Apigenin: Healing Properties and Cancer Effects

    Apigenin is an aglycone Flavonoid; it’s in the Flavone class of the subgroup Anthoxanthins. Apigenin is a natural, active ingredient found almost ubiquitously in plants. With high concentrations in celery and parsley, it is also found in apples, endive, broccoli, cherries, leeks, onions, tomatoes, grapes, grapefruit, chamomile tea, red wine, beans, barley, kumquats, and some berries such as elderberries, as well as in herbs such as basil, oregano, tarragon, cilantro, foxglove and spearmint. Apigenin is an active ingredient in the memory herb, Gingko Biloba.[i]

HEALTH BENEFITS OF APIGENIN

While the FDA has not approved any health claims for flavonoids, there are many scientific studies, in vitro (lab) and in vivo (live animal studies), published on the NIH website, PubMed and elsewhere supporting health benefits from flavonoid consumption and demonstrating their positive impact in many biological processes. Flavonoids such as Apigenin are reported to initiate the production of cell-signaling molecules which stimulate the body’s regulation, response and repair at the molecular level. Flavonoids are shown to support overall health, reduce inflammation, fight free radical damage, and lower the risk of disease as well as to ameliorate disease conditions. 

Flavonoids are probably best known for their antioxidant, anti-inflammatory and anti-allergenic properties. They may lower inflammation that leads to joint pain, digestive problems, skin disorders, and other health issues.[ii] They limit the activity of enzymes that are involved in the formation of free radicals and thus protect the body and help the body heal from free radical damage and a number of illnesses and diseases.

Research on flavonoid-laden celery has found that Luteolin in celery juice may reduce inflammation and allergic responses.[iii] Apigenin likewise reduces inflammation and arthritis symptoms. Additionally, Apigenin may help regulate the immune system to benefit those with autoimmune diseases and provide some protection from developing an autoimmune condition in the first place.[iv]  Allergies are autoimmune conditions, too. A proprietary product, FlavoCare capsules by Dr. Jay’s Naturals, combines these two flavonoids, Apigenin (the primary ingredient) and Luteolin, with the flavones Chrysoeriol and Tricin for augmented, synergistic effect.

Other animal studies focus on the anti-viral and anti-bacterial properties of flavonoids. That’s why some homeopathic users suspect it’s the Apigenin in Elderberry Syrup that accounts for most of the syrup’s effective anti-viral activity they believe helped them and their families fight coronavirus successfully and even prevent other family members from contracting the highly contagious virus from an infected member in the house.

Various experimental models and clinical trials also demonstrate the therapeutic potential of Apigenin for neuroprotection through multiple mechanisms. Researchers hope to maintain and enhance surviving neurons, thereby delaying the progression of neurodegenerative disorders (NDDs) such as Alzheimer’s and Parkinson’s diseases. With Apigenin, the body can reduce the increase of neurotoxic agents such reactive oxygen species (ROS) as well as the associated inflammatory cascades.[v]

Apigenin has also been found to exert anti-diabetic effects in the body by potentiating the GLUT4 response to insulin.[vi] These are just some of the important health benefits of Apigenin.

APIGENIN AND HORMONES

Animal studies show Apigenin has a beneficial effect on many hormones, some of which could be cancer-preventive or have therapeutic applications. A few examples:

  • Testosterone – Apigenin modifies a receptor (TBXA2) and an enzyme’s activity (aromatase) in a manner that brings about increased testosterone activity at relatively low concentrations.[vii]
  • Estrogen — Apigenin in DU-125 and MDA-MB-231 breast cancer cells appears to inhibit proliferation, and in yeast analyses activated both subunits of the estrogen receptor (ERα and ERβ).[viii]
  • Cortisol — In isolated human H295R adrenal cells, 12.5μM of Apigenin decreased cortisol to 47.5% of control (yet was outperformed by both soy isoflavones).[ix]

APIGENIN AS AN ANTI-CANCER AGENT

Abundant evidence speculates that flavonoids like Apigenin may be helpful in the reduction of cancer risk simply by functioning as antioxidants and eliminating free radicals that have been linked to DNA damage and inflammation. But Apigenin does more. In the 1980’s, Birt et al. first demonstrated the effective anti-mutagenic and anti-promotive aspects of Apigenin.[x]

Since then, extensive research in various animal models of cancer and clinical trials have shown the promising chemopreventive and potential therapeutic aspects of Apigenin at each stage of carcinogenesis as well as its anti-tumor activities and low toxicity. Cancer chemoprevention is categorized at the molecular level by the disruption of multiple pathways and processes of the three stages of carcinogenesis: initiation, promotion and progression. The anticarcinogenic properties of Apigenin occur primarily through its impact on these processes: [xi],[xii],[xiii]

  • Regulation of cellular response and reduction of oxidative stress and DNA damage (which set the stage for malignant change),
  • Suppression of inflammation (which creates a fertile environment for cancer),
  • Suppression of angiogenesis (formation of new blood vessels, bad in cancer feeding its growth),
  • Induction of cell cycle inhibition and retardation of cell proliferation (tumor growth) and cell migration (metastasis),
  • Increase of hepatic detoxification enzyme’s efficacy,
  • Induction of cell autophagy (cell regulating mechanism that removes unnecessary or dysfunctional components for orderly degradation and recycling of cellular components) and
  • Induction of cell apoptosis (programmed cell death; destruction of cancer cells).

As Sung noted in the Journal of Cancer Prevention in 2016: [xiv]

“One of the most well-recognized mechanisms of apigenin is the capability to promote cell cycle arrest and induction of apoptosis through the p53-related pathway. A further role of apigenin in chemoprevention is the induction of autophagy in several human cancer cell lines.”

The following results are merely examples among the very many studies of Apigenin’s help in the fight against cancer and a limited enumeration of the many cancers impacted by Apigenin. The volume of studies is too vast to begin to document all here. But results of all we’ve seen and authoritative articles we’ve read tend to be fairly consistent and confirming.

  1. Anticancer Agent – In several experimental and biological studies, Apigenin has been reported as an anticancer agent exhibiting cell growth arrest and apoptosis in different types of tumors such as breast, lung, liver, skin, blood, colon, prostate, pancreatic, cervical, oral, and stomach by modulating several signaling pathways.[xv]
  2. Oral Cancer – Apigenin has been found to lower tumor incidence in DMBA-induced hamsters.[xvi],[xvii] Other studies investigated the chemopreventive potential of Apigenin by analyzing the tumor incidence as well as monitoring lipid peroxidation, antioxidants and phase I and phase II detoxification as biomarkers during DMBA induced hamster buccal pouch carcinogenesis. Oral administration of Apigenin for 15 weeks resulted in reduction of tumor volume and incidence, modulation of cell proliferation, apoptosis, inflammation, and angiogenesis markers, and modulation of phase I and II detoxification cascades.[xviii],[xix]
  3. Breast Cancer – The University of Missouri has conducted several enlightening in vitro studies on Apigenin and breast cancer. In 2012, mice were implanted with cells of a particularly deadly, fast-growing human breast cancer. When treated with Apigenin, cell proliferation (growth) was inhibited and expression of a gene associated with cancer malignancy was reduced. The cancerous growth slowed and the tumors shrank. Angiogenesis was also impeded; the blood vessels feeding the tumors shrank, restricting nutrient flow and starving the tumors of the nutrients needed to spread. [xx] The results were confirmed in a follow-up study when rats with breast cancer were treated with Apigenin. They developed fewer tumors and experienced significant delays in new tumor formation. Researchers at the University of Missouri have concluded:

” … it appears that keeping a minimal level of apigenin in the bloodstream is important to delay the onset of breast cancer ….”[xxi]  

In another study, Apigenin significantly decreased the level of a growth protein involved in growth factor signaling, Her2/neu, indicating Apigenin caused a reduction in breast cancer cell proliferation in the treated mice.[xxii]

  1. Ovarian Cancer — The association between intake of five common dietary flavonoids (myricetin, kaempferol, quercetin, luteolin and apigenin) and ovarian cancer risk was evaluated in a case-control study involving 1,141 patients with ovarian cancer and 1,183 frequency-matched control subjects. The finding: only Apigenin intake was associated with decreased cancer risk, and the association was only of borderline significance.[xxiii] (We suspect the level of impact was due to the poor bioavailability of dietary Apigenin, indicating that significance could increase with improved absorption and higher dosage.)
  2. Rectal Cancer – From a total of 12 studies on the PubMed and EMBASE databases involving 17,481 cases and 740,859 controls, it was concluded that high intake of dietary flavonols, flavones and anthocyanidins may decrease the risk of colorectal cancer. Specifically, high intake of flavonols (such as quercetin) may reduce the risk of colon cancer, and high intake of flavones (such as Apigenin) may reduce the risk of rectal cancer.[xxiv]
  3. Colon Cancer – Studies reflect the beneficial effect of Apigenin against chemical- and mutation-induced colon carcinogenesis. When rats were provided Apigenin in their diet (0.1%) after being induced by azoxymethane injection, apoptosis of luminal surface colonocytes was triggered and the incidence of aberrant crypt foci was reduced (the earliest identifiable lesions in colon cancer development), particularly in the tumor initiation phase. It was noted that the ability of dietary apigenin and naringenin to reduce HMACF, lower proliferation (naringenin only) and increase apoptosis may contribute toward colon cancer prevention. However, these effects were not due to mitigation of iNOS and COX-2 protein levels at the ACF stage of colon cancer.[xxv] In the same model, subcutaneous injections of Apigenin significantly decreased the incidence of peritoneal metastasis of intestinal adenocarcinomas.[xxvi]

    In APC mice, oral Apigenin administration activated the tumor-suppressor gene p53 resulting in a reduced number of polyps. [xxvii] Other studies involving oral administration of Apigenin have shown decreased volume and wet weight of tumors without any undesirable side effects, decreased IGF-I levels and induced apoptosis and cell cycle arrest in tumor xenograph. The anti-metastatic activity of Apigenin in an orthotopic colorectal nude mouse model was reported in a 2013 article, “Apigenin up-regulates transgelin and inhibits invasion and migration of colorectal cancer through decreased phosphorylation of AKT.”[xxviii]

    Apigenin was shown to sensitize human colorectal carcinoma to apoptosis (programmed cell death). A comparative study of nine dietary flavonoids examined their effect on cell growth in HCT116 human colon cancer cells. Among the tested flavonoids, Apigenin was found to be the most potent inhibitor of cell growth. [xxix] Apigenin also induced apoptosis in other colon cancer cell lines.

  4. Prostate Cancer – The chemopreventative effect of Apigenin was explored in at least a dozen in vivo studies (rats, hamsters, etc.) including testing doses, administration routes and treatment frequencies. In transgenic adenocarcinoma of a mouse prostate (TRAMP) model, 20-week oral administration of Apigenin reduced tumor volumes and completely abolished distant organ metastasis by suppression of a signaling pathway.[xxx]

    Deregulation of IGF signaling plays an important role in prostate cancer and contributes to invasion and metastasis. The same research group showed that Apigenin effectively suppressed prostate cancer progression by attenuating insulin-like growth factor (IGF)-I/IGF binding protein-3 signaling and inhibiting angiogenesis (new blood vessel creation to feed the cancer) and metastasis (spread of cancer).[xxxi]

    In another study, Apigenin was shown to interrupt the NF-KB signaling pathways responsible for suppression of the prostate cancer’s progression.[xxxii]

  5. Lung Cancer – Studies imply chemoprevention of lung cancer with Apigenin. In one study, when mice carrying A549 lung cancer xenographs were treated with Apigenin, tumor volume was reduced. This was partially attributable to interruption of the HIF-1a-vascular endothelial growth factor pathway and subsequent suppression of angiogenesis and cell proliferation.[xxxiii]
  6. Pancreatic Cancer – A six-week dietary intake of Apigenin (0.2%) in nude mice with orthotopically-implanted human pancreatic cancer produced significant anti-tumor activity with evidence of activation of mutated p53. With Apigenin treatment, pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis.[xxxiv]

Overall, the majority of these and other findings indicate that Apigenin can inhibit tumor initiation, progression, and metastasis in a wide variety of preclinical cancer models and also has notable effects on apoptosis.

Apigenin’s effects on apoptosis have been studied extensively in cell populations of many different cancers. This programmed cell death is a critical process by which abundant or undesirable cells can be removed. A huge body of evidence demonstrates that deregulation or mutation of apoptosis contributes to numerous pathological conditions such as neurodegenerative diseases, autoimmunity and cancer. Apigenin has been shown either to induce apoptosis directly or to sensitize cells to other pro-apoptotic stimuli in cancer cell lines of oral, esophageal, colorectal, hepatic and pancreatic cancers.[xxxv]

From his own reviews of research and literature regarding Apigenin and cancer, Dr. Joseph Mercola concludes: [xxxvi]

“Apigenin appears so promising in the fight against cancer that researchers said injections of the substance could be a safe alternative to toxic chemotherapy. While chemo is notorious for its sometimes-lethal side effects…, apigenin caused no side effects, even at high doses. But imagine the frustration these researchers must feel, knowing they’ve found a potential safe, inexpensive and natural cancer fighter, but being unable to convince anyone to fund further research ….”

CONCLUSION 

There are no controlled human studies for scientific validation of laboratory tests, animal studies, or clinical and anecdotal results for the effect of various health benefits in humans due primarily to funding difficulties. Nevertheless, results in laboratory tests and clinical trials are promising and enlightening. Of note, they suggest ingestion of Apigenin would be safe and effective for the many health benefits reported, including in the fight against cancer.[xxxvii]

In an article in 2011, researcher Salman Hyder, the Zalk Endowed Professor in Tumor Angiogenesis at the University of Missouri, after announcing positive breast cancer results in mice, concluded: [xxxviii]

“Clinical trials of apigenin with humans could start tomorrow, but we have to wait for medical doctors to carry out that next step. One problem is, because apigenin doesn’t have a known specific target in the cancer cell, funding agencies have been reticent to support the research. Also, since apigenin is easily extracted from plants, pharmaceutical companies don’t stand to profit from the treatment; hence the industry won’t put money into studying something you can grow in your garden.”

Nevertheless, dietary supplementation of nutritious foods and concentrated supplements can offer people the safe opportunity to experience benefits of natural elements for themselves to whatever extent their own unique biology and condition permit, and to the extent of the concentration and bioavailability of the substance they ingest – just as people around the world have been doing for centuries. The only differences are that today, we have controlled laboratory and animal tests, and biomolecular science can both explore the mechanisms by which the elements function in the body and provide scientists opportunities to improve bioavailability.

We know that to experience optimum health benefits of any substance, absorption and cellular bioavailability are very important. The absorption of dietary Apigenin into the bloodstream is unknown, and Apigenin has a sugar molecule attached which makes it too large for full absorption. The active Apigenin in food and herbal sources is in the form of various acylated derivates and Apigenin-7-O-glucoside.[xxxix]

But Dr. Jay’s patented process addresses the absorption problem by concentrating Apigenin with complementary nutrients such as Luteolin and removing a glucose molecule. That makes the flavonoid molecules small enough to enter the cells readily. [xl] This, in theory, should amplify the absorption, dosing and health benefits of Apigenin many times over with Dr. Jay’s FlavoCare capsules, a proprietary benefit not available elsewhere.

FlavoCare is a unique blend of potent aglycone flavonoids designed to support health and well-being and can be found at this link: Flavocare Capsules -Dr. Jay’s Naturals.

 

 

[i] Patel D, Shukla S, Gupta S. Apigenin and cancer chemoprevention: progress, potential and promise (review)Int J Oncol. (2007)

[ii] Li, et al. Advances in the research of celery, an important Apiaceae vegetable crop – PubMed (nih.gov). Crit Rev Biotechnol. (2018 Mar)

[iii] Jang, et al. Anti-allergic effect of luteolin in mice with allergic asthma and rhinitis (nih.gov). Cent Eur J Immunol. (2017)

[iv] Li, et al. Apigenin, a potent suppressor of dendritic cell maturation and migration, protects against collagen‐induced arthritis – Li – 2016 – Journal of Cellular and Molecular Medicine – Wiley Online Library

[v] Nabavi S F, et al. Apigenin as neuroprotective agent: Of mice and men – PubMed (nih.gov). Pharmacol Res. (2018)

[vi] Patel Kamal (lead research analyst). Apigenin. https://examine.com/supplements/apigenin/research/#sources-and-composition. Examine.com. [Last update: 2019 Aug 16]

[vii] Li W, et al. Effects of apigenin on steroidogenesis and steroidogenic acute regulatory gene expression in mouse Leydig cells – PubMed (nih.gov) J Nutr Biochem. (2011)

[viii] Mak P, et al. Apigenin suppresses cancer cell growth through ERbetaNeoplasia. (2006)

[ix] Ohno S, et al. Effects of flavonoid phytochemicals on cortisol production and on activities of steroidogenic enzymes in human adrenocortical H295R cellsJ Steroid Biochem Mol Biol. (2002)

[x] Birt DF, et al. Anti-mutagenesis and anti-promotion by apigenin, robinetin and indole-3-carbinol – PubMed (nih.gov) Carcinogenesis. (1986)

[xi] Sung Bokyung, et al. Role of Apigenin in Cancer Prevention via the Induction of Apoptosis and Autophagy (nih.gov). J. Cancer Prev. (2016 Dec)

[xii] O’Prey J, et al. Effects of dietary flavonoids on major signal transduction pathways in human epithelial cellsBiochem Pharmacol. (2003)

[xiii] Surh YJ. Cancer chemoprevention with dietary phytochemicalsNat Rev Cancer. (2003)

[xiv] Sung Bokyung, et al. Role of Apigenin in Cancer Prevention via the Induction of Apoptosis and Autophagy (nih.gov). J. Cancer Prev. (2016 Dec)

[xv] Muhammad I, et al.  Apigenin as an anticancer agent – PubMed (nih.gov). Phytother Res. (2020 Aug) PMID: 32059077

[xvi] Gomez-Garcia FJ, et al. Effect of the phenolic compounds apigenin and carnosic acid on oral carcinogenesis in hamster induced by DMBA – PubMed (nih.gov)  Oral Dis. (2013 Apr)

[xvii]Baldasquin-Caceres B, et al. Chemopreventive potential of phenolic compounds in oral carcinogenesis – PubMed (nih.gov). Arch Oral Biol. (2014 Oct)

[xviii] Silvan S, et al. Apigenin prevents deregulation in the expression pattern of cell-proliferative, apoptotic, inflammatory and angiogenic markers during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis – PubMed (nih.gov). Arch Oral Biol. 2013

[xix] Silvan S, et al. Chemopreventive potential of apigenin in 7,12-dimethylbenz(a)anthracene induced experimental oral carcinogenesis – PubMed (nih.gov)Eur J Pharmacol. (2011 Nov 30)

[xx] Mafuvadze B. Apigenin induces apoptosis and blocks growth of medroxyprogesterone acetate-dependent BT-474 xenograft tumors – PubMed (nih.gov). Horm Cancer. (2012 Aug)

[xxi] Hyder S., et al. Parsley, Celery Carry Crucial Component for Fight Against Breast Cancer, MU Researcher Finds | News Bureau, University of Missouri (2011 May 09)

[xxii] Mafuvadze B, et al. Apigenin induces apoptosis and blocks growth of medroxyprogesterone acetate-dependent BT-474 xenograft tumors – PubMed (nih.gov)Horm Cancer. (2012 Aug)

[xxiii] Gates MA, et al. Flavonoid intake and ovarian cancer risk in a population-based case-control study – PubMed (nih.gov) Int J Cancer. (2009 Apr 15)

[xxiv] Hui Chang. Dietary Flavonoids and the Risk of Colorectal Cancer: An Updated (greenmedinfo.com). Nutrients. Epub 2018 Jul 23. PMID: 30041489

[xxv] Leonardi T, et al. Apigenin and naringenin suppress colon carcinogenesis through the aberrant crypt stage in azoxymethane-treated rats – PubMed (nih.gov)Exp Biol Med (Maywood) (2010)

[xxvi] Tatsuta A, et al. Suppression by apigenin of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats – PubMed (nih.gov)Clin Exp Metastasis. (2000)

[xxvii] Zhong Y, et al. Molecular targets of apigenin in colorectal cancer cells: involvement of p21, NAG-1 and p53 – PubMed (nih.gov)Eur J Cancer. 2010

[xxviii] Chunhua L, et al. Apigenin up-regulates transgelin and inhibits invasion and migration of colorectal cancer through decreased phosphorylation of AKT – PubMed (nih.gov)J Nutr Biochem. (2013 Oct)

[xxix] Zhong Y, et al. IBID

[xxx]   Shukla S, et al. Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway – PubMed (nih.gov)  Carcinogenesis. (2014 Feb)

[xxxi] Shukla S, et al. Apigenin attenuates insulin-like growth factor-I signaling in an autochthonous mouse prostate cancer model – PubMed (nih.gov). Pharm Res. (2012 Jun)

[xxxii] Shukla S, et al. Apigenin blocks IKKα activation and suppresses prostate cancer progression – PubMed (nih.gov)Oncotarget. (2015 Oct)

[xxxiii]  Liu LZ, et al. Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: implication of chemoprevention of lung cancer – PubMed (nih.gov)Mol Pharmacol. (2005

[xxxiv] King JC, et al. Evidence for activation of mutated p53 by apigenin in human pancreatic cancer – PubMed (nih.gov)Biochim Biophys Acta. 2012;]

[xxxv] Sung B, et al. Role of Apigenin in Cancer Prevention via the Induction of Apoptosis and Autophagy (nih.gov)J Cancer Prev. (2016 Dec)

[xxxvi] Mercola J. Can Celery Help Treat Breast Cancer? (mercola.com). (2012 June 04)

[xxxvii] Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safetyAnnu Rev Nutr. (2002)

[xxxviii] University of Missouri. Breast Cancer Effectively Treated with Chemical Found in Celery, Parsley by MU Researchers | News Bureau, University of Missouri. (2021 May 15)

[xxxix] Svehliková V, et al. Isolation, identification and stability of acylated derivatives of apigenin 7-O-glucoside from chamomile (Chamomilla recutita (L.) Rauschert)Phytochemistry. (2004)

[xl] Flavocare Capsules -Dr. Jay’s Naturals.