Roles of Apigenin in Cancer Prevention

Apigenin, one common flavonoid, has anticancer and chemopreventive effects through its inhibitory properties on the several cellular signaling pathways such as phosphatidylinositol 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling (PI3K/AKT/mTOR signaling pathway). 
In this article, I will review the basic information about of apigenin from its chemical structure, properties to apigenin’s antitumor and chemoprevention effects. You can find these information within subtitles written below;

Apigenin is a member of polyphenolic compounds 

Apigenin is placed in the Flavonoid Class of Polyphenols  

Apigenin containing foods

Apigenin properties and chemical structure

Apigenin Solubility

Apigenin Dosage  

Apigenin and Cancer 

Anti-inflammatory effect of apigenin

Apigenin Anticancer Effects on molecular level

Here we go our apigenin journey :) 

Apigenin is a member of polyphenolic compounds


Polyphenolic compounds are made by plants, mainly it is a product of secondary metabolism of plants. Polyphenols are wide range of biologically active molecules and play a protective roles in plants. They regularly bring into being linked to glycosides or plant sugars. Polyphenols also form a huge family of many thousands of molecules found in everyday foods such as, vegetables, fruits, tea, cocoa, chocolate, wine, grapes, onion, garlic and so on... Nearly 8000 polyphenolic chemicals identified so far and these polyphenols are classified into about 10 different groups by virtue of their chemical structures (Phenolic Acids, Stilbenes, Flavonoids, Lignans and etc.)

Polyphenols are used in the food industry as an additive and in food supplements and cosmetics products.

Apigenin is placed in the Flavonoid Class of Polyphenols  


The largest class of polyphenols is Flavonoids. They are nearly 5000 compound known as flavonoids. They have a common structure of diphenylpropanes (C6-C3-C6) and 1 or more hydroxyl residues.

The subclasses of flavones and flavonols are structurally similar compounds, with flavonols having an extra hydroxyl substitution at the carbon-3 position, and flavone apigenin and flavonol quercetin are the frequently found molecules in foods.

Flavonoids have attracted a great deal of scientific attention because of their variety of biological effects. Studies having been performed so far, identified several activities of flavonoids including, 

  • Free radical scavenging and antioxidant activity,
  • Anti-inflammatory effects,
  • Anticancer activity, inhibiting cellular proliferation, inducing of apoptosis
  • Modulating enzymatic activity
  • Inhibiting platelet aggregation and
  • Reducing plasma levels of low-density lipoproteins.
  • These effects of flavonoids might support to clarify flavonoids’ probable advantage in cancer chemoprevention.

Apigenin containing foods


So far we know, apigenin is plentifully found in fruits, vegetables and beverages. Apigenin is found in foods mostly as glycoside conjugates in its natural form, which are more water soluble than its pure form. In in vivo conditions, these glycoside conjugates are digested and hydrolyzed well by bacterial enzymes in the human intestinal tract to form free apigenin molecules.

Apigenin containing fruits are oranges, apples, cherries and grapes.

Apigenin containing vegetables are onions, celery, parsley, broccoli, sweet green pepper, celery, barley and tomatoes.

Apigenin containing beverages are tea, wine and recently found in beer.

Other apigenin food sources include some spices as oregano, tarragon, cilantro, basil, parsley, onions, oranges, tea, chamomile and wheat sprouts. 

Other apigenin herbs as endives and cloves have also much amount of this bioactive molecules.

Apigenin properties and chemical structure


Apigenin (5,7,4'-trihydroxyflavone), naturally occurring flavonoid, belongs to the flavone subclass of flavonoids.
apigenin chemical formula
Chemical Structure of Apigenin

Pure form of apigenin is a yellow crystalline solid. Structurally, apigenin was first identified in 1900, and synthesized in 1939. Apigenin has a melting point of 347.5 °C and its molecular weight of 270.24 g/mol.

Apigenin Solubility


Apigenin is soluble in dimethylsulfoxide (DMSO) (>100 mg/mL)

Apigenin is also soluble to some extent in acetone and alcohols such as ethyl alcohol (ethanol), octyl alcohol  (n-octanol) and propylene glycol (1.02–1.63 mg/mL).

Apigenin is almost unsolvable in extremely polar solvents such as water (0.00135 mg/mL).

Apigenin is also nearly insoluble in nonpolar solvents such as silicon fluid (0.0728 mg/mL) and safflower oil (0.0317 mg/mL)

Apigenin Dosage 

 
Latest reports have displayed that bioavailability of particular flavonoids can be rather considerably varying. Nutritional consumptions of flavonoids in humans differ from low in Western countriesto high in Asia, 13 mg/day in the USA and 64 mg/day in Japan, respectively. 

Apigenin appears to be taken in humans by intestinal cells. In a randomized crossover research with two one-week involvement periods in sequence, unpaid helpers consumed a food regimen that contained 20 g/day parsley. By the way, it is important to note that parsley is one of the apigenin rich food.

In the parsley-eating group, apigenin excretion via urine was considerably higher than in the basic diet control group. Apigenin’s half-life was found to be around 12 hours.

In another study after the first 2 h of dermal exposure, apigenin containing chamomile flower heads in the form of aqueous alcoholic extracts was shown to be intense in the outermost of the 5 layers of the epidermis called stratum corneum and mainly in charge for the vital block role of the skin. After 3 hours, apigenin spreads through deeper skin layers to be intake afterwards by cutaneous blood and lymph vessels.

Similar to the daily intake of flavonoid in humans as reported previously,  in mice plasma, apigenin feeding at  20 µg/mouse/day dose resulted 0.63–0.78 µM apigenin concentrations. Moreover, feeding mice with 0.2% apigenin in diet for 7 days caused steady-state tissue amounts of 1.5 µM in the liver and 86 µM in the small intestinal mucosa, respectively.

Apigenin has also been reported to have antimutagenic activity in mice skin. Moreover apigenin has the ability of inhibition of ultraviolet (UV) radiation or chemically induced skin cancer development. Performed studies also suggest that apigenin might both relieve oxidative stress and aid in the detoxification of mutagenic xenobiotics. These initial observations with apigenin create more interest in the growth of apigenin as a chemopreventive agent.

Apigenin and Cancer 


Studies shows apigenin as a cancer fighter molecule on different human cancers and cell lines. Scientific investigations, performed so far, have been demonstrated protective roles of apigenin on several human cancers and cell lines originated from different tissues. In these studies, apigenin has been found to be effective on breast cancer, prostate cancer, colon cancer, colorectal cancer, cervical cancer, skin cancer, lung cancer, ovarian cancer, liver cancer, pancreatic cancer and hematologic malignancies.

In breast cancers, apigenin inhibits breast cancer cell proliferation, induce apoptosis, suppress cell invasion and metastasis. Apigenin also has  antiestrogenic activity for these cancer type.

In prostate cancer, apigenin induces apoptosis and G1 phase arrest of cell cycle and inhibits cellular growth. Moreover apigenin also suppresses Hypoxia-inducible factor 1-alpha (HIF-1?) and vascular endothelial growth factor (VEGF) expression. Furthermore, apigenin inhibits focal adhesion kinase (FAK)-Src signalling through paxillin, ERK and MLCK.

For the colon cancer, apigenin was shown to inhibit cell growth, induce G2/M arrest of the cell cycle, increase the stability of p53 protein and, also induce apoptotic cell death.

For the cervical cancer, apigenin was found to inhibit cell growth and cause G1 cell cycle arrest. Moreover, apigenin suppress cervical cancer cell motility, invasion ability and induce apoptosis. 

For the skin cancer apigenin was found to induce autophagy and apoptosis, reduce COX2 levels and MMP1 expression.

With respect to the Lung cancer, apigenin suppress Vascular endothelial growth factor (VEGF) mRNA expression and induce programmed cell death, also known as apoptosis.

In ovarian cancer, apigenin inhibits cell proliferation and vascular endothelial growth factor (VEGF) expression and also diminish cell migration and invasion.

For the liver cancer, apigenin was found to inhibit liver cancer cells proliferation, to induce apoptosis and to enhance radiotherapy approach. 

In studies based on pancreatic cancers, apigenin was found to inhibit activation of focal Adhesion kinase, to suppress Hypoxia-inducible factor 1-alpha (HIF-1?), vascular endothelial growth factor (VEGF) and geminin expression. Apigenin also induce the arrest of G2/M pass of cell cycle in pancreatic cancer cells. 

Apigenin also effective in hematologic malignancies. Apigenin was found to inhibit cell proliferation, to induce apoptosis and also to suppress telomerase activity in hematologic tunors. 

Anti-inflammatory effect of apigenin


The anti-inflammatory effect of apigenin has been shown in several studies.

Notably, apigenin inhibits cyclooxygenase-2 (COX-2) expression by blocking AKT signal transduction and arachidonic acid release.

Cyclooxygenase-2 (COX-2) is a key enzyme in the transformation of arachidonic acid to prostaglandins (PGs), and COX-2 expression plays an important role in inflammation. Moreover, Nicholas et al. reported that apigenin stopped pro-inflammatory cytokine expression, such as Interleukin-1 beta (IL-1ß), Interleukin-8 (IL8), and Tumor necrosis factors (TNF), by inactivating Nuclear factor-kappa B (NFkB) via the inhibition of p65 phosphorylation.

Apigenin Anticancer Effects on Molecular Level


Apigenin anticancer effects are linked to its ability to regulate several numbers of molecular target and signaling pathways. Apigenin affects proteins involved in the apoptosis, control of cell cycle, angiogenesis, cancer cell invasion, metastasis to different tissues and organs,  and signaling pathways. 
Apigenin inhibits cell growth by virtue of effecting several protein such as p34 (CDC2) kinase, cyclin B1, p21/WAF1, cdk2 kinase, Rb, p53 protein and HuR proteins.

Apigenin induces apoptosis by its effect on Bax localization, cytochrome c release, BCL-2, Bax/BCL2 ratio, caspase-3 (CASP3), poly-(ADP-ribose) polymerase (PARP), procaspase-9 (proCASP9) and c-FLIP proteins.

Apigenin diminishes tumor angiogenesis with its interaction to IL-6/STAT3 pathway, extracellular signal-regulated kinase-1/2 (ERK) signaling, extracellular matrix degrading enzyme MMP-2, Platelet-derived growth factor (PDGF) receptor beta (PDGFR-beta), hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF), PI3K/Akt/p70S6K1 and HDM/p53 signalling pathways.

Apigenin inhibits the migration, invasion and metastasis through blocking MMP-9 and focal adhesion kinase (FAK) expression.

apigenin and mTOR signalling
Apigenin affects AKT and mTOR signalling


Apigenin also inhibits both AKT also known as protein kinase B (PKB) and mammalian target of rapamycin (mTOR) signaling pathways. Apigenin activates 5' adenosine monophosphate- (AMP) activated protein kinase (AMPK) through Ca(2+)/CaM-dependent protein kinase kinase ß (CaMKKß), further inhibiting activity of mTOR. Apigenin also inhibits AKT, which activates mTOR by negatively regulating TSC2 and Pras40.


This page will be updated regulary as the new striking research papers are published.

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