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Apigenin
Apigenin by Ray Sahelian, M.D. (index of hundreds of topics)
Apigenin is one of the flavonoids - more precisely one of the citrus
bioflavonoids. Apigenin, just like most flavonoids, has antioxidant,
anti-inflammatory, and anti-tumor properties... perhaps apigenin can
even block the formation of uric acid leading to beneficial effects in
gout.
Apigenin is found in high amounts in parsley, thyme, and
peppermint. Apigenin is also found in a number of herbs, including
chamomile, lemon balm, perilla, vervain, and yarrow.
Benefits of Apigenin
As with many flavonoids, apigenin has potential to reduce the risk of
cancer since it has anti-tumor activity. Apigenin also could potentially
be useful in allergic conditions since it can have anti-inflammatory
properties.
Apigenin Research Update
Synergistic interaction between hesperidin, a natural flavonoid, and
diazepam.
Eur J Pharmacol. 2005 Apr 11;512(2-3):189-98.
It has been recently reported the presence in Valeriana of the flavone
6-methylapigenin and the flavanone glycoside hesperidin. The
apigenin derivative is a ligand for the benzodiazepine binding site in
the gamma-aminobutyric acid receptor type A (GABA(A)) and has
anxiolytic properties. Hesperidin has sedative and sleep-enhancing
properties but is not a ligand for the benzodiazepine binding site. 6Methylapigenin is able to potentiate the sleep-enhancing effect of
hesperidin. In this work we demonstrate that this property is shared
with various GABA(A) receptor ligands, among them the agonist
diazepam, which was used to study the potentiation as measured in
the hole board test. Isobolar analysis of the results showed the
interaction being synergistic. We discarded pharmacokinetic effects
or a direct action of hesperidin on the benzodiazepine binding site. A
possible use of hesperidin properties to decrease the effective
therapeutic doses of benzodiazepines is suggested.
Dietary flavonoids as proteasome inhibitors and apoptosis inducers
in human leukemia cells.
Biochem Pharmacol. 2005 May 15;69(10):1421-32.
Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP.
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and
Department of Pathology, School of Medicine, Wayne State University, 640
HWCRC, 4100 John R, Detroit, MI
It has been shown that proteasome activity is required for cancer cell
survival and consumption of fruits and vegetables is associated with
decreased cancer risk. Previously, we reported that grape extract
could inhibit proteasome activity and induce apoptosis in tumor cells.
In this study, we examined the flavonoids apigenin, quercetin,
kaempferol and myricetin for their proteasome-inhibitory and
apoptosis-inducing abilities in human tumor cells. Our results
suggested that the proteasome may be a target of these dietary
flavonoids in human tumor cells and that inhibition of the
proteasome by flavonoids may be one of the mechanisms responsible
for their cancer-preventive effects.
Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1
and HDM2/p53 pathways.
FASEB J. 2005 Mar;19(3):342-53. Fang J, Xia C, Cao Z, Zheng JZ, Reed E, Jiang
BH.
The Mary Babb Randolph Cancer Center, Department of Microbiology,
Immunology and Cell Biology, West Virginia University, Morgantown, West
Virginia
Apigenin is a nontoxic dietary flavonoid that has been shown to
possess anti-tumor properties and therefore poses special interest for
the development of a novel chemopreventive and/or
chemotherapeutic agent for cancer. Ovarian cancer is one of the most
common causes of cancer death among women. Here we demonstrate
that apigenin inhibits expression of vascular endothelial growth
factor (VEGF) in human ovarian cancer cells. VEGF plays an
important role in tumor angiogenesis and growth. We found that
apigenin inhibited VEGF expression at the transcriptional level
through expression of hypoxia-inducible factor 1alpha (HIF-1alpha).
Apigenin inhibited expression of HIF-1alpha and VEGF via the
PI3K/AKT/p70S6K1 and HDM2/p53 pathways. Apigenin inhibited
tube formation in vitro by endothelial cells. These findings reveal a
novel role of apigenin in inhibiting HIF-1 and VEGF expression that is
important for tumor angiogenesis and growth, identifying new
signaling molecules that mediate this regulation.
Ibuprofen and apigenin induce apoptosis and cell cycle arrest in
activated microglia.
Neurosci Lett. 2005 Feb 28;375(2):91-6.
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 antiinflammatory 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.
Flavonoid apigenin inhibits motility and invasiveness of carcinoma
cells in vitro.
Int J Cancer. 2005 Mar 10;114(1):12-8.
Investigations of the mechanisms of the cancer-preventive activity of
apigenin (4',5,7,-trihydroxyflavone), a plant-derived, anticarcinogenic flavonoid, showed its interference with cell
proliferation, survival, and gap junctional coupling. We used a model
based on non-invasive HeLa wild-type cells and their connexin43
(Cx43) transfected counterparts to correlate the effect of apigenin on
tumour cell invasiveness with its influence on cell motility. Both cell
lines displayed similar motile properties in control conditions.
Apigenin treatment resulted in a significant and reversible inhibition
of translocation of both HeLa wild-type cells and HeLa Cx43
transfectants. The effect of apigenin on cell proliferation was less
pronounced especially at low apigenin concentration, whereas its
influence on cell motility correlated with the reduction of the invasive
potential of HeLa Cx43 cells as shown by an invasion assay based on
the confrontation of tumour cell spheroids with chick embryo heart
fragments. HeLa Cx43 cells were highly invasive in controls, but did
not invade the heart tissue at tumour cell aggregate-fibroblast capsule
interfaces in the presence of apigenin and failed to fully engulf these
heart fragments. Because the motility of chick heart fibroblasts was
only slightly affected by apigenin, these observations indicate that
apigenin exerts its anti-invasive effect on HeLa cells predominantly
via a specific inhibition of tumour cell motility. This inhibitory effect
of apigenin on tumour cell invasiveness in vitro demonstrates that
apigenin may exert its anti-tumorigenic effect in vivo via inhibition of
tumour cell penetration of the healthy tissue.
Apigenin induced apoptosis through p53-dependent pathway in
human cervical cancer cells.
Life Sci. 2005 Feb 4;76(12):1367-79.
Apigenin is a widely distributed plant flavonoid and was proposed as
an antitumor agent. In this study, we reported for the first time that
apigenin inhibited the growth of human cervical carcinoma cells
(HeLa) and through apoptotic pathway. The results showed that
apigenin significantly decreased the viability of HeLa cells at 37-74
microM and the IC50 value was 35.89 microM. Apigenin-induced
apoptosis in HeLa cells was confirmed by DNA fragmentation assay
and induction of sub-G1 phase by flow cytometry. Apigenin-treated
HeLa cells were arrested at G1 phase, which was associated with a
marked increment of the expression of p21/WAF1 protein. The
induction of p21/WAF1 appeared to be transcriptionally upregulated
and was p53-dependent. In addition, apigenin induced Fas/APO-1 and
caspase-3 expression which were also correlated with apoptosis.
Apigenin decreased in the protein expression of Bcl-2 protein, which
is an anti-apoptotic factor. The conclusion of this study is the apigenin
induced p53 expression which caused cell cycle arrest and apoptosis.
These findings suggest that apigenin has strong potential for
development as an agent for preventing cervical cancer.
Decreased pro-inflammatory cytokine production by LPS-stimulated
PBMC upon in vitro incubation with the flavonoids apigenin, luteolin
or chrysin, due to selective elimination of monocytes / macrophages.
Biochem Pharmacol. 2005 Jan 15;69(2):241-8.
Apigenin and its structural analogues chrysin and luteolin were used
to evaluate their capacity to inhibit the production of proinflammatory cytokines by lipopolysaccharide (LPS)-stimulated
human peripheral blood mononuclear cells (PBMC). Furthermore,
flowcytometric analysis was performed to compare the effects of
apigenin, chrysin, luteolin, quercetin and naringenin on the different
cell types present in PBMC. LPS-stimulated PBMC were cultured in
the presence of the flavonoids and TNFalpha, IL-1beta and IL-6 were
measured in the supernatants. In parallel, metabolic activity of the
PBMC was determined by measuring succinate dehydrogenase
activity. Apigenin, chrysin and luteolin dose-dependently inhibited
both pro-inflammatory cytokine production and metabolic activity of
LPS-stimulated PBMC. With increasing concentration of apigenin,
chrysin or luteolin the monocytes/macrophages disappeared as
measured by flowcytometry. This also appeared to occur in the nonLPS-stimulated PBMC. At the same time there was an increase in dead
cells. T- and B-lymphocytes were not affected. Quercetin and
naringenin had virtually no effects on cytokines, metabolic activity or
on the number of cells in the studied cell populations. In conclusion,
monocytes were specifically eliminated in PBMC by apigenin, chrysin
or luteolin treatment in vitro at low concentrations (around 8
microM), in which apigenin appeared to be the most potent.
The flavones luteolin and apigenin inhibit in vitro antigen-specific
proliferation and interferon-gamma production by murine and
human autoimmune T cells.
Biochem Pharmacol. 2004 Aug 15;68(4):621-9.
Plant-derived flavonoids are inhibitors of various intracellular
processes, notably phosphorylation pathways, and potential
inhibitors of cellular autoimmunity. In this study, the inhibiting
effects of various flavonoids on antigen-specific proliferation and
interferon-gamma (IFN-gamma) production by human and murine
autoreactive T cells were evaluated in vitro. T-cell responses were
evaluated for the human autoantigen alpha B-crystallin, a candidate
autoantigen in multiple sclerosis, and for the murine encephalitogen
proteolipid protein peptide PLP (139-151). The flavones apigenin and
luteolin were found to be strong inhibitors of both murine and human
T-cell responses while fisitin, quercitin, morin and hesperitin,
members of the subclasses of flavonoles and flavanones, were
ineffective. Antigen-specific IFN-gamma production was reduced
more effectively by flavones than T-cell proliferation, suggesting that
the intracellular pathway for IFN-gamma production in T cells is
particularly sensitive to flavone inhibition. These results indicate that
flavones but not flavanoles or flavanones are effective inhibitors of
the potentially pathogenic function of autoreactive T cells. The effects
of flavones were the same for human and murine autoreactive T cells,
stressing the usefulness of animal models of autoimmunity for
further studies on the effects of flavonones on autoimmune diseases.
Flavonoids such as luteolin, fisetin and apigenin are inhibitors of
interleukin-4 and interleukin-13 production by activated human
basophils.
Int Arch Allergy Immunol. 2004 Jun;134(2):135-40.
BACKGROUND: We have previously shown that fisetin, a flavonol,
inhibits IL-4 and IL-13 synthesis by allergen- or anti-IgE-antibodystimulated basophils. This time, we investigated the inhibition of IL-4
and IL-13 production by basophils by other flavonoids and attempted
to determine the fundamental structure of flavonoids related to
inhibition. We additionally investigated whether flavonoids suppress
leukotriene C4 synthesis by basophils and IL-4 synthesis by T cells in
response to anti-CD3 antibody. METHODS: Highly purified
peripheral basophils were stimulated for 12 h with anti-IgE antibody
alone or anti-IgE antibody plus IL-3 in the presence of various
concentrations of 18 different kinds of flavones and flavonols. IL-4
and IL-13 concentrations in the supernatants were then measured.
Leukotriene C4 synthesis was also measured after basophils were
stimulated for 1 h in the presence of flavonoids. Regarding the
inhibitory activity of flavonoids on IL-4 synthesis by T cells,
peripheral blood mononuclear cells were cultured with flavonoids in
anti-CD3-antibody-bound plates for 2 days. RESULTS: Luteolin,
fisetin and apigenin were found to be the strongest inhibitors of both
IL-4 and IL-13 production by basophils but did not affect leukotriene
C4 synthesis. At higher concentrations, these flavonoids suppressed
IL-4 production by T cells. Based on a hierarchy of inhibitory activity,
the basic structure for IL-4 inhibition by basophils was determined.
CONCLUSIONS: Due to the inhibitory activity of flavonoids on IL-4
and IL-13 synthesis, it can be expected that the intake of flavonoids,
depending on the quantity and quality, may ameliorate allergic
symptoms or prevent the onset of allergic diseases.
Antidepressant-like effects of apigenin and 2,4,5-trimethoxycinnamic
acid from Perilla frutescens plant in the forced swimming test.
Biol Pharm Bull. 2003 Apr;26(4):474-80.
We studied the effects of apigenin and 2,4,5-trimethoxycinnamic acid
(TMCA) on the behavioral despair test (forced swimming test), and
the central noradrenergic, dopaminergic and serotonergic activities
in mice. Apigenin at intraperitoneal doses of 12.5 and 25 mg/kg
significantly decreased the duration of immobility in the forced
swimming test in mice. At 100 mg/kg, the duration of immobility was
returned to the control level in the test. These behavioral and
biochemical results indicate the antidepressant properties of
apigenin, which may be mediated by the dopaminergic mechanisms in
the mouse brain.
Molecular modeling of flavonoids that inhibits xanthine oxidase.
Biochem Biophys Res Commun. 2002 May 31;294(1):167-72.
The inhibition of xanthine oxidase activity by various flavonoids was
assessed. All of the tested flavonoids were competitive inhibitors, and
from the kinetic analysis suggested that flavonoids bind to the
reactive site. To further understand the stereochemistry between
these flavonoids and xanthine oxidase, structure-based molecular
modeling was performed. Apigenin was the most potent inhibitor
which showed the most favorable interaction in the reactive site. The
bicyclic benzopyranone ring of apigenin stacked with phenyl of Phe
914, and the phenolic group stretched to the space surrounding with
several hydrophobic residues. Quercetin and myricetin composed a 3hydroxyl group on benzopyranone which resulting in reduction of
binding affinity. The phenolic group of genistein positioned in
opposite orientation comparison with apigenin, and resulted in a
weaker interaction with xanthine oxidase. Isovitexin showed the
weakest inhibitory effect among the compounds tested. The bulky
group of sugar in isovitexin may hamper its interaction with xanthine
oxidase.