APIGENIN

Apigenin has only pre-clinical lab results showing mechanisms that support both metabolic health and direct action on cancer. Though clearly promising, translation to clinical evidence of action is limited bu its bioavailability.

Parsley contains high levels, both in fresh and dried forms which may be meaningful, and more likely in combination with other functional foods.

TYPICAL ABSORPTION LEVELS

10 – 20%

EXAMPLES OF IMPROVED OUTCOMES

NO

PRE-DIAGNOSIS OR PREVENTION

NO

Highlighted Studies

..given emerging [pre-clinical] evidence that it may interact beneficially with chemotherapeutic drugs, this is worthy of emphasis. In addition, more effective access to intestinal tissues from the oral route raises the possibility that apigenin may be of particular relevance to gastrointestinal disorders including colorectal cancer

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Furthermore, binding of FoxO3a with p27/Kip1 was markedly increased after 10 and 20 μM apigenin treatment resulting in G 0 /G 1 -phase cell cycle arrest, which was consistent with the effects elicited by PI3K/Akt inhibitor, LY294002. These results provide convincing evidence that apigenin effectively suppressed prostate cancer progression [in laboratory models]

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We further demonstrated that the downregulation of MMP-9 by apigenin was mediated by the AKT/p70S6K1 pathway. These findings help to address the question with common interests to the public of whether oral uptake of flavonoids is effective in preventing cancer. Our results demonstrate for the first time that oral uptake of apigenin can inhibit tumor metastasis [in a pre-clinical animal model]

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Additionally, it has been shown that apigenin or isovitexin affected CSC [Cancer Stem Cell ] metabolism and reduced CSCs through various mechanisms,… The findings of this study demonstrate that apigenin and isovitexin are potent candidates for treating cancer due to their antagonistic effects on CSC metabolism [test tube study]

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TABLE OF REFERENCES

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https://www.mdpi.com/1422-0067/13/6/7271Lab study1We developed an orthotopic ovarian tumor model and found that apigenin oral administration inhibited ovarian tumor micrometastasis in liver, lung, small intestine and stomach in different degrees. We also found that apigenin specifically inhibited MMP-9, but not MMP-2 expression in both tumor tissues and cancer cells. We found that AKT is an essential molecule for apigenin-inhibited MMP-9 expression. AKT may transmit the signal through p70S6K1 to activate MMP-9 expression. Since most patients (80%) with ovarian cancer have metastatic disease [21], these findings reveal a protective role of apigenin in cancer metastasis via oral uptake, highlighting a new rationale for apigenin in ovarian cancer prevention and treatment in the future.To determine the amount of micrometastasis in the organs, we quantified the Alu expression levels in different tissue samples. Low doses of apigenin treatment significantly decrease the magnitude of micrometastasis in the liver and stomach, while high doses of apigenin treatment greatly inhibited the micrometastasis in all the four organs tested (Figure 3a,b). Collectively, our in vivo experiments indicate that apigenin inhibits ovarian cancer micrometastasis. As apigenin was administered via the oral route, it indicates that oral uptake of apigenin also has an effect in inhibiting tumor metastasis. Thus, it would be interesting to further investigate the metabolism and pharmacokinetics of apigenin after oral administration in the future
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051376/#Lab study1. The anti-CSC properties of apigenin and isovitexin have been linked to the modulation of different signaling pathways, such as the NF-κB, Wnt/β-catenin PI3K/Akt, and c-Met signaling pathways, and enzyme activities via stem cell stimulation, the induction of apoptosis, and morphological alterations. Therefore, they are effective inhibitors of distant metastasis in cancer, which can be applied as an adjuvant to radiotherapy and chemotherapy for numerous cancers that are resistant to presently available regimens.This is the first study that offers a review of the literature on the mechanisms of action of apigenin and isovitexin against different CSCs, though there are various other studies on the impact of apigenin and isovitexin on cancer cells rather than CSCs. Taken together, based on the results of this review, these active constituents will function as lead compounds for future antitumor drug discovery targeting CSCs as well as other types of cancer cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244166/Lab study1Furthermore, we demonstrated that apigenin inhibited stemness features of TNBC cells in both in vitro and in vivo assays. Our mechanism study demonstrated that apigenin decreased YAP/TAZ activity and the expression of target genes, such as CTGF and CYR61, in TNBC cells. We also showed that apigenin disrupted the YAP/TAZ-TEADs protein–protein interaction and decreased expression of TAZ sensitized TNBC cells to apigenin treatment. Collectively, our studies suggest that apigenin is a promising therapeutic agent for the treatment of TNBC patients with high YAP/TAZWe also examined the effects of apigenin on the tumor-initiating properties of TNBC cells using an in vivo limited dilution assay. As shown in Fig. 4a, 1 × 106 and 1 × 105 MDA-MB-231 cells formed tumor xenografts with 100% efficiency in the control group, but the tumor formation efficiency of the apigenin-treated group decreased to 50% and 20%, respectively. When cells were seeded at a density of 1 × 104 cells per site, the tumor formation efficiency in the apigenin-treated group decreased to 0%, whereas the control group retained 75% of its efficiency
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067669/Lab study1Based on the synergistic antitumor activity profiles of combined APG and TRAIL treatments in vitro and in vivo and the absence of cytotoxicity in normal tissues, we believe that APG has strong therapeutic value for use in combination with TRAIL against lung cancer that warrants further investigation.Our findings argue that the novel anticancer effects of APG in lung cancer cells involve TRAIL sensitization through the augmented expression of its receptors via NF-κB downregulation and deactivation, JNK activation and the subsequent increase of p53. Wherefore it is suggested that APG could be useful as a new strategy for overcoming TRAIL resistance in cancer therapy.Screenshot from 2024-01-30 19-19-20
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173069/Lab study1In summary, our results imply that apigenin suppresses cancer invasion by inhibiting EMT by suppressing NF-κB-Snail signaling. Our results provide a new mechanistic basis for the therapeutic application of apigenin in HCC patients. Apigenin may be an effective alternative treatment for persistent carcinoma, as well as a new candidate anti-metastasis drug.Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. In this study, we investigated the effects of apigenin on migration and metastasis in experimental human [liver} hepatocellular carcinoma (HCC) cell lines in vitro and in vivo. Apigenin dose-dependently inhibited proliferation, migration, and invasion by human HCC cells. It also suppressed tumor growth in PLC cell xenograftsScreenshot from 2024-03-30 18-23-06
https://academic.oup.com/carcin/article/28/4/858/2391756?login=falseLab study1Angiogenesis is the formation of new blood vessels and is required for tumor growth and metastasis. In this study, we showed that apigenin-inhibited expression of HIF-1 and VEGF in different cancer cells under both normoxic and hypoxic conditions. We demonstrated that apigenin significantly inhibited tumor angiogenesis in vivo , by using both the chicken chorioallantoic membrane and Matrigel plug assays. The inhibition of tumor angiogenesis was associated with the decrease of HIF-1 and VEGF in tumor tissues. Taken together, our results show that apigenin suppresses tumor angiogenesis through HIF-1 and VEGF expressionDuring tumor growth, there is low oxygen environment inside the tumor. Therefore, it is interesting to know whether apigenin could inhibit HIF-1α and VEGF expression induced by hypoxia. Under hypoxia condition, accumulation of HIF-1α and VEGF proteins was observed in PC-3 cells and addition of apigenin suppressed hypoxia-induced HIF-1α and VEGF expression ( Figure 1C ). Similarly, the induction of HIF-1α and VEGF by hypoxia was abrogated in several different cancer cells by apigenin treatment ( Figure 2 ). These results suggest that apigenin inhibits HIF-1α and VEGF expression under both normoxic and hypoxic conditions in different cancer cells.
https://www.frontiersin.org/articles/10.3389/fphar.2021.681477/fullAbsorption and dosage1Therefore in principle it should be possible, using oral dosing of apigenin capsules, to reach circulatory concentrations that are able to influence the biology of systemic targets. Circulatory apigenin should be available to act through the extracellular milieu for a substantial time. As indicated above there is a persistence of 6–9h after oral ingestionCareful examination of the available data indicates that it is unlikely that dietary ingestion of apigenin-containing plant materials–even those with very high levels such as parsley–will lead to biologically meaningful effects on cells...Use of apigenin supplements, with purified apigenin in capsules, can achieve biologically relevant plasma concentrations that would be capable of influencing cellular behaviors
https://academic.oup.com/carcin/article/35/2/452/2462568Absorption and dosage, Lab study1 A study on the bioavailability of apigenin from apiin-rich parsley in healthy human subjects has been demonstrated ( 49 ). Consumption of single oral bolus of 2g blanched parsley corresponding to 65.8±15.5 μM apigenin per kilogram body weight resulted in 127±81nM/l apigenin plasma concentration after 7.2 h. Our studies on TRAMP mice at 20 and 50 μg/day corresponds to ~50 and 120mg/day of flavone intake by an adult human with the plasma apigenin concentration ranging from 0.63 to 1.15 μM/l. These results indicate that the bioavailable concentration of apigenin has a therapeutic effectIn the present study, we demonstrate tumor growth suppression by apigenin intake was associated with reduced proliferation of tumor cells, which in turn was linked with the inhibition of Akt/PKB and FoxO3a activation. Proapoptotic protein, BIM, which was negatively regulated by Akt through FoxO3a, was upregulated in the prostates of apigenin-supplemented mice. Inhibition of activated levels of Akt and FoxO3a were confirmed in LNCaP and PC-3 prostate cancer cells by western blotting, immunoprecipitation, IHC and DNA-binding assay. To the best of our knowledge, our results for the first time demonstrate the involvement of the Akt/FoxO3a-signaling axis in apigenin-mediated prostate cancer suppression.
https://www.nature.com/articles/srep21731Lab study1In the present study, we showed that apigenin suppressed murine melanoma B16F10 cell lung metastasis in mice, and inhibited cell migration and invasion in human and murine melanoma cells. Further study indicated that apigenin effectively suppressed STAT3 phosphorylation, decreased STAT3 nuclear localization and inhibited STAT3 transcriptional activity. Apigenin also down-regulated STAT3 target genes MMP-2, MMP-9, VEGF and Twist1, which are involved in cell migration and invasion. More importantly, overexpression of STAT3 or Twist1 partially reversed apigenin-impaired cell migration and invasion. Our data not only reveal a novel anti-metastasis mechanism of apigenin but also support the notion that STAT3 is an attractive and promising target for melanoma treatment.These data suggest that although the bioavailability of apigenin is limited, the slow absorption and slow elimination properties may lead to possible accumulation of apigenin in the tissues to effectively impart its chemopreventive effects42. Indeed, in our study, oral administration with apigenin for 24 consecutive days significantly inhibited melanoma lung metastasis in mice. Daily intragastric injection of apigenin has also been reported to inhibit the progression and metastasis of ovarian cancer and prostate cancer in animal models26,43. Thus, daily oral intake of apigenin is able to prevent tumor progression and metastasis.
https://www.sciencedirect.com/science/article/pii/S2213453023000964#Lab study1Overall, apigenin could promote autophagy via up-regulating the protein expressions of ULK1, Beclin 1, LC3B, ATG5, and ATG13, and down-regulating the mTOR, P70S6K and ATG4. In addition, apigenin treatment increased the iron concentration, decreased the GSH content of, and increased MDA content. Apigenin also increased the protein expressions of P62, HMOX1, and ferritin, decreased the protein expressions of SLC7A11 and GPX4, and induced ferroptosis in Ishikawa cells. For in vivo, apigenin inhibited tumor growth through autophagy and ferroptosis. The normal physiological functions of the heart, liver, spleen, lung, and kidney and bodyweight of mice were not affected. Our data illustrate that apigenin can be highly effective anti-cancer agent with low toxicity.We found that iron accumulation, lipid peroxidation, glutathione consumption, p62, HMOX1, and ferritin were increased, while, solute carrier family 7 member 11 and glutathione peroxidase 4 were decreased. Ferrostatin-1, an iron-death inhibitor could reverse the effects of apigenin in Ishikawa cells. On the other hand, apigenin could promote autophagy via up-regulating Beclin 1, ULK1, ATG5, ATG13, and LC3B and down-regulating AMPK, mTOR, P70S6K, and ATG4. Furthermore, apigenin could inhibit tumor tissue proliferation and restrict tumor growth via ferroptosis in vivo.

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