Ellagic Acid - A Dietary Polyphenol with Anticancer Activity that Deserves More Consideration
Laboratory for Immunology and Hematology Research, Rabin Medical Center, Hasharon Hospital, Petah-Tiqva, the Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel
Academic Editor: Lunawati L Bennett
Received: March 21, 2023 | Accepted: June 28, 2023 | Published: July 13, 2023
Recent Progress in Nutrition 2023, Volume 3, Issue 3, doi:10.21926/rpn.2303011
Recommended citation: Djaldetti M. Ellagic Acid - A Dietary Polyphenol with Anticancer Activity that Deserves More Consideration. Recent Progress in Nutrition 2023; 3(3): 011; doi:10.21926/rpn.2303011.
© 2023 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Pomegranate (Punicca granatum) has a long history of use as a delectable fruit and a remedy for various inflammatory and other illnesses [1,2]. No wonder it makes sense that the fruit has been treasured by virtually all religions and is thought to have mystical characteristics . Research showed that ellagic acid (EA), a polyphenol being the most active substance in pomegranate is found in more vegetables and fruits like strawberries, blackberries, raspberries, cranberries, pecans, wolfberries, and other plant foods. Along with EA, fruits and vegetables also contain a significant amount of polyphenols that have anti-inflammatory, antioxidant, and immunomodulatory activities, highlighting the health benefits of the Mediterranean diet . Moreover, the discovery that polyphenols, particularly those in pomegranates, have an anticancer effect has stimulated scientific research to identify the processes underlying their detrimental impact on the development of cancer cells. Polyphenols, especially EA, may induce cancer cells to undergo a mitotic arrest at the G2/M phase, damage DNA, encourage apoptosis, alter glycolytic pathways, and interfere with mitochondrial function [5,6,7,8]. Incubation of normal human lung fibroblast cells (HEL299) serving as control, and colon (Caco2), breast (MCF-7 and 578T) and prostatic (DU145) cancer cells with 10-100 µM/L of EA for 24 hours resulted in increased adenosine triphosphate (ATP) and metalloproteinases production in the control cells, whereas that of the cancer cells was dose-dependently decreased, explaining their enhanced apoptosis and decreased viability observed after the EA effect . EA has been demonstrated to influence the immunological balance between mononuclear cells and those from the HT-29 and RKO human colon cancer cell lines. Both lower and higher EA concentrations reduced IL-1β, IL-6, IL-1ra and IL-10 production by mononuclear cells, but had no impact on IFNγ generation. It was suggested that suppressed production of proinflammatory cytokines would attenuate inflammatory reactions and slow cancer development [2,10]. Recent studies showed that EA might affect several hub genes and the cellular tumor antigen P53 and WNT signaling pathways in cancer cells leading to apoptosis and cell death [11,12]. Additionally it was reported that EA interfered with the mitochondrial functions in colon carcinoma (HCT116) and breast adenocarcinoma (MCF7) cell lines by inhibiting Drp-1 mitochondrial dynamic protein which is essential for cell division . Figure 1 demonstrates that EA damages cancer cells by inducing phagocytosis, autophagocytosis and necrosis. In addition to chemotherapy and radiotherapy, EA exerts a significant anticancer effect . These and other studies indicate that EA is a promising additive to the armamentarium of anti-cancer remedies. On the other hand, the advantageous effects of EA were primarily seen when applied to animals or in vitro. With the hope that the hereby-reported findings will encourage clinical trials, this work aimed to review recent observations regarding the mechanism of the carcinopreventive effect of EA on the various forms of cancer.
Figure 1 Ellagic acid exerts chemoprevention by inducing phagocytosis, autophagocytosis and even death of the cancers cells via various mechanisms detailed in the text. In addition, it activates mononuclear cells for cytokine production and a cross talk between immune and cancer cells.
2. Esophageal and Gastric Cancers - Table 1
Research on the carcinopreventive impact of EA on esophageal cancer has been carried out on rats with N-nitroso methyl benzylamine (NMBA)-induced carcinogenesis. The incidence of tumors in the tumor-bearing animals was reduced by EA administration to the animals by 66.7% as opposed to 100% in the untreated animals, but their multiplicity was unaffected . Diets reach in phytochemicals, including EA have a protective effect against the onset and progression of gastrointestinal tract cancers [16,17,18]. This effect was attributed to an impaired NMBA cells’ metabolism , a process observed in the liver microsomes and esophageal explants taken from rats NMBA bearing cancers fed with a diet containing EA and other polyphenols . Studies in vitro indicate that EA is effective against gastric cancer development. Treatment with EA of AGS and SNU601 gastric cancer cells decreased the production of the matrix metalloproteinases MMP7 and MMP9 implicated in cell migration and metastasis, as well as lowering the activity of several proinflammatory factors, including cyclooxygenases 1 and 2 (COX1, COX2) . Increased AGS cancer cells’ death was reported in vitro and in vivo in immunosuppressed mice bearing human gastric cancer tumors following administration of EA. In these investigations the effect of EA processed through alterations of genes linked with apoptosis and inflammation including inhibited proinflammatory cytokine production, leading to a significant decrease in tumor size .
3. Colorectal Cancer
Colorectal cancer gained a tarnished reputation being a malignancy with high morbidity and fatality rates. Ways to support surgical and medical treatment with natural polyphenols have shown promising results, however observed predominantly on colorectal carcinoma cells in vitro . Treatment of SW480 colon cancer cells with EA caused apoptotic cell death mediated through activation of P53 and P21 and downregulation of insulin-like growth factor (IGF-II) which is highly expressed in this type of cancer cells . In rats with 1,2-dimethylhydrazine (DMH)-induced colon cancer, ornithine oxidase expression was raised. After oral administration of EA to the animals, their antioxidant activities were severely compromised, resulting in decreased tumor progression . Similar results under comparable experimental conditions showed enhanced production of the proapoptotic protein P53 and decreased malignant cell proliferation . Given to mice bearing DMH-induced colon carcinoma, EA was found to be a potent anti-inflammatory mediator acting by reducing NF-kB, COX-2iNOS and the proinflammatory cytokines IL-6 and TNF-α . The PI3K/AKT (phosphatidylinositol 3-kinase) pathway, which is essential for the maintenance of the normal cell cycle, was inactivated in subsequent investigations with HCT-15 colon cancer cells treated with EA and induced a cell cycle arrest at G2/M phase. Additionally, EA increased ROS production, encouraged apoptosis and inhibited cancer cell proliferation . The anti-proliferative and pro-apoptotic activity of EA was detected to be dose-dependent in cells of the colorectal cancer lines HCT-116 and Caco-2, processes mediated by depression of p-AKT activity and reduced expression of the growth promotion protein K-Ras . HCT-116 colon cancer cells treated with EA showed increased apoptosis and inhibited cell cycle and proliferation by altering the expression of many genes and TGF-β1/Smad3 signaling pathways [27,28]. Reducing the phosphorylation of adenosine monophosphate-activated protein kinase AMPK/mTOR pathway is another mechanism by which EA induces apoptosis and autophagy and inhibits the growth of HCT116 cells . Notable, not only EA may affect cancer cells. It has been reported that pomegranate juice inhibits proliferation and promotes apoptosis in HT-29 human colon cancer cells by targeting TNFα induced COX2 and suppressing activation of AKT, an essential protein needed for cell development . EA exhibits complementary effects to traditional chemotherapy. When given together, EA boosted the cytotoxicity of 5-fluorouracil, the leading drug now available for the treatment of colon cancer, thus enhancing its ability to reduce the proliferation of colorectal carcinoma cells . When EA and cisplatin were given together to mice with colon cancer caused by DMH, the damaged colon epithelium's appearance improved  and the cisplatin cytotoxicity was significantly subsided by reducing ROS injury sorafenib to the cells . EA research has drawn attention to the anti-cancer effect of urolithin, a metabolite produced by gut microbiota from food-derived EA. It was shown that urolithin enhanced the effect of 5-fluorouracil, by increasing caspase 8 and 9 activation and the drug's ability to arrest the cell cycle at the G2/M phase . When EA and urolithins were administered to Caco-2 cells, the inhibition of cell growth during the S- and G2/M phase was more pronounced. This effect was accompanied by altered expression of growth factor receptors and MARK signaling genes controlling cell cycle and proliferation . The fundamental idea is that EA possesses a favorable effect in suppressing the growth of colon cancer cells, which should be further investigated and its quality as a chemoprevention should be affirmed.
4. Hepatocellular and Other Cancers - Table 2
Hepatocellular carcinoma has been recognized as one of the most malignant and deadly cancers. The lack of effective medications attracted researchers’ interest in the carcinopreventive effects of nutrients and their phytochemicals, comprising EA . Studies have shown that EA may restrain the advancement of hepatocellular carcinoma through several pathways . Hepatocellular carcinoma HepG2 cells exposed to EA exhibited enhanced apoptosis and mitotic arrest at the G1 phase, activities brought on by activation of the p21 gene inducing DNA damage, and downregulation of the MCM2-7 genes involved in genome replication . It was shown that EA alters lipid metabolism with a positive impact on liver disorders by inhibiting the secretion of the lipid transporter apolipoprotein B from human hepatoma cells HepG2, while increasing the secretion of apolipoprotein A . Notably, pomegranate derivatives and metabolites may function as carcinopreventive agents in addition to EA. Pomegranate emulsion made from pomegranate aqueous extract and pomegranate seed oil administered in a diethylnitrosamine (DENA) induced model of rat hepatic carcinoma prompted the suppression of the oxidative stress associated with liver cancer progression through nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant mechanisms . Rats with DENA hepatocellular tumors responded favorably to a combination of EA and cineole (eucalyptol), as evidenced by the reduction of tumor-related growth factors like transforming growth factor beta-1 (TGF-1), vascular endothelial growth factor (VEGF), metalloproteinase-9, and other tumor markers, as well as an improvement in histological findings . In rats with hepatocellular carcinoma, the carcinopreventive effect of EA was compared with that of doxorubicin. When contrasted to untreated rats, treated animals significantly decreased their levels of VEGF, signal transducer and activator of transcription 3 (STAT3), transmission activator glypican-3, alpha-fetoprotein, and cytokine signaling 3 . EA decreased the cardiotoxicity of doxorubicin in treated animals and enhanced the apoptotic and anti-viability effects of doxorubicin and cisplatin on hepatocellular cancer cells . Similar results were obtained in a hepatocellular carcinoma model when EA was given together with sorafenib, a potent protein kinase inhibitor, an activity exerted by increasing ROS and the mitochondrial membrane potential of the cancer cells . The EA intestinal metabolite, urolithin A, was found to wield an anti-inflammatory, anti-proliferative and antioxidant effect on the intestinal tract. In addition, it reduced Ras-related C3 botulinum toxin substrate 1 (Rac1) and p21-activated kinase (PAK1) activity involved in cancer cells' cytoskeleton reorganization, motility and growth , thus providing potential chemoprevention . HepG2 hepatoma cells showed decreased proliferation and reduced oxidative stress mediated by inhibited activity of β-catenin, c-Myc and cyclin D1, cytoplasmic proteins that sustain normal intercellular adhesion and regulate cellular differentiation and proliferation. On the other hand, p53 and mitogen-activated protein kinase (p38-MAPK) expression was amplified . EA enhanced the radiosensitizing effect on the development of HepG2 cells by increased ROS generation, an arrest in the G2/M phase and inhibited production of the proinflammatory mediators IL-6, COX-2 and TNF-α . At the very least in vitro, EA appears to be a hopeful adjuvant in treating hepatocellular carcinoma.
5. Pancreatic Carcinoma
Despite advancements in surgery and chemotherapy, pancreatic carcinoma is notorious for having the worst fatality rates of all cancers. In order to act as therapeutic adjuvants, attempts are made to mobilize phytochemicals, along with EA. In vitro research has produced encouraging findings. Human pancreatic carcinoma cells MIA, PaCa-2 and HPAF-II treated with EA demonstrated increased apoptosis and reduced cell proliferation by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (Nf-kB) activity. This effect was augmented when EA was given with embelin, a phytochemical isolated from the herb Ardisiae Japonicae which operated by decreasing STAT-3 phosphorylation . Cheng et al.  incubated human pancreatic cancer cells PANC-1 with EA and observed a dose-dependent suppression of cell growth, mitotic arrest at the G1 phase and reduced cell migration. EA-treated PANC-1 xenografted mice showed longer lifetimes and subdued tumor growth. The favorable effect of EA on tumor progression was explained by its restraining effect on COX-2 and Nf-kB activity. Triggering the mitochondrial pathway of apoptosis in the cancer cells and inhibiting Nf-kB activation are other ways by which EA attenuates tumor development . In PANC-1 tumor-bearing nude mice, the decrease of growth, angiogenesis, and metastasis, and treatment with EA considerably inhibited tumor progression . EA induced apoptosis on PANC-1, AsPC-1 and MIA PaCA-2 pancreatic cancer cell lines through activation of caspases 3 and 9, suppression of metalloproteinase 2 and 9 expression, as well as that of TGFβ (transforming factor β) which is mighty cell proliferation inhibitor . The available information provides a strong foundation for future studies that will stabilize the prospect of using EA as an additional therapeutic option for this precarious type of cancer.
6. Lung Cancer
In vitro research suggests that polyphenols, particularly EA, may exhibit an anti-cancer effect in this malignancy. Lung cancer cells (A549) treated with 0.06 µM of EA showed a marked inhibition of sphingosine kinase 1 (SphK1) production, an enzyme critical for cancer cell proliferation and survival. In contrast, human embryonic kidney cells serving as control were not affected . Duan et al.  have reported that EA inhibited lung cancer cell development by suppressing ATP level, the inner membrane mitochondrial potential on the one hand, and AMPK activation on the other. Also, when given to tumor-bearing mice, EA slowed tumor growth, reduced HIF1α level and raised AMPK production. The effect of EA on N-nitroso diethylamine-induced tumorigenesis mice was compared with that of quercetin, another polyphenol found in large quantities in fruits and vegetables. Quercetin could lower tumor incidence from 76.4% of the control values to 44.4%, whereas EA could reduce it to 20% from 72.2% of the control. Due to an increase in glutathione levels and a reduction in ascorbate-dependent lipid peroxidation, both polyphenols impacted tumor formation . Notable, the growth of lung cancer cells can be affected not only by EA but also by pomegranate leaves extract which was shown to reduce the proliferation and halt the cell cycle in the G2/M phase in a dose-dependent matter in non-small lung carcinoma A549 and H-1299 cell lines. The extract decreased the quantity of ROS species and the mitochondrial membrane potential leading to enhanced apoptosis. When applied to the non-small lung carcinoma H-1299 cell line the extract prevented migration by reducing MMP-2 and MP-9 expression . However, even though the in vitro results are impressive, additional basic and clinical research is necessary to secure the position of EA as a helpful additive for treating lung cancer.
7. Breast Cancer
Breast cancer is one of the most often diagnosed cancers in women. Using pomegranate juice and EA as adjuvants in treating breast cancer has been shown to boost the effectiveness of standard chemotherapy and hormonal therapy with estrogen receptor modulators . Estrogen receptor-positive MCF7 and estrogen negative MDA-MB-231 breast cancer cells treated with pomegranate juice reduced cancer cell proliferation, increased cell-to-cell adhesion and decreased cell migration without altering the function of normal breast cells . Treatment of breast cancer WA4 stem cells with pomegranate extract containing EA, ursolic acid and luteolin-induced cell cycle arrest in the G0/G1 phase, inhibited cell viability and enhanced apoptosis . Studies indicate that EA may prevent MCF-7 breast cancer cells’ development through several mechanisms, such as inhibited cell proliferation by reducing the activity of the transforming growth factor (TGFβ/Smad3) signaling pathway , stopping the mitotic cycle in the G0/G1 phase and dysregulation of a total of 4,738 genes . EA causes downregulation of cyclin-dependent kinase (CDK6), an enzyme with high proliferative activity in cancer cells presenting an additional way to trigger apoptosis and decrease colonization in breast cancer cells . Shi et al.  observed that treatment of breast cancer cells with EA and GDC-0941, a PI3K (phosphatidylinositol 3-kinase) inhibitor that plays an essential role in cell development, leads to a decrease in cell growth and migration and enhanced apoptosis. Angiogenesis, a key factor in cancer expansion is also restricted by EA by down-regulation of the VRGFR-signaling pathway, a crucial promoter of vascular growth in breast cancer xenografts and restrained the development of MDA-MB-231 breast cancer cells . Using an ACI inbred rat strain breast cancer model similar to estrogen-dependent human breast tumors Munagala et al.  detected that EA induces a dysregulation of many microRNA strains leading to inhibited breast cancer tumorigenesis. Notably, urolithin A, a protein generated from EA by the gut microbiota, may function as a breast cancer resistance protein (BCRP) that inhibits the development of drug resistance to chemotherapeutic drugs by acting as a xenobiotic transporter . EA treatment made NIH3T3 breast cancer cells more sensitive to γ-irradiation. In MCF breast cancer cells combined administration of EA and γ-irradiation promoted apoptosis by upregulating the pro-apoptotic Bax protein and inhibiting Bcl-2, both proteins actively involved in apoptotic cell death .
8. Cancers of the Genital Tract
Female reproductive system tumors are prevalent and rank fourth in severity, behind colorectal, lung, and breast malignancies. Despite the significant advancement in diagnostic and treatment modalities, they continue to have a high mortality risk. Studies on the anticancer action of EA show that this polyphenol exhibits promising effects in these malignancies. Regrettably, research on the mechanism by which EA may affect cancers of the genital tract has been carried out primarily in vitro with ovarian, cervix and endometrial cancer cell lines. By activating Beclin-1, Baxh, AMPK, and other autophagy-related proteins, treatment of SKOV-3 ovarian cancer cells with EA suppressed cell proliferation and migration and accelerated apoptosis and autophagy. Inhibition of Akt, which is involved in cell migration and invasion, and mTORC1, a protein synthesis activator, furthered this process . In cells of the A2780 ovarian cancer cell line, proliferation and migration were suppressed under the influence of EA, luteolin, and pomegranate juice. This was explained by the inhibition of the activities of the matrix metalloproteinases MMP2 and MMP9 . Intermittent treatment of cisplatin resistance-induced A2780 cells with EA for 26 weeks completely prevented the development of drug resistance, while promoting apoptosis, inhibition of cell growth and migration, and lesser ROS generation . Endometrial cancer cells incubated with EA displayed reduced ROS generation and NHE1 levels, hampering the segment transmission of DNA to RNA and subsequently altering cancer cell development . Cell cycle arrest, death, and reduced endometrial cancer cell survival were caused by EA's inhibition of the PIK3CA and PIK3R signaling pathways, which regulate cell proliferation and differentiation. When used on endometrial cancer-bearing mice, EA reduced the number of lung metastases . EA caused cytotoxic and apoptotic effects in Hela and NIH-3T3 cervical cancer lines  and induced mitotic arrest at the G1 phase by suppressing the STAT3 signal transducer . HeLa cells exposed to EA showed a strong antiestrogen activity proceeding primarily through estrogen receptor ERβ and to a lesser extent via ERα . Remarkably, EA from pomegranate peel extract rather than the fruit itself may prevent the proliferation and differentiation of HeLa cells by blocking the AKT/mTOR intracellular signaling pathway, which controls the cell cycle. Additionally it increased the level of Insulin Growth Factor Binding Protein-7 (IGFBP7), which is crucial for cell growth and differentiation . When administered in conjunction with the anticancer polyphenol curcumin, the suppressive effect of EA on the mitotic arrest of HeLa cells in the G2/M phase was doubled , the signaling pathway P53 was repaired and the impairment of ROS formation and DNA damage was amplified .
9. Prostate Cancer
Prostate cancer is a frequent malignancy in men and the second leading cause of mortality [72,90]. While encouraging results from laboratory tests show that EA inhibits cancer cell development, angiogenesis, and metastatic qualities in this type of tumor, clinical investigations on the EA anti-cancer activity are still in the early stages [90,91]. EA reduced PC3 human prostate cancer cells proliferation and viability by decreasing a few signaling proteins including STAT3, ERK (extracellular signal-regulated kinase) and AKT . In addition EA promoted caspases activation, inhibited the anti-apoptotic protein BAX2 and increased BAX, the pro-apoptotic protein . Applied on LnCap human prostatic cancer cells EA triggered an anti-angiogenic effect by significantly reducing heme oxygenase activity and several members of the MMP cytochrome enzymes family . The chromatographic level of a key indicator of neuroendocrine tumors was decreased, while p75NGFR (low-affinity nerve growth factor receptor) was increased . EA inhibited the migration of androgen-dependent human PC3 and rat PLS10 prostate cancer cell lines by a slight inhibition of MMP2 in both types of cells and the collagenase IV activity in cells from the PLS-10 line . EA repressed cell proliferation and induced apoptosis in androgen-dependent LNCaP androgen-dependent cells by enhancing Bax/Bcl-2 ratio, caspase 3 activation and cell cycle-related tumor proteins. EA did not affect PC-3 or DU145 androgen-dependent human prostate cancer cells. Applied on an animal model with prostate cancer-bearing rats, EA suppressed tumor development by activating caspase 3 apoptosis and decreasing lipid peroxidation . EA combined with the two pomegranate juice components, i.e., luteolin and punicic acid inhibited the growth and migration of both hormone-dependent and independent prostate carcinoma cells through inhibition of CXCL12/CXCR4 axis which is crucial for tumor development, cell viability and metastasis. In addition the generation of IL-8 and VEGF was suppressed .
10. Other Sorts of Cancer
EA-induced apoptosis, GO/G1 mitotic arrest and DNA damage in TSGH8301 human bladder cells by enhancing p21, p53 and ROS species production and activation of mitochondria signaling pathways . EA treatment reduced tumor infiltration and angiogenesis and improved mitomycin C activity in human bladder cancer xenografts. Due to VEGF-A (vascular endothelial growth factor-A) suppression caused by the treatment of four human bladder cancer lines with EA inhibited the development of these cancerous cells . EA inhibited the cell growth and migration of WM115 and A375 melanoma cells through the downregulation of p-EGFR (epidermal growth factor receptor) and vimentin (filament protein preserving cell structure) . The mitotic cell cycle in U251 human glioblastoma cells was blocked in the G0/G1 phase by EA upregulation of the mitogen-activated DR4, DR5 and MAP kinases leading to markedly increased apoptosis .
To sum up, studies conducted in vitro indicate that EA significantly inhibits the development, proliferation and mobility of cancer cells derived from different human cancer cell lines through several pathways. Nearly all reports conclude that conventional chemotherapy combined with EA may represent an effective therapeutic approach for cancer management. To accomplish this goal extensive clinical studies on the subject are advised. Although the positive effects of EA have been assessed in a limited number of individuals receiving conventional treatment for colorectal and prostate cancer , there is a critical need to extend the in vitro findings to other cancer types in both animal and clinical research.
The assistance of Ms. Varda Sagi, the Institution's head librarian, in gathering the references is highly appreciated.
The author did all the research work of the study.
The author has no conflict of interest in the manuscript.
- Jurenka JS. Therapeutic applications of pomegranate (Punica granatum L.): A review. Altern Med Rev. 2008; 13: 128-144.
- Rahimi VB, Ghadiri M, Ramezani M, Askari VR. Antiinflammatory and anti-cancer activities of pomegranate and its constituent, ellagic acid: Evidence from cellular, animal, and clinical studies. Phytother Res. 2020; 34: 685-720. [CrossRef]
- Langley P. Why a pomegranate? BMJ. 2000; 321: 1153-1154. [CrossRef]
- Dayi T, Oniz A. Effects of the Mediterranean diet polyphenols on cancer development. J Prev Med Hyg. 2022; 63: E74-E80.
- Boehning AL, Essien SA, Underwood EL, Dash PK, Boehning D. Cell type-dependent effects of ellagic acid on cellular metabolism. Biomed Pharmacother. 2018; 106: 411-418. [CrossRef]
- Sharma K, Kesharwani P, Prajapati SK, Jain A, Jain D, Mody N, et al. An insight into anticancer bioactives from Punica granatum (Pomegranate). Anticancer Agents Med Chem. 2022; 22: 694-702. [CrossRef]
- Zhang T, Chen HS, Wang LF, Bai MH, Wang YC, Jiang XF, et al. Ellagic acid exerts anti-proliferation effects via modulation of Tgf-β/Smad3 signaling in MCF-7 breast cancer cells. Asian Pac J Cancer Prev. 2014; 15: 273-276. [CrossRef]
- Ceci C, Lacal PM, Tentori L, De Martino MG, Miano R, Graziani G. Experimental evidence of the antitumor, antimetastatic and antiangiogenic activity of ellagic acid. Nutrients. 2018; 10: 1756. [CrossRef]
- Losso JN, Bansode RR, Trappey II A, Bawadi HA, Truax R. In vitro anti-proliferative activities of ellagic acid. J Nutr Biochem. 2004; 15: 672-678. [CrossRef]
- Bessler H, Djaldetti M. On the link between ellagic acid and the immune balance between human mononuclear and colon carcinoma cells. Immunol Curr Res. 2017; 1: 105.
- Cheshomi H, Bahrami AR, Rafatpanah H, Matin MM. The effects of ellagic acid and other pomegranate (Punica granatum L.) derivatives on human gastric cancer AGS cells. Hum Exp Toxicol. 2022; 41: 9603271211064534. [CrossRef]
- Mohammadinejad A, Mohajeri T, Aleyaghoob G, Heidarian F, Kazemi Oskuee R. Ellagic acid as a potent anticancer drug: A comprehensive review on in vitro, in vivo, in silico, and drug delivery studies. Biotechnol Appl Biochem. 2022; 69: 2323-2356. [CrossRef]
- Yakobov S, Dhingra R, Margulets V, Dhingra A, Crandall M, Kirshenbaum LA. Ellagic acid inhibits mitochondrial fission protein Drp-1 and cell proliferation in cancer. Mol Cell Biochem. 2023. doi: 10.1007/s11010-022-04627-6. [CrossRef]
- Xue P, Zhang G, Zhang J, Ren L. Synergism of ellagic acid in combination with radiotherapy and chemotherapy for cancer treatment. Phytomedicine. 2022; 99: 153998. [CrossRef]
- Siglin JC, Barch DH, Stoner GD. Effects of dietary phenethyl isothiocyanate, ellagic acid, sulindac and calcium on the induction and progression of N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats. Carcinogenesis. 1995; 16: 1101-1106. [CrossRef]
- Al-Ishaq RK, Overy AJ, Büsselberg D. Phytochemicals and gastrointestinal cancer: Cellular mechanisms and effects to change cancer progression. Biomolecules. 2020; 10: 105. [CrossRef]
- Mandal S, Stoner GD. Inhibition of N-nitrosobenzylmethylamine-induced esophageal tumorigenesis in rats by ellagic acid. Carcinogenesis. 1990; 11: 55-61. [CrossRef]
- Kresty LA, Morse MA, Morgan C, Carlton PS, Lu J, Gupta A, et al. Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries. Cancer Res. 2001; 61: 6112-6119.
- de Boer JG, Yang H, Holcroft J, Skov K. Chemoprotection against N-nitrosomethylbenzylamine-induced mutation in the rat esophagus. Nutr Cancer. 2004; 50: 168-173. [CrossRef]
- Reen RK, Nines R, Stoner GD. Modulation of N-nitrosomethylbenzylamine metabolism by black raspberries in the esophagus and liver of Fischer 344 rats. Nutr Cancer. 2006; 54: 47-57. [CrossRef]
- Lim SC, Hwang H, Han SI. Ellagic acid inhibits extracellular acidity-Induced invasiveness and expression of COX1, COX2, Snail, Twist 1, and c-myc in gastric carcinoma cells. Nutrients. 2019; 11: 3023. [CrossRef]
- Cheshomi H, Bahrami AR, Matin MM. Ellagic acid and human cancers: A systems pharmacology and docking study to identify principal hub genes and main mechanisms of action. Mol Divers. 2021; 25: 333-349. [CrossRef]
- Narayanan BA, Re GG. IGF-II down regulation associated cell cycle arrest in colon cancer cells exposed to phenolic antioxidant ellagic acid. Anticancer Res. 2001; 21: 359-364.
- Umesalma S, Nagendraprabhu P, Sudhandiran G. Antiproliferative and apoptotic-inducing potential of ellagic acid against 1,2-dimethyl hydrazine-induced colon tumorigenesis in Wistar rats. Mol Cell Biochem. 2014; 388: 157-172. [CrossRef]
- Umesalma S, Nagendraprabhu P, Sudhandiran G. Ellagic acid inhibits proliferation and induced apoptosis via the Akt signaling pathway in HCT-15 colon adenocarcinoma cells. Mol Cell Biochem. 2015; 399: 303-313. [CrossRef]
- Yousef AI, El-Masry OS, Abdel Mohsen MA. Impact of cellular genetic make-up on colorectal cancer cell lines response to ellagic acid: Implications of small interfering RNA. Asian Pac J Cancer Prev. 2016; 17: 743-748. [CrossRef]
- Zhao J, Li G, Bo W, Zhou Y, Dang S, Wei J, et al. Multiple effects of ellagic acid on human colorectal carcinoma cells identified by gene expression profile analysis. Int J Oncol. 2017; 50: 613-621. [CrossRef]
- Zhao J, Li G, Wei J, Dang S, Yu X, Ding L, et al. Ellagic acid induces cell cycle arrest and apoptosis via the TGF‑β1/Smad3 signaling pathway in human colon cancer HCT‑116 cells. Oncol Rep. 2020; 44: 768-776. [CrossRef]
- Ni X, Shang FS, Wang TF, Wu DJ, Chen DG, Zhuang B. Ellagic acid induces apoptosis and autophagy in colon cancer through the AMPK/mTOR pathway. Tissue Cell. 2023; 81: 102032. [CrossRef]
- Goyal Y, Koul A, Ranawat P. Ellagic acid modulates cisplatin toxicity in DMH induced colorectal cancer: Studies on membrane alterations. Biochem Biophys Rep. 2022; 31: 101319. [CrossRef]
- Goyal Y, Koul A, Ranawat P. Ellagic acid ameliorates cisplatin toxicity in chemically induced colon carcinogenesis. Mol Cell Biochem. 2019; 453: 205-215. [CrossRef]
- González-Sarrías A, Espín JC, Tomás-Barberán FA, García-Conesa MT. Gene expression, cell cycle arrest and MAPK signalling regulation in Caco-2 cells exposed to ellagic acid and its metabolites, urolithins. Mol Nutr Food Res. 2009; 53: 6866-6898. [CrossRef]
- Núñez-Sánchez MA, González-Sarrías A, Romo-Vaquero M, García-Villalba R, Selma MV, Tomás-Barberán FA, et al. Dietary phenolics against colorectal cancer--From promising preclinical results to poor translation into clinical trials: Pitfalls and future needs. Mol Nutr Food Res. 2015; 59: 1274-1291. [CrossRef]
- Kumar KN, Raja SB, Vidhya N, Devaraj SN. Ellagic acid modulates antioxidant status, ornithine decarboxylase expression, and aberrant crypt foci progression in 1,2-dimethylhydrazine-instigated colon preneoplastic lesions in rats. J Agric Food Chem. 2012; 60: 3665-3672. [CrossRef]
- Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D. Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem. 2006; 54: 980-985. [CrossRef]
- Kao TY, Chung YC, Hou YC, Tsai YW, Chen CH, Chang HP, et al. Effects of ellagic acid on chemosensitivity to 5-fluorouracil in colorectal carcinoma cells. Anticancer Res. 2012; 32: 4413-4418.
- González-Sarrías A, Tomé-Carneiro J, Bellesia A, Tomás-Barberán FA, Espín JC. The ellagic acid-derived gut microbiota metabolite, urolithin A, potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells. Food Funct. 2015; 6: 1460-1469. [CrossRef]
- Glauert HP, Calfee-Mason K, Stemm DN, Tharappel JC, Spear BT. Dietary antioxidants in the prevention of hepatocarcinogenesis: A review. Mol Nutr Food Res. 2010; 54: 875-896. [CrossRef]
- Aishwarya V, Solaipriya S, Sivaramakrishnan V. Role of ellagic acid for the prevention and treatment of liver diseases. Phytother Res. 2021; 35: 2925-2944. [CrossRef]
- Qiu S, Zhong C, Zhao B, Li G, Wang J, Jehan S, et al. Transcriptome analysis of signaling pathways targeted by ellagic acid in hepatocellular carcinoma cells. Biochim Biophys Acta Gen Subj. 2021; 1865: 129911. [CrossRef]
- Ieda A, Wada M, Moriyasu Y, Okuno Y, Zaima N, Moriyama T. Ellagic acid suppresses ApoB secretion and enhances ApoA-1 secretion from human hepatoma Cells, HepG2. Molecules. 2021; 26: 3885. [CrossRef]
- Bishayee A, Deepak B, Thoppil RJ, Darvesh AS, Nevo E, Lansky EP. Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms. Carcinogenesis. 2011; 32: 888-896. [CrossRef]
- Abdallah HM, El Awdan SA, Abdel-Rahman RF, Farrag AR, Allam RM. 1,8 cineole and ellagic acid inhibit hepatocarcinogenesis via upregulation of MiR-122 and suppression of TGF-β1, FSCN1, Vimentin, VEGF, and MMP-9. PLoS One. 2022; 17: e0258998. [CrossRef]
- Zaazaa AM, Lokman MS, Shalby AB, Ahmed HH, El-Toumy SA. Ellagic acid holds promise against hepatocellular carcinoma in an experimental model: Mechanisms of action. Asian Pac J Cancer Prev. 2018; 19: 387-393.
- Zhong C, Qiu S, Li J, Shen J, Zu Y, Shi J, et al. Ellagic acid synergistically potentiates inhibitory activities of chemotherapeutic agents to human hepatocellular carcinoma. Phytomedicine. 2019; 59: 152921. [CrossRef]
- Salimi A, Saboji M, Seydi E. Synergistic effects of ellagic acid and sorafenib on hepatocytes and mitochondria isolated from a hepatocellular carcinoma rat model. Nutr Cancer. 2021; 73: 2460-2468. [CrossRef]
- Alauddin M, Okumura T, Rajaxavier J, Khozooei S, Pöschel S, Takeda S, et al. Gut bacterial metabolite urolithin A decreases actin polymerization and migration in cancer cells. Mol Nutr Food Res. 2020; 64: e1900390. [CrossRef]
- Kujawska M, Jodynis-Liebert J. Potential of the ellagic acid-derived gut microbiota metabolite - Urolithin A in gastrointestinal protection. World J Gastroenterol. 2020; 26: 3170-3181. [CrossRef]
- Wang Y, Qiu Z, Zhou B, Liu C, Ruan J, Yan Q, et al. In vitro antiproliferative and antioxidant effects of urolithin A, the colonic metabolite of ellagic acid, on hepatocellular carcinomas HepG2 cells. Toxicol In Vitro. 2015; 29: 1107-1115. [CrossRef]
- Das U, Biswas S, Chattopadhyay S, Chakraborty A, Dey Sharma R, Banerji A, et al. Radiosensitizing effect of ellagic acid on growth of hepatocellular carcinoma cells: An in vitro study. Sci Rep. 2017; 7: 14043. [CrossRef]
- Edderkaoui M, Lugea A, Hui H, Eibl G, Lu QY, Moro A, et al. Ellagic acid and embelin affect key cellular components of pancreatic adenocarcinoma, cancer, and stellate cells. Nutr Cancer. 2013; 65: 1232-1244. [CrossRef]
- Cheng H, Lu C, Tang R, Pan Y, Bao S, Qiu Y, et al. Ellagic acid inhibits the proliferation of human pancreatic carcinoma PANC-1 cells in vitro and in vivo. Oncotarget. 2017; 8: 12301-12310. [CrossRef]
- Edderkaoui M, Odinokova I, Ohno I, Gukovsky I, Go VL, Pandol SJ, et al. Ellagic acid induces apoptosis through inhibition of nuclear factor kappa B in pancreatic cancer cells. World J Gastroenterol. 2008;14: 3672-3680. [CrossRef]
- Zhao M, Tang SN, Marsh JL, Shankar S, Srivastava RK. Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice. Cancer Lett. 2013; 337: 210-217. [CrossRef]
- Kim JY, Choi YJ, Kim HJ. Determining the effect of ellagic acid on the proliferation and migration of pancreatic cancer cell lines. Transl Cancer Res. 2021; 10: 424-433. [CrossRef]
- Duan J, Li Y, Gao H, Yang D, He X, Fang Y, et al. Phenolic compound ellagic acid inhibits mitochondrial respiration and tumor growth in lung cancer. Food Funct. 2020; 11: 6332-6339. [CrossRef]
- Khanduja KL, Gandhi RK, Pathania V, Syal N. Prevention of N-nitrosodiethylamine-induced lung tumorigenesis by ellagic acid and quercetin in mice. Food Chem Toxicol. 1999; 37: 313-318. [CrossRef]
- Chen HS, Bai MH, Zhang T, Li GD, Liu M. Ellagic acid induces cell cycle arrest and apoptosis through TGF-β/Smad3 signaling pathway in human breast cancer MCF-7 cells. Int J Oncol. 2015; 46: 1730-1738. [CrossRef]
- Yousuf M, Shamsi A, Khan P, Shahbaaz M, AlAjmi MF, Hussain A, et al. Ellagic acid controls cell roliferation and induces apoptosis in breast cancer cells via inhibition of cyclin-dependent kinase 6. Int J Mol Sci. 2020; 21: 3526. [CrossRef]
- Wang N, Wang ZY, Mo SL, Loo TY, Wang DM, Luo HB, et al. Ellagic acid, a phenolic compound, exerts anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer. Breast Cancer Res Treat. 2012; 134: 943-955. [CrossRef]
- Munagala R, Aqil F, Vadhanam MV, Gupta RC. MicroRNA 'signature' during estrogen-mediated mammary carcinogenesis and its reversal by ellagic acid intervention. Cancer Lett. 2013; 339: 175-184. [CrossRef]
- Ahire V, Kumar A, Mishra KP, Kulkarni G. Ellagic acid enhances apoptotic sensitivity of breast cancer cells to γ-radiation. Nutr Cancer. 2017; 69: 904-910. [CrossRef]
- Elsaid FG, Alshehri MA, Shati AA, Al-Kahtani MA, Alsheri AS, Massoud EE, et al. The anti-tumourigenic effect of ellagic acid in SKOV-3 ovarian cancer cells entails activation of autophagy mediated by inhibiting Akt and activating AMPK. Clin Exp Pharmacol Physiol. 2020; 47: 1611-1621. [CrossRef]
- Liu H, Zeng Z, Wang S, Li T, Mastriani E, Li QH, et al. Main components of pomegranate, ellagic acid and luteolin, inhibit metastasis of ovarian cancer by down-regulating MMP2 and MMP9. Cancer Biol Ther. 2017; 18: 990-999. [CrossRef]
- Engelke LH, Hamacher A, Proksch P, Kassack MU. Ellagic acid and resveratrol prevent the development of cisplatin resistance in the epithelial ovarian cancer cell Line A2780. J Cancer. 2016; 7: 353-363. [CrossRef]
- Abdelazeem KN, Singh Y, Lang F, Salker MS. Negative effect of ellagic acid on cytosolic pH regulation and glycolytic flux in human endometrial cancer cells. Cell Physiol Biochem. 2017; 41: 2374-2382. [CrossRef]
- Wang Y, Ren F, Li B, Song Z, Chen P, Ouyang L. Ellagic acid exerts antitumor effects via the PI3K signaling pathway in endometrial cancer. J Cancer. 2019; 10: 3303-3314. [CrossRef]
- Li LW, Na C, Tian SY, Chen J, Ma R, Gao Y, et al. Ellagic acid induces HeLa cell apoptosis via regulating signal transducer and activator of transcription 3 signaling. Exp Ther Med. 2018; 16: 29-36. [CrossRef]
- Guo H, Zhang D, Fu Q. Inhibition of cervical cancer by promoting IGFBP7 expression using ellagic acid from pomegranate peel. Med Sci Monit. 2016; 22: 4881-4886. [CrossRef]
- Pani S, Mohapatra S, Sahoo A, Baral B, Debata PR. Shifting of cell cycle arrest from the S-phase to G2/M phase and downregulation of EGFR expression by phytochemical combinations in HeLa cervical cancer cells. J Biochem Mol Toxicol. 2022; 36: e22947. [CrossRef]
- Kumar D, Basu S, Parija L, Rout D, Manna S, Dandapat J, et al. Curcumin and Ellagic acid synergistically induce ROS generation, DNA damage, p53 accumulation and apoptosis in HeLa cervical carcinoma cells. Biomed Pharmacother. 2016; 81: 31-37. [CrossRef]
- Eskandari E, Heidarian E, Amini SA, Saffari-Chaleshtori J. Evaluating the effects of ellagic acid on pSTAT3, pAKT, and pERK1/2 signaling pathways in prostate cancer PC3 cells. J Cancer Res Ther. 2016; 12: 1266-1271. [CrossRef]
- Malik A, Afaq S, Shahid M, Akhtar K, Assiri A. Influence of ellagic acid on prostate cancer cell proliferation: A caspase-dependent pathway. Asian Pac J Trop Med. 2011; 4: 550-555. [CrossRef]
- Vanella L, Di Giacomo C, Acquaviva R, Barbagallo I, Li Volti G, Cardile V, et al. Effects of ellagic acid on angiogenic factors in prostate cancer cells. Cancers. 2013; 5: 726-738. [CrossRef]
- Pitchakarn P, Chewonarin T, Ogawa K, Suzuki S, Asamoto M, Takahashi S, et al. Ellagic acid inhibits migration and invasion by prostate cancer cell lines. Asian Pac J Cancer Prev. 2013; 14: 2859-2863. [CrossRef]
- Naiki-Ito A, Chewonarin T, Tang M, Pitchakarn P, Kuno T, Ogawa K, et al. Ellagic acid, a component of pomegranate fruit juice, suppresses androgen-dependent prostate carcinogenesis via induction of apoptosis. Prostate. 2015; 75: 151-160. [CrossRef]
- Ho CC, Huang AC, Yu CS, Lien JC, Wu SH, Huang YP, et al. Ellagic acid induces apoptosis in TSGH8301 human bladder cancer cells through the endoplasmic reticulum stress- and mitochondria-dependent signaling pathways. Environ Toxicol. 2014; 29: 1262-1274. [CrossRef]
- Ceci C, Tentori L, Atzori MG, Lacal PM, Bonanno E, Scimeca M, et al. Ellagic acid Inhibits bladder cancer invasiveness and in vivo tumor growth. Nutrients. 2016; 8: 744. [CrossRef]
- Wang F, Chen J, Xiang D, Lian X, Wu C, Quan J. Ellagic acid inhibits cell proliferation, migration, and invasion in melanoma via EGFR pathway. Am J Transl Res. 2020; 12: 2295-2304.
- Wang D, Chen Q, Liu B, Li Y, Tan Y, Yang B. Ellagic acid inhibits proliferation and induces apoptosis in human glioblastoma cells. Acta Cir Bras. 2016; 31: 143-149. [CrossRef]
- Gupta P, Mohammad T, Khan P, Alajmi MF, Hussain A, Rehman MT, et al. Evaluation of ellagic acid as an inhibitor of sphingosine kinase 1: A targeted approach towards anticancer therapy. Biomed Pharmacother. 2019; 118: 109245. [CrossRef]
- Li Y, Yang F, Zheng W, Hu M, Wang J, Ma S, et al. Punica granatum (pomegranate) leaves extract induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in non-small cell lung cancer in vitro. Biomed Pharmacother. 2016; 80: 227-235. [CrossRef]
- Jaman MS, Sayeed MA. Ellagic acid, sulforaphane, and ursolic acid in the prevention and therapy of breast cancer: Current evidence and future perspectives. Breast Cancer. 2018; 25: 517-528. [CrossRef]
- Rocha A, Wang L, Penichet M, Martins-Green M. Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer. Breast Cancer Res Treat. 2012; 136: 647-658. [CrossRef]
- Dai Z, Nair V, Khan M, Ciolino HP. Pomegranate extract inhibits the proliferation and viability of MMTV-Wnt-1 mouse mammary cancer stem cells in vitro. Oncol Rep. 2010; 24: 1087-1091.
- Shi L, Gao X, Li X, Jiang N, Luo F, Gu C, et al. Ellagic acid enhances the efficacy of PI3K inhibitor GDC-0941 in breast cancer cells. Curr Mol Med. 2015; 15: 478-486. [CrossRef]
- González-Sarrías A, Miguel V, Merino G, Lucas R, Morales JC, Tomás-Barberán F, et al. The gut microbiota ellagic acid-derived metabolite urolithin A and its sulfate conjugate are substrates for the drug efflux transporter breast cancer resistance protein (ABCG2/BCRP). J Agric Food Chem. 2013; 61: 4352-4359. [CrossRef]
- Gonzalez-Castillo M, Jesus Loera M, Ascacio-Valdes J, Rodríguez-Herrera R, Zugasti-Cruz A, Salinas-Santander M, et al. Punicalin and ellagic acid from pomegranate peel extract facilitate apoptotic behavior in the Hela cell line. Pak J Pharm Sci. 2021; 34: 2181-2189.
- Papoutsi Z, Kassi E, Tsiapara A, Fokialakis N, Chrousos GP, Moutsatsou P. Evaluation of estrogenic/antiestrogenic activity of ellagic acid via the estrogen receptor subtypes ERα and ERβ. J Agric Food Chem. 2005; 53: 7715-7720. [CrossRef]
- Wang L, Martins-Green M. Pomegranate and its components as alternative treatment for prostate cancer. Int J Mol Sci. 2014;15: 14949-1466. [CrossRef]
- Bell C, Hawthorne S. Ellagic acid, pomegranate and prostate cancer--A mini review. J Pharm Pharmacol. 2008; 60: 139-144. [CrossRef]
- Vanella L, Barbagallo I, Acquaviva R, Di Giacomo C, Cardile V, Abraham NG, et al. Ellagic acid: Cytodifferentiating and antiproliferative effects in human prostatic cancer cell lines. Curr Pharm Des. 2013; 19: 2728-2736. [CrossRef]
- Wang L, Li W, Lin M, Garcia M, Mulholland D, Lilly M, et al. Luteolin, ellagic acid and punicic acid are natural products that inhibit prostate cancer metastasis. Carcinogenesis. 2014; 35: 2321-2330. [CrossRef]