Pomegranate (Punica granatum), was one of the earliest fruits from warmer parts of the world to become popular in Europe. Native to the Middle East, traditional uses include for the treatment of dysentery and diarrhoea. It now seems that the more scientists look, the more they are finding about this famous fruit. Research findings published over the past year alone, have implications for the management of conditions such as bowel disease, skin conditions, cancer and pain.
Multiple therapeutically active polyphenols are found in the fruits of pomegranate, including anthocyanins and anthocyanidins, flavones, flavonoids and flavonols. The rind or peels, often discarded when juice products are prepared, are also rich in useful phytochemicals and have a high content of hydrolysable ellagitannins such as punicalagin, ellagic acid and punicic acid.
Dietary factors are increasingly linked with the risks of certain cancers(1,2,3). While the incidence of prostate cancer in Asian countries is low compared to the West, this incidence increases by as much as 20-fold in Asian immigrants to the United States. Their adoption of a Western diet, a reduced intake of soy, tea, fish, fruits, and vegetables and increased intake of red meat and fat-rich foods, are thought to be largely contributory(4, 5].
Many foods rich in polyphenols have been associated with cancer prevention, effects attributable largely to their antioxidant and free radical scavenging properties. Pomegranate is one of these, and anti-cancer effects have been measured in vitro for pomegranate fruit extracts using a wide range of different cancer cell lines, including ovarian(6), bladder(7), thyroid(8), breast(9) and prostate cancer, and multiple myeloma(10).
Flavonoid-rich polyphenol fractions have been reported to exert anti-proliferative, anti-invasive, anti-inflammatory and other anti-cancer actions in breast and prostate cancer cells in vitro and in animal studies(11). Pomegranate extracts also inhibit the formation of new blood vessels (angiogenesis) by cancer cells(12), and have been shown to have potential to help suppress the final steps of carcinogenesis and metastasis(2, 13, 14).
The state of the gut community of microbes is increasingly linked with a large number of chronic health conditions, and there is growing evidence of an influence of the gut microbiota on mechanisms of prostate cancer initiation and/or progression(15). Changes to the gut microbiome through changes in dietary composition and increased intake of vegetables and polyphenols, may help to modify the risk of prostate cancer through its role in the regulation of chronic inflammation, apoptotic (cell death) processes, cytokines, and hormonal production(15).
Ellagitannins are bioactive polyphenols and a principle component of pomegranate peels and other foods such as seeds, nuts and berries with chemopreventive potential against prostate and other cancers. Too large to be absorbed into the bloodstream intact, they are partially hydrolyzed in the gut to ellagic acid. Ellagic acid and its metabolite urolithin A, produced by colonic microflora, have demonstrated significant antioxidant and anticancer effects, including antiproliferative and apoptotic activities(16, 17), and inhibition of angiogenesis(18, 19), in a range of cancer types.
At least 6 clinical trials involving prostate cancer patients have been undertaken, and while these suggest daily ingestion of sufficiently large doses of pomegranate extracts can produce a significant slowing of PSA increase (20-23), further trials with larger patient numbers and longer treatment durations, are required.
A recent review also supports potential applications to help protect against breast cancer(9). This is supported by a significant number of studies including reports that pomegranate extracts induce cell cycle arrest in the G0/G1 phase, and induce cytotoxicity in a dose- and time-dependent manner. Inhibitory effects of pomegranate juice on bladder cancer development, have also been reported recently in rats(7). Correction of the expression of pro-inflammatory cytokines and suppression of angiogenesis, were associated with these benefits.
The traditional uses of pomegranate rinds for the treatment of dysentery and diarrhea, is a reflection of both their tannin content and proven antimicrobial activities, but also suggests potential gastrointestinal protective and anti-inflammatory properties.
Ellagitannins seem to contribute to most of the beneficial analgesic and anti-inflammatory actions of pomegranate in a rat model of inflammatory bowel disease(24). Again, their metabolites ellagic acid and urolithin A, formed by the gut microbiotica following pomegranate consumption, seem to be involved. Urolithin A is increasingly linked not only to protecting against bowel and other cancers, but to having beneficial anti-inflammatory actions of possible relevance to inflammatory bowel conditions such as ulcerative colitis and Crohn’s disease, and other gastrointestinal conditions(25). Protective effects against gastric ulcers have been recently reported in animal studies(26). Anthelminthic activity, thus helping to expel parasitic worms from the gut, is another recently documented application shown against nematodes in sheep(27).
In vitro and animal studies have demonstrated that topical application and oral consumption of pomegranate reduces UVB-induced skin damage from the sun(28). Oral feeding of pomegranate fruit extract to mice protected them from the adverse effects of UVB radiation, by interfering with early stages of photocarcinogenesis(29).
A double-blind, placebo-controlled trial involving female subjects age 20–40s found daily ingestion of an ellagic acid-rich pomegranate extract had an inhibitory effect on skin pigmentation caused by UV irradiation(30). Another trial found protection against UVB irradiation following oral ingestion of pomegranate juice or pomegranate extract, in a group of healthy females aged 30-45 years(28). Influences on the gut or skin microbiome, have again been implicated in these photoprotective effects.
Eczema or dermatitis is a frequent side effect of chemotherapy and radiotherapy treatment in cancer patients, and recent research found pomegranate to promote skin regeneration processes after skin damage induced by 5-fluorouracil(31). This suggests a potential use of pomegranate as an adjuvant during treatment with this and perhaps other chemotherapy drugs. Welsh dental researchers have also recently reported that the peel ellagitannin punicalagin in combination with zinc, may promote anti-inflammatory and fibroblast responses to aid healing of oral cavity wounds(32).
Potential neuroprotective effects have been recently reported in animal models of Parkinsons disease(33, 34). A pilot clinical trial also found pomegranate to protect against memory impairment and improve memory retention performance for up to 6 weeks after cardiac surgery(35). As with cancer protective and gastroprotective activities, urolithin A has been implicated in these neuroprotective activities(25, 36).
Preliminary clinical trials recently conducted at Harvard Medical School, have also found supplementation with pomegranate juice by pregnant women may help to protect their fetuses against intrauterine growth restriction, a serious complication with a risk of perinatal death or neurodevelopmental impairment among surviving infants(37, 38). A pomegranate seed extract has also been reported to protect against tramadol-induced testicular toxicity in animal studies(39). Usage of this painkilling drug is now very common in hospital and community settings around the world, and taking adjunctive pomegranate may help protect against its negative effects on male fertility, particularly during adolescence.
- Colli J.L., Colli A. International comparisons of prostate cancer mortality rates with dietary practices and sunlight levels. Urol. Oncol. 2006;24:184–194. doi: 10.1016/j.urolonc.2005.05.023.
- Khan N., Afaq F., Mukhtar H. Cancer Chemoprevention Through Dietary Antioxidants: Progress and Promise. Antioxid. Redox Signal. 2008;10:475–510. doi: 10.1089/ars.2007.1740.
- Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492.
- Lin PH, Aronson W, Freedland SJ. Nutrition, dietary interventions and prostate cancer: the latest evidence. BMC Med. 2015;13:3. Published 2015 Jan 8. doi:10.1186/s12916-014-0234-y
- Livingstone TL, Beasy G, Mills RD, et al. Plant Bioactives and the Prevention of Prostate Cancer: Evidence from Human Studies. Nutrients. 2019;11(9):2245. Published 2019 Sep 18. doi:10.3390/nu11092245.
- Liu H, Zeng Z, Wang S, 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(12):990-999. doi:10.1080/15384047.2017.1394542
- Mortada WI, Awadalla A, Khater SM, Barakat NM, Husseiny SM, Shokeir AA. Preventive effect of pomegranate juice against chemically induced bladder cancer: An experimental study. Heliyon. 2020 Oct 8;6(10):e05192. doi: 10.1016/j.heliyon.2020.e05192. PMID: 33083625; PMCID: PMC7551357.
- Li Y., Ye T., Yang F., Hu M., Liang L., He H., Li Z., Zeng A., Li Y., Yao Y. Punica granatum (pomegranate) peel extract exerts potent antitumor and anti-metastasis activity in thyroid cancer. RSC Adv. 2016; 6:84523–84535. doi: 10.1039/C6RA13167K.
- Moga MA, Dimienescu OG, Bălan A, et al. Pharmacological and Therapeutic Properties of Punica granatum Phytochemicals: Possible Roles in Breast Cancer. Molecules. 2021;26(4):1054. Published 2021 Feb 17. doi:10.3390/molecules26041054.
- Tibullo D, Caporarello N, Giallongo C, et al. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM). Nutrients. 2016;8(10):611. Published 2016 Oct 1. doi:10.3390/nu8100611
- Turrini E, Ferruzzi L, Fimognari C. Potential Effects of Pomegranate Polyphenols in Cancer Prevention and Therapy. Oxid Med Cell Longev. 2015;2015:938475. doi:10.1155/2015/938475
- Lansky E.P., Newman R.A. Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J. Ethnopharmacol. 2007;109:177–206. doi: 10.1016/j.jep.2006.09.006.
- 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. doi: 10.1007/s10549-012-2264-5.
- Ahmadiankia N. Molecular targets of pomegranate (Punica granatum) in preventing cancer metastasis. Iran J Basic Med Sci. 2019;22(9):977-988. doi:10.22038/ijbms.2019.34653.8217Crocetto F, Boccellino M, Barone B, et al. The Crosstalk between Prostate Cancer and Microbiota Inflammation: Nutraceutical Products Are Useful to Balance This Interplay?. Nutrients. 2020;12(9):2648. Published 2020 Aug 31. doi:10.3390/nu12092648.
- Crocetto F, Boccellino M, Barone B, et al. The Crosstalk between Prostate Cancer and Microbiota Inflammation: Nutraceutical Products Are Useful to Balance This Interplay?. Nutrients. 2020;12(9):2648. Published 2020 Aug 31. doi:10.3390/nu12092648
- Zhao W, Shi F, Guo Z, Zhao J, Song X, Yang H. Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog. 2018;57(2):193-200. doi:10.1002/mc.22746.
- Qiu Z, Zhou J, Zhang C, Cheng Y, Hu J, Zheng G. Antiproliferative effect of urolithin A, the ellagic acid-derived colonic metabolite, on hepatocellular carcinoma HepG2.2.15 cells by targeting Lin28a/let-7a axis. Braz J Med Biol Res. 2018;51(7):e7220. doi:10.1590/1414-431×20187220.
- Vicinanza R, Zhang Y, Henning SM, Heber D. Pomegranate Juice Metabolites, Ellagic Acid and Urolithin A, Synergistically Inhibit Androgen-Independent Prostate Cancer Cell Growth via Distinct Effects on Cell Cycle Control and Apoptosis. Evid Based Complement Alternat Med. 2013;2013:247504. doi:10.1155/2013/247504.
- 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 Nov 14;10(11):1756. doi: 10.3390/nu10111756. PMID: 30441769; PMCID: PMC6266224.
- Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer–the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014;17(2):180-186. doi:10.1038/pcan.2014.6.
- Paller CJ, Ye X, Wozniak PJ, et al. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis. 2013;16(1):50-55. doi:10.1038/pcan.2012.20.
- Paller CJ, Pantuck A, Carducci MA. A review of pomegranate in prostate cancer. Prostate Cancer Prostatic Dis. 2017;20(3):265-270. doi:10.1038/pcan.2017.19.
- Freedland SJ, Carducci M, Kroeger N, et al. A double-blind, randomized, neoadjuvant study of the tissue effects of POMx pills in men with prostate cancer before radical prostatectomy. Cancer Prev Res (Phila). 2013;6(10):1120-1127. doi:10.1158/1940-6207.CAPR-12-0423.
- Parisio C, Lucarini E, Micheli L, et al. Pomegranate Mesocarp against Colitis-Induced Visceral Pain in Rats: Effects of a Decoction and Its Fractions. Int J Mol Sci. 2020;21(12):4304. Published 2020 Jun 17. doi:10.3390/ijms21124304.
- Kujawska M, Jodynis-Liebert J. Potential of the ellagic acid-derived gut microbiota metabolite – Urolithin A in gastrointestinal protection. World J Gastroenterol. 2020 Jun 21;26(23):3170-3181. doi: 10.3748/wjg.v26.i23.3170. PMID: 32684733; PMCID: PMC7336321.
- Abd El-Rady NM, Dahpy MA, Ahmed A, et al. Interplay of Biochemical, Genetic, and Immunohistochemical Factors in the Etio-Pathogenesis of Gastric Ulcer in Rats: A Comparative Study of the Effect of Pomegranate Loaded Nanoparticles Versus Pomegranate Peel Extract. Front Physiol. 2021;12:649462. Published 2021 Mar 23. doi:10.3389/fphys.2021.649462
- Castagna F, Britti D, Oliverio M, Bosco A, Bonacci S, Iriti G, Ragusa M, Musolino V, Rinaldi L, Palma E, Musella V. In Vitro Anthelminthic Efficacy of Aqueous Pomegranate (Punica granatum L.) Extracts against Gastrointestinal Nematodes of Sheep. Pathogens. 2020 Dec 18;9(12):1063. doi: 10.3390/pathogens9121063. PMID: 33353177; PMCID: PMC7766728.
- Henning SM, Yang J, Lee RP, et al. Pomegranate Juice and Extract Consumption Increases the Resistance to UVB-induced Erythema and Changes the Skin Microbiome in Healthy Women: a Randomized Controlled Trial. Sci Rep. 2019;9(1):14528. Published 2019 Oct 10. doi:10.1038/s41598-019-50926-2.
- Afaq F, Khan N, Syed DN, Mukhtar H. Oral feeding of pomegranate fruit extract inhibits early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. Photochem Photobiol. 2010;86(6):1318–1326. doi: 10.1111/j.1751-1097.2010.00815.x.
- Kasai K, Yoshimura M, Koga T, Arii M, Kawasaki S. Effects of oral administration of ellagic acid-rich pomegranate extract on ultraviolet-induced pigmentation in the human skin. J Nutr Sci Vitaminol (Tokyo). 2006 Oct;52(5):383-8. doi: 10.3177/jnsv.52.383. PMID: 17190110.
- Rapa SF, Magliocca G, Pepe G, et al. Protective Effect of Pomegranate on Oxidative Stress and Inflammatory Response Induced by 5-Fluorouracil in Human Keratinocytes. Antioxidants (Basel). 2021;10(2):203. Published 2021 Jan 30. doi:10.3390/antiox10020203
- Celiksoy V, Moses RL, Sloan AJ, Moseley R, Heard CM. Evaluation of the In Vitro Oral Wound Healing Effects of Pomegranate (Punica granatum) Rind Extract and Punicalagin, in Combination with Zn (II). Biomolecules. 2020;10(9):1234. Published 2020 Aug 25. doi:10.3390/biom10091234
- Kujawska M, Jourdes M, Kurpik M, et al. Neuroprotective Effects of Pomegranate Juice against Parkinson’s Disease and Presence of Ellagitannins-Derived Metabolite-Urolithin A-In the Brain. Int J Mol Sci. 2019;21(1):202. Published 2019 Dec 27. doi:10.3390/ijms21010202
- Fathy SM, El-Dash HA, Said NI. Neuroprotective effects of pomegranate (Punica granatum L.) juice and seed extract in paraquat-induced mouse model of Parkinson’s disease. BMC Complement Med Ther. 2021;21(1):130. Published 2021 Apr 26. doi:10.1186/s12906-021-03298-y
- Ropacki SA, Patel SM, Hartman RE. Pomegranate Supplementation Protects against Memory Dysfunction after Heart Surgery: A Pilot Study. Evid Based Complement Alternat Med. 2013;2013:932401. doi:10.1155/2013/932401.
- Braidy N, et al. Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer’s disease. Oncotarget. 2016;7:64589–64604. doi: 10.18632/oncotarget.10905.
- Matthews LG, Smyser CD, Cherkerzian S, Alexopoulos D, Kenley J, Tuuli MG, Nelson DM, Inder TE. Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study. PLoS One. 2019 Aug 21;14(8):e0219596. doi: 10.1371/journal.pone.0219596. PMID: 31433809; PMCID: PMC6703683.
- Ross MM, Cherkerzian S, Mikulis ND, Turner D, Robinson J, Inder TE, Matthews LG. A randomized controlled trial investigating the impact of maternal dietary supplementation with pomegranate juice on brain injury in infants with IUGR. Sci Rep. 2021 Feb 11;11(1):3569. doi: 10.1038/s41598-021-82144-0. PMID: 33574371; PMCID: PMC7878922.
- Minisy FM, Shawki HH, El Omri A, Massoud AA, Omara EA, Metwally FG, Badawy MA, Hassan NA, Hassan NS, Oishi H. Pomegranate Seeds Extract Possesses a Protective Effect against Tramadol-Induced Testicular Toxicity in Experimental Rats. Biomed Res Int. 2020 Mar 9;2020:2732958. doi: 10.1155/2020/2732958. PMID: 32219129; PMCID: PMC7085358.