubMed2005

Inhibitory effects of apigenin on the growth of gastric carcinoma SGC-7901 cells.

AIM: To explore the growth inhibition and apoptosis-inducing effect of apigenin on human gastric carcinoma SGC-7901 cells. METHODS: The effects of apigenin on the growth, clone formation and proliferation of human gastric carcinoma SGC-7901 cells were observed by MTT, clone-forming assay, and morphological observation. Fluorescent staining and flow cytometry analysis were used to detect apoptosis of cells. RESULTS: Apigenin obviously inhibited the growth, clone formation and proliferation of SGC-7901 cells in a dose-dependent manner. Inhibition of growth was observed on d 1 at the concentration of 80 micromol/L, while after 4 d, the inhibition rate (IR) was 90%. The growth IRs at the concentration of 20, 40, and 80 micromol/L were 38%, 71%, and 99% respectively on the 7th d. After the cells were treated with apigenin for 48 h, the number of clone-forming in control, 20, 40, and 80 micromol/L groups was 217+/-16.9, 170+/-11.1 (P < 0.05), 98+/-11.1 (P < 0.05), and 25+/-3.5 (P < 0.05) respectively. Typical morphological changes of apoptosis was found by fluorescent staining. The cell nuclei had lost its smooth boundaries, chromatin was condensed, and cell nuclei were broken. Flow cytometry detected typical apoptosis peak. After the cells were treated with apigenin for 48 h, the apoptosis rates were 5.76%, 19.17%, and 29.30% respectively in 20, 40, and 80 micromol/L groups. CONCLUSION: Apigenin shows obvious inhibition on the growth and clone formation of SGC-7901 cells by inducing apoptosis.

Apigenin↗
PubMed2003

[Effect of emodin and apigenin on invasion of human ovarian carcinoma HO-8910PM cells in vitro].

BACKGROUND & OBJECTIVE: Emodin inhibited the activity of TPK and CK2 and the degradation of I-kappaB. Apigenin inhibited the activity of MAPK and PI(3)K. In this study the authors observed the effect of emodin and apigenin on the invasion of HO-8910PM cells in vitro. METHODS: Trypan blue dye exclusion assay was used to examine the cytotoxity of emodin and apigenin. Reconstituted basement membrane invasion assay was utilized to evaluate the invasive activity. Type IV collagenase production was analyzed by PAGE substrate zymography. RESULTS: Emodin had weaker cytotoxity on HO-8910PM cells than apigenin, their IC(50) after treatment with the chemicals for 48 hours were (35.30+/-3.50) micromol/L, and (28.92+/-2.60)micromol/L, while emodin significantly inhibited membrane invasion and adhesion and migration of HO-8910PM cells. Their inhibition rates after treated with the chemical of 40 micromol/L were (45.31+/-3.10)%,(25.42+/-1.70)%, and (41.59+/-1.90)%. Emodin inhibited the production but not activity of MMP-9. Apigenin inhibited migration and adhesion of HO-8910PM cells, their inhibition rates after treated with the chemical of 40 micromol/L were (29.04+/-1.70)% and (30.80+/-3.00)%, while weakly inhibited membrane invasion (the inhibition rate only was 12.1%) and inhibited neither production nor activity of MMP-9. CONCLUSION: Both emodin and apigenin had cytotoxicity on HO-8910PM cells. Emodin was a potential agent inhibiting tumor invasion and metastasis.

Antineoplastic Agents↗
PubMed2004

Hierarchy of carcinoma cell responses to apigenin: gap junctional coupling versus proliferation.

We discriminated the role of gap junctional communication and phenotypic constitution of tumour cells in determining their responsiveness to apigenin. Effects of apigenin on intercellular communication and proliferation of two lines of carcinoma cells, uncoupled HeLa cells and their coupled Cx43-transfected counterparts, were analysed and compared with the responses of highly coupled BICR/M1Rk cells. Dye transfer analyses demonstrated that apigenin decreases the degree of coupling in Cx43-coupled populations of HeLa cells but does not affect BICR/M1Rk cells. Similarly, no communication enhancement was observed in originally uncoupled HeLa cell populations. A G2-specific growth arrest paralleled by the induction of apoptosis was observed which was more pronounced and correlated with higher number of apoptotic events in coupled HeLa Cx43 transfectants than in parental cell line. On the other hand, apoptosis was not observed in highly coupled BICR/M1Rk cells, instead, these cells were only transiently blocked in G2 which might be a result of their ability to metabolise apigenin. These data demonstrate a hierarchy of systems determining cellular sensitivity to apigenin. Gap junctional coupling does not influence the quality of cell cycle-related responses to apigenin but modulates their magnitude. This modulating effect of gap junctional coupling depends, however, on a cellular context determined by specific cell phenotype and can be overcome by tissue-specific compensatory mechanisms.

Animals↗
PubMed1994

Apigenin induces morphological differentiation and G2-M arrest in rat neuronal cells.

Flavonoids are pigments of edible plants. We have recently reported that most flavonoids induce G1 arrest in human cancer cells, and that genistein (an isoflavone) specifically inhibits their cell cycle at G2-M phase. In the present study, apigenin (a flavone) was found to inhibit the proliferation of B104 rat neuronal cells, and flow-cytometric analysis showed that apigenin arrested their cell cycle at G2-M phase. This effect was dose-dependent and reversible when apigenin was removed from the culture medium. Microscopic observation showed that apigenin did not significantly increase the mitotic index compared with the control. Further, apigenin induced morphological differentiation, that is, elongation and arborization of neurites in B104 cells. This is the first report to show that apigenin inhibited the proliferation of malignant tumor cells by G2-M arrest and induced morphological differentiation.

Animals↗
PubMed1994

Apigenin and tangeretin enhance gap junctional intercellular communication in rat liver epithelial cells.

Two flavones, apigenin and tangeretin, were studied for their ability to modulate gap junctional intercellular communication (GJIC) in the rat liver epithelial cell line REL. Their cytotoxicity was first determined by cell density and neutral red uptake assays: neither apigenin nor tangeretin are cytotoxic at 10 and 25 microM, the concentrations used in our experiments. We then studied GJIC using the dye transfer assay and we observed that both apigenin and tangeretin enhance it, the maximum stimulation (x 1.7-1.8) being achieved at 25 microM for 24 h. When the dye transfer was enhanced, the amount of connexin 43 increased, which was demonstrated by Western blot and immunofluorescence analysis. For apigenin only, Northern blot analysis showed an accumulation of connexin 43 mRNA. In addition, the incubation of REL cells with the two compounds, for 1 or 24 h, prevented the inhibition of dye transfer by 12-O-tetradecanoylphorbol-13-acetate (1 or 10 ng/ml). The enhancement of GJIC by apigenin could be one of the major mechanisms responsible for apigenin's anti-tumour promoting action in vivo. As for tangeretin, its capacity to enhance GJIC completes its potential protective properties towards the post-initiation process.

Animals↗
PubMed2004

Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part III. Apigenin, baicalelin, kaempherol, luteolin and quercetin.

Flavonoids are found universally in plants and act as free radical scavenging and chelating agents with antiinflammatory, antiischemic, vasodilating and chemoprotective properties. In this study, the antilipoperoxidative and cytoprotective effects of apigenin, baicalein, kaempferol, luteolin and quercetin against doxorubicin-induced oxidative stress were investigated in isolated rat heart cardiac myocytes, mitochondria and microsomes. After preincubation of cardiomyocytes with the test compounds for 1 h the cardiomyocytes were treated with the toxic agent, doxorubicin (100 micro M for 8 h). Cardiomyocyte protection was assessed by extracellular LDH and cellular ADP and ATP production. Cytoprotection was concentration dependent for baicalein > luteolin congruent with apigenin > quercetin > kaempferol. All test compounds had signi fi cantly better protective effects than dexrazoxan, an agent currently used for adjuvant therapy during anthracycline antibiotic therapy. In microsomes/mitochondria the IC(50) values of lipid peroxidation inhibition for quercetin, baicalein, kaempferol, luteolin, and apigenin were 3.1 +/- 0.2/8.2 +/- 0.6, 3.3 +/- 0.3/9.6 +/- 0.5, 3.9 +/- 0.3/10.1 +/- 0.8, 22.9 +/- 1.7/18.2 +/- 0.7, and 338.8 +/- 23.1/73.1 +/- 6.4 mM, respectively. The antilipoperoxidative activity of apigenin differed from its cytoprotective effects, but correlated with the free radical scavenging of 2,2-diphenyl-1-picrylhydrazyl radical and half peak oxidation potential (E(p/2)). Apigenin was the least effective of the flavonoids studied in all models except the cardiomyocyte model where its cardiomyocyte cytoprotective effect was comparable to other compounds.

Animals↗
PubMed2004

Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein.

Apigenin, a plant-derived flavone, is a potent inhibitor of cell proliferation and angiogenesis, but the mechanisms leading to the pathological anti-angiogenic effects of apigenin are still unclear. In this study, we found that apigenin inhibited the hypoxia-induced expression of vascular endothelial growth factor (VEGF) mRNA in human umbilical artery endothelial cells. Apigenin also suppressed the expression of erythropoietin mRNA, which is a typical hypoxia-inducible gene, via the degradation of hypoxia-inducible factor 1 (HIF-1) alpha. We investigated the effect of apigenin on the interaction of HIF-1alpha with heat shock protein 90 (Hsp90), which is reported to be important for the stabilization of HIF-1alpha, and found that VEGF expression was inhibited via degradation of HIF-1alpha through interference with the function of Hsp90.

Angiogenesis Inhibitors↗
PubMed2004

Ibuprofen and apigenin induce apoptosis and cell cycle arrest in activated microglia.

In case of injury or disease, microglia are recruited to the site of the pathology and become activated as evidenced by morphological changes and expression of pro-inflammatory cytokines. Evidence suggests that microglia proliferate by cell division to create gliosis at the site of pathological conditions such as the amyloid plaques in Alzheimer's disease and the substantia nigra of Parkinson's disease patients. The hyperactivation of microglia contributes to neurotoxicity. In the present study we tested the hypothesis that anti-inflammatory compounds modulate the progression of cell cycle and induce apoptosis of the activated cells. We investigated the effects of ibuprofen (non-steroidal anti-inflammatory drug) and apigenin (a flavonoid with anti-inflammatory and anti-proliferative properties) on the cell cycle of the murine microglial cell line BV-2. The findings indicate that apigenin-induced cell cycle arrest preferentially in the G2/M phase and ibuprofen caused S phase arrest. The binding of annexin V-FITC to the membranes of cells which indicates the apoptotic process were examined, whereas the DNA was stained with propidium iodide. Both apigenin and ibuprofen induced apoptosis significantly in early and late stages. The induction of apoptosis by ibuprofen and apigenin was confirmed using TUNEL assay, revealing that 25 microM apigenin and 250 microM ibuprofen significantly increased apoptosis in BV-2 cells. The results from the present study suggest that anti-inflammatory compounds might inhibit microglial proliferation by modulating the cell cycle progression and apoptosis.

Animals↗
PubMed2000

Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla.

Dried flowers of Matricaria chamomilla L. are largely used to provide sedative as well as spasmolytic effects. In the present study, we examined in particular the pharmacological property of a fraction isolated from a methanolic extract of M. chamomilla, which was identified by HPLC-MS-MS analysis as apigenin. By radioreceptor binding assays, we demonstrated the ability of the flavone to displace a specific radioligand, [(3)H]Ro 15-1788, from the central benzodiazepine binding site. Electrophysiological studies performed on cultured cerebellar granule cells showed that apigenin reduced GABA (gamma-aminobutyric acid)-activated Cl(-) currents in a dose-dependent fashion. The effect was blocked by co-application of Ro 15-1788, a specific benzodiazepine receptor antagonist. Accordingly, apigenin reduced the latency in the onset of picrotoxin-induced convulsions. Moreover, apigenin injected i.p. in rats reduced locomotor activity, but did not demonstrate anxiolytic, myorelaxant, or anticonvulsant activities. The present results seem to suggest that the inhibitory activity of apigenin on locomotor behaviour in rats cannot be ascribed to an interaction with GABA(A)-benzodiazepine receptor but to other neurotransmission systems, since it is not blocked by Ro 15-1788.

Animals↗
PubMed2002

Effects of apigenin and tt-farnesol on glucosyltransferase activity, biofilm viability and caries development in rats.

Propolis, a resinous hive product secreted by Apis mellifera bees, has been shown to reduce the incidence of dental caries in rats. Several compounds, mainly polyphenolics, have been identified in propolis. Apigenin and tt-farnesol demonstrated biological activity against mutans streptococci. We determined here their effects, alone or in combination, on glucosyltransferase activity, biofilm viability, and development of caries in rats. Sprague-Dawley rats were infected with Streptococcus sobrinus 6715 and treated topically twice daily as follows: (1) tt-farnesol, (2) apigenin, (3) vehicle control, (4) fluoride, (5) apigenin +tt-farnesol, and (6) chlorhexidine. Apigenin (1.33 mM) inhibited the activity of glucosyltransferases in solution (90-95%) and on the surface of saliva-coated hydroxyapatite beads (35-58%); it was devoid of antibacterial activity. tt-Farnesol (1.33 mM) showed modest antibacterial activity against biofilms and its effects on glucosyltransferases were minimal. The incidence of smooth-surface caries was significantly reduced by apigenin +tt-farnesol (60%), fluoride (70%), and chlorhexidine (72%) treatments compared to control (P < 0.05).

Analysis of Variance↗
PubMed2004

Protective role of Apigenin on the status of lipid peroxidation and antioxidant defense against hepatocarcinogenesis in Wistar albino rats.

Apigenin, a dietary plant derived flavone subclass of flavonoid is expected to play a role in cancer chemoprevention and cancer chemotherapy. Here we designed our experiment to establish whether treatment of apigenin (25 mg/kg body weight) for 14 consecutive days to (N-nitrosodiethylamine) DEN induced (200 mg/kg body weight; by single ip. injection) and phenobarbital promoted (0.05% through drinking water for 14 successive weeks) rats provide protection against the oxidative stress caused by the carcinogen. The level of lipid peroxidation (LPO) markedly increased in carcinogen administered animals, which was brought back to near normal by apigenin treatment. In contrast the activities/levels of the antioxidant status both in liver and kidney were decreased in carcinogen administered animals, which was recouped back to near normal upon apigenin administration. From our findings we concluded that apigenin prevents LPO and protects antioxidant system in DEN induced and phenobarbital promoted hepatocellular carcinogenesis.

Animals↗
PubMed2004

Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration.

The metabolism of apigenin, a weak estrogenic flavonoid phytochemical, was investigated in the rat. After a single oral administration of radiolabeled apigenin, 51.0% of radioactivity was recovered in urine, 12.0% in feces, 1.2% in the blood, 0.4% in the kidneys, 9.4% in the intestine, 1.2% in the liver, and 24.8% in the rest of the body within 10 days. Sex differences appear with regard to the nature of compounds eliminated via the urinary route: immature male and female rats, like mature female rats, excreted a higher percentage of the mono-glucuronoconjugate of apigenin than the mono-sulfoconjugate of apigenin (10.0-31.6% versus 2.0-3.6%, respectively). Mature male rats excreted the same compounds in an inverse ratio (4.9% and 13.9%, respectively). Radioactivity appeared in the blood only 24 h after oral administration. Blood kinetics showed a high elimination half-time (91.8 h), a distribution volume of 259 ml, and a plasmatic clearance of 1.95 ml/h. All of the parameters calculated from these experiments suggested a slow metabolism of apigenin, with a slow absorption and a slow elimination phase. Thus, a possible accumulation of this flavonoid in the body can be hypothesized.

Administration, Oral↗
PubMed2004

Metabolism of apigenin by rat liver phase I and phase ii enzymes and by isolated perfused rat liver.

The metabolism of apigenin, a low estrogenic flavonoid phytochemical, was investigated in rat using liver models both in vitro (subcellular fractions) and ex vivo (isolated perfused liver). In vitro, phase I metabolism led to the formation of three monohydroxylated derivatives: luteolin which was the major metabolite (K(m) = 22.5 +/- 1.5 microM; V(max) = 5.605 +/- 0.090 nmol/min/mg protein, means +/- S.E.M.), scutellarein, and iso-scutellarein. These oxidative pathways were mediated by cytochrome P450 monooxygenases (P450s). The use of P450 inhibitors and inducers showed that CYP1A1, CYP2B, and CYP2E1 are involved. In vitro studies of phase II metabolism indicated that apigenin underwent conjugation giving three monoglucuronoconjugates and one monosulfoconjugate. Luteolin led to the formation of four monoglucuronoconjugates, two sulfoconjugates, and one methylconjugate identified as diosmetin. Ex vivo during the apigenin perfusion of an isolated rat liver, none of the phase I metabolites could be recovered. In contrast, two monoglucuronoconjugates and one of the sulfoconjugates of apigenin already identified in vitro were recovered. Moreover, two new derivatives were isolated and identified as a diglucuronoconjugate and a glucuronosulfoconjugate. This work provides new data about the metabolism of apigenin and shows the interest value of using various experimental models in metabolic studies.

Animals↗