Apigenin and its impact on gastrointestinal cancers

Lefort EC, Blay J. Molecular Nutrition & Food Research. 2012. DOI: 10.1002/mnfr.201200424
Apigenin (4′,5,7-trihydroxyflavone, 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many fruits, vegetables, and herbs, the most abundant sources being the leafy herb parsley and dried flowers of chamomile. Present in dietary sources as a glycoside, it is cleaved in the gastrointestinal lumen to be absorbed and distributed as apigenin itself. For this reason, the epithelium of the gastrointestinal tract is exposed to higher concentrations of apigenin than tissues at other locations.
This would also be true for epithelial cancers of the gastrointestinal tract. We consider the evidence for actions of apigenin that might hinder the ability of gastrointestinal cancers to progress and spread. Apigenin has been shown to inhibit cell growth, sensitize cancer cells to elimination by apoptosis, and hinder the development of blood vessels to serve the growing tumor. It also has actions that alter the relationship of the cancer cells with their microenvironment. Apigenin is able to reduce cancer cell glucose uptake, inhibit remodeling of the extracellular matrix, inhibit cell adhesion molecules that participate in cancer progression, and oppose chemokine signaling pathways that direct the course of metastasis into other locations. As such, apigenin may provide some additional benefit beyond existing drugs in slowing the emergence of metastatic disease.

Apigenin, a Component of Matricaria recutita Flowers, is a Central Benzodiazepine Receptors-Ligand with Anxiolytic Effects
The dried flower heads of Matricaria recutita L. (Asteraceae) are used in folk medicine to prepare a spasmolytic and sedative tea. Our fractionation of the aqueous extract of this plant led to the detection of several fractions with significant affinity for the central benzodiazepine receptor and to the isolation and identification of 5,7,4′-trihydroxyflavone (apigenin) in one of them. Apigenin competitively inhibited the binding of flunitrazepam with a Ki of 4 µM and had no effect on muscarinic receptors, α1-adrenoceptors, and on the binding of muscimol to GABAA receptors.Apigenin had a clear anxiolytic activity in mice in the elevated plusmaze without evidencing sedation or muscle relaxant effects at doses similar to those used for classical benzodiazepines and no anticonvulsant action was detected. However, a 10-fold increase in dosage produced a mild sedative effect since a 26% reduction in ambulatory locomotor activity and a 35% decrement in hole-board parameters were evident. The results reported in this paper demonstrate that apigenin is a ligand for the central benzodiazepine receptors exerting anxiolytic and slight sedative effects but not being anticonvulsant or myorelaxant.
Viola H, Wasowski C, de Stein L, Wolfman C, Silveira R, Dajas F, Medina JH & Paladini AC. Planta Med 1995; 61(3) Pp.213-6 DOI: 10.1055/s-2006-958058

Apigenin: The Anxiolytic Constituent of Turnera aphrodisiaca
Turnera aphrodisiaca. Ward (Turneraceae) has been traditionally used for the treatment of anxiety neurosis and as aphrodisiac, but no attempts have been made to investigate the plant systematically for its traditional claims. The current investigation was carried out ot isolate the bioactive constituent(s) from T. aphrodisiaca. using bioactivity-guided fractionation. Antianxiety activity-guided fractionation of methanol extract of the plant led to isolation of 5,7,4′ -trihydroxy flavone apigenin. Its structure was elucidated by UV and NMR data. Apigenin exhibited significant anxiolytic activity at a dose of 2 mg/kg, p.o., in mice using elevated plus maze model of anxiety. It is concluded that apigenin is responsible for anxiolytic effects of this traditionally used plant.
Kumar S & Sharma A. Pharmaceutical Biology. 2006, Vol. 44, No. 2, Pp. 84–90

Behavioral characterisation of the flavonoids apigenin and chrysin
The behavioral effects of acute administration of two flavonoids, apigenin and chrysin, contained in Matricaria chamomilla and in Passiflora incarnata, respectively, were studied in rats. The data demonstrate that in our experimental conditions, the two flavonoids were equally able to reduce locomotor activity when injected in rats at a minimal effective dose of 25 mg/kg. However, while chrysin exhibited a clear anxiolytic effect when injected at the dose of 1 mg/kg, apigenin failed to exert this activity. The sedative effect of these flavonoids cannot be ascribed to an interaction with GABA–benzodiazepine receptors, since it was not counteracted by the benzodiazepine antagonist Flumazenil. To the contrary, the anxiolytic effect of chrysin, which was blocked by the injection of Flumazenil, could be linked to an activation of the GABAA receptor unit.
Zanoli P & Avallone R & Baraldi M. Fitoterapia. Volume 71, Supplement 1, 1 August 2000, Pp. S117-S123 doi:10.1016/S0367-326X(00)00186-6

Apigenin Suppresses Cancer Cell Growth through ERβ1
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) β is mediated by this ER subtype. It was found that both genistein and apigenin, although not 17β-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 ERβ transactivation, particularly at lower concentrations. However, in mammalian assay, apigenin was found to be more ERβ-selective than genistein, which has equal potency in inducing transactivation through ERα and ERβ. Small interfering RNA-mediated downregulation of ERβ 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 ERβ. The differential use of ERα and ERβ signaling for transaction between genistein and apigenin demonstrates the complexity of phytoestrogen action in the context of their anticancer properties.
Mak P, Leung Y-K, Tang W-Y, Harwood C & Ho S-M. Neoplasia. 2006 November; 8(11) Pp.896–904.

Apigenin inhibits proliferation of ovarian cancer A2780 cells through Id1
Apigenin, a common dietary flavonoid, has been shown to possess anti-tumor properties. However, the mechanism by which apigenin inhibits cancer cells is not fully understood. Id1 (inhibitor of differentiation or DNA binding protein 1) contributes to tumorigenesis by stimulating cell proliferation, inhibiting cell differentiation and facilitating tumor neoangiogenesis. Elevated Id1 is found in ovarian cancers and its level correlates with the malignant potential of ovarian tumors. Therefore, Id1 is a potential target for ovarian cancer treatment. Here, we demonstrate that apigenin inhibits proliferation and tumorigenesis of human ovarian cancer A2780 cells through Id1. Apigenin suppressed the expression of Id1 through activating transcription factor 3 (ATF3). Our results may elucidate a new mechanism underlying the inhibitory effects of apigenin on cancer cells.
Li Z-d, Hu X-w, Wang Y-t & Fang J. FEBS Letters. Volume 583, Issue 12, 18 June 2009, Pp. 1999-2003 doi:10.1016/j.febslet.2009.05.013

Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages
Prostaglandins biosynthesis and nitric oxide production have been implicated in the process of carcinogenesis and inflammation. In this study, we investigated the effect of various flavonoids and (–)-epigallocatechin-3-gallate on the activities of inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Apigenin, genistein and kaempferol were markedly active inhibitors of transcriptional activation of COX-2, with IC50 < 15 μM. In addition, apigenin and kaempferol were also markedly active inhibitors of transcriptional activation of iNOS, with IC50 < 15 μM. Of those compounds tested, apigenin was the most potent inhibitor of transcriptional activation of both COX-2 and iNOS. Western and northern blot analyses demonstrated that apigenin significantly blocked protein and mRNA expression of COX-2 and iNOS in LPS-activated macrophages. Transient transfection experiments showed that LPS caused an ~4-fold increase in both COX-2 and iNOS promoter activities, these increments were suppressed by apigenin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that apigenin blocked the LPS-induced activation of nuclear factor-kB (NF-kB). The inhibition of NF-kB activation occurs through the prevention of inhibitor kB (IkB) degradation. Transient transfection experiments also showed that apigenin inhibited NF-kB-dependent transcriptional activity. Finally, we showed that apigenin could inhibit the IkB kinase activity induced by LPS or interferon-γ. The results of further studies suggest that suppression of transcriptional activation of COX-2 and iNOS by apigenin might mainly be mediated through inhibition of IkB kinase activity. This study suggests that modulation of COX-2 and iNOS by apigenin and related flavonoids may be important in the prevention of carcinogenesis and inflammation.
Liang Y-C, Huang Y-T, Tsai S-H, Lin-Shiau S-YChen C-F & Lin J-K. Carcinogenesis (1999) 20 (10) Pp. 1945-52. doi: 10.1093/carcin/20.10.1945

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