Apigenin

1 Achyrocline sp. 2 Agrimonia sp. 3 Ailanthus sp. 4 Antennaria sp. 5 Arum sp. 6 Asphodelus sp. 7 Baccharis sp. 8 Ballota sp. 9 Baptisia sp. 10 Capsicum sp. 11 Chamaemelum sp. 12 Chamomilla sp. 13 Cirsium sp. 14 Convallaria sp. 15 Daphne sp. 16 Dendranthema sp. 17 Eclipta sp. 18 Equisetum sp. 19 Erica sp. 20 Eriodictyon sp. 21 Euphrasia sp. 22 Galium sp. 23 Helichrysum sp. 24 Jatropha sp. 25 Lemna sp. 26 Leucanthemum sp. 27 Lippia sp. 28 Lycopus sp. 29 Marchantia sp. 30 Marrubium sp. 31 Mentha sp. 32 Ocimum sp. 33 Olea sp. 34 Ononis sp. 35 Origanum sp. 36 Passiflora sp. 37 Perilla sp. 38 Pimpinella sp. 39 Pinguicula sp. 40 Platanus sp. 41 Primula sp. 42 Salix sp. 43 Salvia sp. 44 Silybum sp. 45 Tanacetum sp. 46 Teucrium sp. 47 Thymus sp. 48 Verbascum sp. 49 Veronica sp.

Apigenin is a competitive CYP2C9 inhibitor with a Ki of 2 μM.

In Vitro:Apigenin inhibits cytochrome P450 2C9 (CYP2C9) with a Ki of 2 μM in the CYP2C9 RECO system (a purified, reconstituted enzyme system containing recombinant human CYP2C9, P450 reductase, cytochrome b5, and liposomes)[1]. Apigenin inhibits the cell proliferation. The growth inhibition rate (IR) of 20, 40, and 80 μM of Apigenin is 38%, 71%, and 99% respectively on the 7thd. after exposure to Apigenin for 24 or 48 h, the clone formation of SGC-7901 cells is suppressed in a dose- and time-dependent manner. The cloning efficiency in 80 μM is 9.8% and 5% after treatment with Apigenin for 24 and 48 h, while in the control group it is 40.4% and 43.4%[2].

In Vivo:Apigenin (API), a natural flavonoid, possesses a broad spectrum of biological properties, including antioxidative, anti-inflammatory, anticancer, and neuroprotective effects. Apigenin (125 mg/kg and 250  mg/kg) alleviates Adriamycin (ADR) (24 mg/kg)-induced myocardial injury. Apigenin inhibits serum aspartate amino transferase (AST) release. Apigenin reduces serum lactate dehydrogenase (LDH) release. Apigenin reduces serum creatine kinase (CK) contents[3].

References:
[1]. Si D, et al. Mechanism of CYP2C9 inhibition by flavones and flavonols. Drug Metab Dispos. 2009 Mar;37(3):629-34. [2]. Wu K, et al. Inhibitory effects of apigenin on the growth of gastric carcinoma SGC-7901 cells. World J Gastroenterol. 2005 Aug 7;11(29):4461-4. [3]. Yu W, et al. Apigenin Attenuates Adriamycin-Induced Cardiomyocyte Apoptosis via the PI3K/AKT/mTOR Pathway. Evid Based Complement Alternat Med. 2017;2017:2590676.

Exposure of breast cancer cells to a subcytotoxic dose of apigenin causes growth inhibition, oxidative stress, and hypophosphorylation of Akt.[Pubmed:25019465]

Exp Mol Pathol. 2014 Oct;97(2):211-7.

Epidemiological studies show that fruit- and vegetable-rich diets are associated with a reduced risk of developing certain forms of cancer, including breast cancer. In this study we demonstrate that a subcytotoxic concentration of Apigenin, which is a flavone found at high concentrations in parsley, onions, grapefruit, oranges, and chamomile tea, inhibited DNA synthesis in a panel of human breast cancer cell lines (MDA-MB-231, MBA-MB-468, MCF-7, SK-BR-3). Decreased proliferation of MDA-MB-468 cells in the presence of Apigenin was associated with G2/M phase cell cycle arrest and the production of reactive oxygen species. Apigenin-treated MDA-MB-468 cells also showed reduced phosphorylation of Akt (protein kinase B), which is an essential effector serine/threonine kinase in the phosphatidylinositide 3-kinase pathway that promotes tumor growth and progression. However, exposure to the antioxidant reduced glutathione failed to reverse Apigenin-mediated inhibition of Akt phosphorylation and cell proliferation, indicating that these effects were not due to oxidative stress. Taken together, these findings suggest that low-dose Apigenin has the potential to slow or prevent breast cancer progression.

Apigenin inhibits TGF-beta-induced VEGF expression in human prostate carcinoma cells via a Smad2/3- and Src-dependent mechanism.[Pubmed:23359392]

Mol Carcinog. 2014 Aug;53(8):598-609.

Cancer progression relies on establishment of the blood supply necessary for tumor growth and ultimately metastasis. Prostate cancer mortality is primarily attributed to development of metastases rather than primary, organ-confined disease. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis in prostate tissue. Our previous studies have demonstrated that the chemopreventive bioflavonoid Apigenin inhibited hypoxia-induced elevation of VEGF production at low oxygen conditions characteristic for solid tumors. Low oxygen (hypoxia) and transforming growth factor-beta (TGF-beta) are two major factors responsible for increased VEGF secretion. In the present study, experiments were performed to investigate the inhibitory effect of Apigenin on TGF-beta-induced VEGF production and the mechanisms underlying this action. Our results demonstrate that VEGF expression is induced by TGF-beta1 in human prostate cancer PC3-M and LNCaP C4-2B cells, and treatment with Apigenin markedly decreased VEGF production. Additionally, Apigenin inhibited TGF-beta1-induced phosphorylation and nuclear translocation of Smad2 and Smad3. Further experiments demonstrated that specific transient knockdown of Smad2 or Smad3 blunted Apigenin's effect on VEGF expression. We also found that Apigenin inhibited Src, FAK, and Akt phosphorylation in PC3-M and LNCaP C4-2B cells. Furthermore, constitutively active Src reversed the inhibitory effect of Apigenin on VEGF expression and Smad2/3 phosphorylation. Taken together, our results suggest that Apigenin inhibits prostate carcinogenesis by modulating TGF-beta-activated pathways linked to cancer progression and metastases, in particular the Smad2/3 and Src/FAK/Akt pathways. These findings provide new insights into molecular pathways targeted by Apigenin, and reveal a novel molecular mechanism underlying the antiangiogenic potential of Apigenin.

Intestinal anti-inflammatory activity of apigenin K in two rat colitis models induced by trinitrobenzenesulfonic acid and dextran sulphate sodium.[Pubmed:25654996]

Br J Nutr. 2015 Feb 28;113(4):618-26.

Flavonoids are polyphenolic compounds that are widespread in nature, and consumed as part of the human diet in significant amounts. The aim of the present study was to test the intestinal anti-inflammatory activity of Apigenin K, a soluble form of Apigenin, in two models of rat colitis, namely the trinitrobenzenesulfonic acid (TNBS) model and the dextran sulphate sodium (DSS) model. Apigenin K (1, 3 and 10 mg/kg; by the oral route; n 4-6 per group) was administered as a pre-treatment to rats with TNBS and DSS colitis, and colonic status was checked by macroscopic and biochemical examination. Apigenin K pre-treatment resulted in the amelioration of morphological signs and biochemical markers in the TNBS model. The results demonstrated a reduction in the inflamed area, as well as lower values of score and colonic weight:length ratio compared with the TNBS group. Myeloperoxidase (MPO) activity was reduced by 30 % (P< 0.05). Moreover, Apigenin K pre-treatment ameliorated morphological signs and biochemical markers in the DSS model. Thus, macroscopic damage was significantly reduced and the colonic weight:length ratio was lowered by approximately 10 %, while colonic MPO and alkaline phosphatase activities were decreased by 35 and 21 %, respectively (P< 0.05). Apigenin K pre-treatment also tended to normalise the expression of a number of colonic inflammatory markers (e.g. TNF-alpha, transforming growth factor-beta, IL-6, intercellular adhesion molecule 1 or chemokine (C-C motif) ligand 2). In conclusion, Apigenin K is found to have anti-inflammatory effects in two preclinical models of inflammatory bowel disease.

Apigenin inhibits enterovirus 71 replication through suppressing viral IRES activity and modulating cellular JNK pathway.[Pubmed:24971492]

Antiviral Res. 2014 Sep;109:30-41.

Enterovirus 71 (EV71) is a member of genus Enterovirus in Picornaviridae family, which is one of the major causative agents for hand, foot and mouth disease (HFMD), and sometimes associated with severe central nervous system diseases in children. Currently there are no effective therapeutic medicines or vaccines for the disease. In this report, we found that Apigenin and luteolin, two flavones that differ only in the number of hydroxyl groups could inhibit EV71-mediated cytopathogenic effect (CPE) and EV71 replication with low cytotoxicity. Both molecules also showed inhibitory effect on the viral polyprotein expression. They prevented EV71-induced cell apoptosis, intracellular reactive oxygen species (ROS) generation and cytokines up-regulation. Time-of-drug addition study demonstrated that Apigenin and luteolin acted after viral entry. We examined the effect of Apigenin and luteolin on 2A(pro) and 3C(pro) activity, two viral proteases responsible for viral polyprotein processing, and found that they showed less inhibitory activity on 2A(pro) or 3C(pro). Further studies demonstrated that Apigenin, but not luteolin could interfere with viral IRES activity. Also, Apigenin inhibited EV71-induced c-Jun N-terminal kinase (JNK) activation which is critical for viral replication, in contrast to luteolin that did not. This study demonstrated that Apigenin may inhibit EV71 replication through suppressing viral IRES activity and modulating cellular JNK pathway. It also provided evidence that one hydroxyl group difference in the B ring between Apigenin and luteolin resulted in the distinct antiviral mechanisms. This study will provide the basis for better drug development and further identification of potential drug targets.

Apigenin Induces Apoptosis through a Mitochondria/Caspase-Pathway in Human Breast Cancer MDA-MB-453 Cells.[Pubmed:19430615]

J Clin Biochem Nutr. 2009 May;44(3):260-5.

In this study, we investigated the mechanistic role of the caspase cascade in extrinsic and intrinsic apoptosis induced by Apigenin, which has been targeted as a candidate in the development of noncytotoxic anticancer medicines. Treatment with Apigenin (1-100 microM) significantly inhibited the proliferation of MDA-MB-453 human breast cancer cells in a dose- and time-dependent manner with IC(50) values of 59.44 and 35.15 microM at 24 and 72 h, respectively. This inhibition resulted in the induction of apoptosis and the release of cytochrome c in cells exposed to Apigenin at its 72 h IC(50). Subsequently, caspase-9, which acts in mitochondria-mediated apoptosis, was cleaved by Apigenin. In addition, Apigenin activated caspase-3, which functions downstream of caspase-9. The Apigenin-induced activation of caspase-3 was accompanied by the cleavage of capases-6, -7, and -8. These results are supported by evidence showing that the activity patterns of caspases-3, -8, and -9 were similar. The present study supports the hypothesis that Apigenin-induced apoptosis involves the activation of both the intrinsic and extrinsic apoptotic pathways.

Apigenin protects endothelium-dependent relaxation of rat aorta against oxidative stress.[Pubmed:19549516]

Eur J Pharmacol. 2009 Aug 15;616(1-3):200-5.

Apigenin is shown to have cardiovascular effects, but the effects of Apigenin on aortas injured by exogenous oxidants are unknown. The objective of this study was to investigate the effect of Apigenin on endothelium-dependent vasorelaxation in isolated rat aortic rings exposed to superoxide anion produced by pyrogallol, and its mechanism. The male Sprague-Dawley rat thoracic aorta was rapidly dissected out and the effect of Apigenin on tension of aortic rings pretreated with 500 microM pyrogallol, inducing oxidative stress injury, was measured. The activity of nitric oxide synthase (NOS), the level of nitric oxide (NO) and the inhibition of superoxide anion in aortic tissues were measured. We found that pretreatment with pyrogallol concentration-dependently decreased acetylcholine-induced endothelium-dependent vasorelaxation. Apigenin (0.5-72.0 microM) evoked a concentration-dependent relaxation in aortas (pD(2): 5.304+/-0.049), which was weakened by L-NAME (the maximal relaxation fell from 87.6+/-6.7% to 37.1+/-8.8%, P<0.01), but not by aminoguanidine and indomethacin. Apigenin markedly attenuated the inhibition of vasorelaxation induced by pyrogallol (the maximal relaxation elevated from 55.8%+/-6.6% to 69.5%+/-6.4%, and the pD(2) increased from 6.559+/-0.119 to 7.057+/-0.145, P<0.01) and increased the inhibition of superoxide anion (from 94.6% to 74.5%), the NO level (from 77.1% to 94.4%), and the constitutive NOS activity (from 35.1% to 62.5%). These results indicate that pyrogallol decreased endothelium-dependent vasorelaxation in rat aortas via oxidative stress, which was markedly attenuated by Apigenin. This may be mediated by weakening the oxidative stress and the NO reduction.

Suppression of protein kinase C and nuclear oncogene expression as possible molecular mechanisms of cancer chemoprevention by apigenin and curcumin.[Pubmed:9589348]

J Cell Biochem Suppl. 1997;28-29:39-48.

Apigenin, a less-toxic and non-mutagenic flavonoid, suppressed 12-0-tetradecanoyl-phorbol-13-acetate-(TPA)-mediated tumor promotion of mouse skin. TPA had the ability to activate protein kinase C (PKC) and induced nuclear proto-oncogene expression. Our study indicates that Apigenin inhibited PKC by competing with adenosine triphosphate (ATP). Apigenin also reduced the level of TPA-stimulated phosphorylation of cellular proteins and inhibited TPA-induced c-jun and c-fos expression. Curcumin, a dietary pigment phytopolyphenol, is also a potent inhibitor of tumor promotion induced by TPA in mouse skin. When mouse fibroblast cells were treated with TPA alone, PKC translocated from the cytosolic fraction to the particulate fraction. Treatment with 15 or 20 microM curcumin for 15 min inhibited TPA-induced PKC activity in the particulate fraction by 26-60%. Curcumin also inhibited PKC activity in vitro by competing with phosphatidylserine. Curcumin (10 microM) suppressed the expression of c-jun in TPA-treated cells. Fifteen flavonoids were examined for their effects on morphological changes in soft agar and cellular growth in v-H-ras transformed NIH3T3 cells. The results demonstrated that only Apigenin, kaempferol, and genistein exhibited the reverting effect on the transformed morphology of these cells. Based on these findings, it is suggested that the suppression of PKC activity and nuclear oncogene expression might contribute to the molecular mechanisms of inhibition of TPA-induced tumor promotion by Apigenin and curcumin.

Reversion of v-H-ras-transformed NIH 3T3 cells by apigenin through inhibiting mitogen activated protein kinase and its downstream oncogenes.[Pubmed:7626110]

Biochem Biophys Res Commun. 1995 Jul 26;212(3):767-75.

Apigenin, a plant flavonoid, induced the reversion of transformed phenotypes of v-H-ras-transformed NIH 3T3 cells at a quite low concentration of 12.5 microM. In the present study, we have examined the components of this Ras-mediated signaling transduction to determine whether they were involved in the Apigenin-induced reversion process. Interestingly, the consitutively activated mitogen activated protein kinase (MAPK) in the ras transformant was inhibited significantly and rapidly by 25 microM Apigenin within 30 min, and this reduction continued for more than 4 h. Corroborating these observations, expression of the downstream oncogenes c-jun and c-fos was also dramatically reduced during the first 4 h of treatment. We found that the levels of ras protein and mRNA were not affected by 24 h of treatment with Apigenin. These findings indicate that Apigenin-induced reversion of v-H-ras-transformed NIH 3T3 cells may occur by inhibiting MAPK activity and its downstream oncogenes rather than by affecting the expression of the ras gene.

Apigenin induces morphological differentiation and G2-M arrest in rat neuronal cells.[Pubmed:7980517]

Biochem Biophys Res Commun. 1994 Oct 28;204(2):578-84.

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.

Apigenin (4',5,7-Trihydroxyflavone) is a competitive CYP2C9 inhibitor with a Ki of 2 μM.

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