Skip to main content
SpringerLink
Log in

Punica granatum L. Constituents for Cancer Prevention, Chemosensitisation and Therapeutic Treatment

  • Chapter
  • First Online:
Natural Products for Cancer Chemoprevention

Abstract

Cancer is still a major public health burden because its incidence and mortality continue to increase worldwide. The limited treatment options for patients with advanced stages, the severe toxicity, the onset of multiple drug resistance and the high costs of current anticancer therapies favor poor prognosis and high mortality rates. Thus, the identification and development of preventive and cost effective therapeutic strategies to reverse cancer-associated morbidity and mortality are needed. Vegetable and fruit consumption is associated with decreased risk of cancer because of its chemopreventive and chemotherapeutic effects. The use of Punica granatum preparations has a long ethnomedical history and preclinical research has reported many pharmacological activities, including chemopreventive, chemosensitisation and chemotherapeutic effects. Many of these health beneficial effects are related to its complex chemical composition and synergistic interactions of its colonic microbial metabolites including ellagic acid, ellagitannins, punicic acid, flavonoids, anthocyanidins, anthocyanins, and estrogenic flavonols. This chapter summarizes the scientific evidence supporting anticancer effects of pomegranate constituents, focusing on its molecular targets and anticancer mechanisms of action, along with a critical evaluation of pomegranate polyphenols as future anticancer agents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

[B(a)P]:

benzo(a)pyrene

27HC:

27-hydroxycholesterol

5-FU:

5-fluorouracil

8-OHdG:

8-hydroxy-2-deoxyguanosine

AA:

Arachidonic acid

ACF:

Aberrant cryptic foci

ADR:

Adriamycin

AKT:

Serine-threonine kinase B

ALDH:

Aldehyde dehydrogenase

AOM:

Azoxymethane

APC:

Adenomatous polyposis coli

Bax:

Bcl-2 associated X protein

BCa:

Breast cancer

Bcl-2:

Protein B Cell Lymphoma-2

Bcl-xL:

B cell lymphoma-extralarge

BCR:

Biochemical recurrent

BIP/GRP78:

Binding-immunoglobulin protein

CASP:

Caspase

CDDP:

Cisplatin

Cdk:

Cyclin-dependent kinase

c-MYC:

v-myc avian myelocytomatosis viral oncogene homolog

COX-2:

Cyclooxygenase 2

CP:

Cyclophosphamide

CRC:

Colorectal cancer

CSCs:

Cancer stem cells

CXCL:

C-X-C motif chemokine ligand

CXCR4:

Chemokine receptor 4

CYP:

Cytochrome P450

CYP1A1:

Cytochrome P450 1A1

CYP1B1:

Cytochrome P450 1B1

DENA:

Diethylnitrosamine

DMBA:

7,12-dimethylbenz[a]anthracene

DMH:

1,2-dimethylhydrazine dihydrochloride

DSB:

DNA double strand break

DTX:

Docetaxel

E2:

Estradiol

EA:

Ellagic acid

ERE:

Estrogen response elements

ERK:

Extracellular signal-regulated kinase

ERS:

Endoplasmic reticulum stress

ER-α:

Estrogen receptor alpha

ER-β:

Estrogen receptor beta

ETs:

Ellagitannins

FGF:

Fibroblast growth factor

G-CSF:

Granulocyte colony-stimulating factor

GST:

Glutathione S-transferase

HBMEC:

Human brain microvascular endothelial cells

HGF:

Hepatocyte growth factor

HIF-1𝛼:

Hypoxia inducible factor 1 alpha

HMMR:

Hyaluronan-mediated motility receptor

HO:

Heme oxygenasse

HR:

Homologous recombination

ICAM1:

Intercellular adhesion molecule 1

IFO:

Ifosfamide

IGF-1:

Insulin-like growth factor-1

IGFBP7:

Insulin-like growth factor binding protein 7

IKKα:

Inhibitor of NF-𝜅B kinase subunit-α

IL-15:

Interleukin 15

INPP5:

Inositol polyphosphate-5-phosphatase

I𝜅Bα:

Inhibitor of 𝜅B-α

JNK:

c-Jun N-terminal kinases

LC3-II:

Microtubule-associated protein light chain 3

LDH:

Lactate dehydrogenase

LOX:

Lipoxygenase

MAPKs:

Mitogen-activated protein kinases

MARCKS:

Myristoylated alanine-rich protein kinase C

MCP-1:

Monocyte chemoattractant protein-1

MIF:

Migration inhibitory factor

MIP-1α:

Macrophage inflammatory proteins 1 alpha

miRNAs:

Microribonucleic acids

MM:

Multiple myeloma

MMPs:

Metalloproteinases

MnSOD:

Manganese superoxide dismutase

mTOR:

Mammalian target of rapamycin

MTX:

Methotrexate

NF-𝜅B:

Nuclear factor kappa B

NO:

Nitric oxide

NOS2:

Nitric oxide synthase 2

NQO1:

NAD(P)H: quinone oxido-reductase 1

Nrf2:

Hepatic nuclear factor E2-related factor 2

NTCU:

N-nitroso-trischloroethylurea

ODC:

Ornithine decarboxylase

OPG:

Osteoprotegerin

p70S6:

Phosphorylated ribosomal protein S6

PARP:

Poly-ADP-ribose polymerases

PC:

Punicalagin

PCa:

Prostate cancer

PCNA:

Proliferating cell nuclear antigen

Pes:

Pomegranate extracts

PFE:

Pomegranate fruit extract

PFJ:

Pomegranate fermented juice

PGE2:

Prostaglandin E2

PgLE:

Punica granatum leaves extract

PI3K:

Phosphoinositide 3-kinase

PJ:

Pomegranate juice

PJEs:

Pomegranate juice extracts

PKC:

Protein kinase C

PLA2:

Phospholipase A2

PPAR:

Peroxisome proliferator-activated receptor

PPE:

Pomegranate peel extract

PR:

Progesterone receptor

PSA:

Prostatic antigen

PSADT:

PSA doubling time

PSO:

Pomegranate seed oil

PuA:

Punicic acid

RA:

Retinoic acid

ROS:

Reactive oxygen species

SA-β-Gal:

Senescence-associated β-galactosidase

SHBG:

Sex hormone binding globulin

Sp:

Specificity protein

STAT3:

Signal transducer and activator of transcription 3

TAM:

Tamoxifen

TCa:

Thyroid cancer

TCF4/LEF1:

T cell factor/lymphoid enhancer binding protein

TGF:

Transforming growth factor

TIMPs:

Tissue inhibitors of metalloproteinase

TNF-α:

Tumor necrosis factor alpha

TPA:

12-O-tetradecanoylphorbol-13-acetate

TRAMP:

Transgenic adenocarcinoma mouse prostate

UBUC:

Urinary bladder urothelial carcinoma

UDP:

Uridine diphosphate

UGT:

Glucuronosyl-transferase

Uro-A:

Urolithin A

Uro-B:

Urolithin B

Uro-C:

Urolithin C

VCAM-1:

Vascular cell adhesion molecule 1

VEGF:

Vascular endothelial growth factor

References

  • Adams LS, Seeram NP, Aggarwal BB, Takada Y, Heber D (2006) Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem 54:980–985

    Article  CAS  PubMed  Google Scholar 

  • Adams LS, Zhang Y, Seeram NP, Heber D, Chen S (2010) Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Cancer Prev Res (Phila) 3:108–113

    Article  CAS  Google Scholar 

  • Adaramoye O, Erguen B, Nitzsche B, Höpfner M, Jung K, Rabien A (2017) Punicalagin, a polyphenol from pomegranate fruit, induces growth inhibition and apoptosis in human PC-3 and LNCaP cells. Chem Biol Interact 274:100–106

    Article  CAS  PubMed  Google Scholar 

  • Adhami VM, Khan N, Mukhtar H (2009) Cancer chemoprevention by pomegranate: laboratory and clinical evidence. Nutr Cancer 6:811–815

    Article  Google Scholar 

  • Adhami VM, Siddiqui IA, Syed DN, Lall RK, Mukhtar H (2012) Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the tramp model. Carcinogenesis 33:644–651

    Article  CAS  PubMed  Google Scholar 

  • Afaq F, Malik A, Syed D, Maes D, Matsui MS, Mukhtar H (2005a) Pomegranate fruit extract modulates UV-B mediated phosphorylation of mitogen-activated protein kinases and activation of nuclear factor kappa B in normal human epidermal keratinocytes. Photochem Photobiol 81:38–45

    Article  CAS  PubMed  Google Scholar 

  • Afaq F, Saleem M, Krueger CG, Reed JD, Mukhtar H (2005b) Anthocyaninand hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in CD-1 mice. Int J Cancer 113:423–433

    Article  CAS  PubMed  Google Scholar 

  • Afaq F, Khan N, Syed DN, Mukhtar H (2010) Oral feeding of pomegranate fruit extract inhibits early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. Photochem Photobiol 86:1318–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akhtar S, Ismail T, Fraternale D, Sestile P (2015) Pomegranate peel and peel extracts: chemistry and food features. Food Chem 174:417–425

    Article  CAS  PubMed  Google Scholar 

  • Alaoui-Jamali MA, Bismar TA, Gupta A, Szarek WA, Su J, Song W et al (2009) A novel experimental heme oxygenase-1-targeted therapy for hormone-refractory prostate cancer. Cancer Res 69:8017–8024

    Article  CAS  PubMed  Google Scholar 

  • Albrecht M, Jiang W, Kumi-Diaka J, Lansky EP, Gommersall LM, Patel A et al (2004) Pomegranate extracts potently suppresses proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 7:274–283

    Article  CAS  PubMed  Google Scholar 

  • Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS et al (2008) Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25:2097–2116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arapitsas P (2012) Hydrolyzable tannin analysis in food. Food Chem 135:1708–1717

    Article  CAS  PubMed  Google Scholar 

  • Arun N, Singh DP (2012) Punica granatum: a review on pharmacological and therapeutic properties. IJPSR 3:1240–1245

    Google Scholar 

  • Asmaa MJ, Ali AJH, Farid JM, Azman S (2015) Growth inhibitory effects of crude pomegranate peel extract on chronic myeloid leukemia, K562 cells. Int J App Basic Med Res 5:100–105

    Article  CAS  Google Scholar 

  • Attard G, Sarker D, Reid A, Molife R, Parker C, de Bon JS (2006) Improving the outcome of patients with castration-resistant prostate cancer through rational drug development. Br J Cancer 95:767–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banerjee S, Kambhampati S, Banerjee SK, Haque I (2011) Pomegranate sensitizes tamoxifen action in ER-𝛼 positive breast cancer cells. J Cell Commun Signal 5:317–324

    Article  PubMed  PubMed Central  Google Scholar 

  • Banerjee N, Talcott S, Safe S, Mertens-Talcott SU (2012) Cytotoxicity of pomegranate polyphenolics in breast cancer cells in vitro and vivo: potential role of miRNA-27a and miRNA-155 in cell survival and inflammation. Breast Cancer Res Treat 136:21–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banerjee N, Kim H, Talcott S, Mertens-Talcott S (2013) Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR. Carcinogenesis 34:2814–2822

    Article  CAS  PubMed  Google Scholar 

  • Barker N, Clevers H (2006) Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5:997–1014

    Article  CAS  PubMed  Google Scholar 

  • Barnard RJ (2004) Prevention of cancer through lifestyle changes. Evid Based Complement Altern Med 1:233–239

    Article  Google Scholar 

  • Basu A, Penugonda K (2009) Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 67:49–56

    Article  PubMed  Google Scholar 

  • Bhandari PR (2012) Pomegranate (Punica granatum L). Ancient seeds for modern cure? Review of potential therapeutic applications. Int J Nutr Pharmacol Neurol Dis 2:171–184

    Article  CAS  Google Scholar 

  • Bhatia D, Thoppil RJ, Mandal A, Samtani KA, Darvesh AS, Bishayee A (2013) Pomegranate bioactive constituents suppress cell proliferation and induce apoptosis in an experimental model of hepatocellular carcinoma: role of Wnt/𝛽-catenin signaling pathway. Evid Based Complement Alternat Med 2013, 371813, 15 p. https://doi.org/10.1155/2013/371813. Epub 2013 Mar 28

  • Bishayee A, Bhatia D, Thoppil RJ, Darvesh AS, Nevo E, Lansky EP (2011) Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms. Carcinogenesis 32:888–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bishayee A, Thoppil RJ, Darvesh AS, Ohanyan V, Meszaros JG, Bhatia D (2013) Pomegranate phytoconstituents blunt the inflammatory cascade in a chemically induced rodent model of hepatocellular carcinogenesis. J Nutr Biochem 24:178–187

    Article  CAS  PubMed  Google Scholar 

  • Bishayee A, Mandal A, Bhattacharyya P, Bhatia D (2016) Pomegranate exerts chemoprevention of experimentally induced mammary tumorigenesis by suppression of cell proliferation and induction of apoptosis. Nutr Cancer 68:120–130

    Article  CAS  PubMed  Google Scholar 

  • Bishop FL, Rea A, Lewith H, Chan YK, Saville J, Prescott P et al (2011) Complementary medicine use by men with prostate cancer: a systematic review of prevalence studies. Prostate Cancer Prostatic Dis 14:1–13

    Article  CAS  PubMed  Google Scholar 

  • Boateng J, Verghese M, Shackleford L, Walker LT, Khatiwada J, Ogutu S et al (2007) Selected fruits reduce azoxymethane (AOM)-induced aberrant crypt foci (ACF) in fisher 344 male rats. Food Chem Toxicol 45:725–732

    Article  CAS  PubMed  Google Scholar 

  • Boeing H, Bechthold A, Bub A, Ellinger S, Haller D, Kroke A et al (2012) Critical review: vegetables and fruit in the prevention of chronic diseases. Eur J Nutr 51:637–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boroushaki MT, Rajabian A, Farzadnia M, Hoseini A, Poorlashkari M, Taghavi A et al (2015) Protective effect of pomegranate seed oil against cisplatin-induced nephrotoxicity in rat. Ren Fail 37:1338–1343

    Article  CAS  PubMed  Google Scholar 

  • Braumann C, Guenther N, Loeffler LM, Dubiel W (2009) Liver metastases after colonic carcinoma—palliative chemotherapy plus curcumin. Int J Color Dis 24:859–860

    Article  Google Scholar 

  • Campbell SE, Stone WL, Lee S, Whaley S, Yang H, Qui M et al (2006) Comparative effects of RRR-alpha- and RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines. BMC Cancer 6:13. https://doi.org/10.1186/1471-2407-6-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cayır K, Karadeniz A, Simşek N, Yıldırım S, Karakuş E, Kara A et al (2011) Pomegranate seed extract attenuates chemotherapy-induced acute nephrotoxicity and hepatotoxicity in rats. J Med Food 14:1254–1262

    Article  PubMed  CAS  Google Scholar 

  • Çelik F, Gocmez C, Bozkurt M, Kaplan I, Kamasak K, Akil E et al (2013) Neuroprotective effects of carvacrol and pomegranate against methotrexate induced toxicity in rats. Eur Rev Med Pharmacol Sci 17:2988–2993

    PubMed  Google Scholar 

  • Cerdá B, Llorach R, Cerón JJ, Espín JC, Tomás-Barberán FA (2003) Evaluation of the bioavailability and metabolism in the rat of punicalagin, an antioxidant polyphenol from pomegranate juice. Eur J Nutr 42:18–28

    Article  PubMed  CAS  Google Scholar 

  • Cerdá B, Espín JC, Parra S, Martinez P, Tomás-Barberán FA (2004) The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans. Eur J Nutr 43:205–220

    Article  PubMed  CAS  Google Scholar 

  • Cerdá B, Periago P, Espín JC, Tomás-Barberán FA (2005) Identification of urolithin A as a metabolite produced by human colon microflora from ellagic acid and related compounds. J Agric Food Chem 53:5571–5576

    Article  PubMed  CAS  Google Scholar 

  • Chang C-P, Chan Y-Y, Li C-F, Chien L-H, Lee S-T, Wu T-F (2018) Deciphering the molecular mechanism underlying the inhibitory efficacy of Taiwanese local pomegranate peels against urinary bladder urothelial carcinoma. Nutrients 10(5):E543. https://doi.org/10.3390/nu10050543

    Article  CAS  PubMed  Google Scholar 

  • Chen HS, Bai MH, Zhang T, Li GD, Liu M (2015) Ellagic acid induces cell cycle arrest and apoptosis through TGF-β/Smad3 signaling pathway in human breast cancer MCF-7 cells. Int J Oncol 46:1730–1738

    Article  CAS  PubMed  Google Scholar 

  • Chen XX, Lam KH, Feng Y, Xu K, Sze SCW, Tang CW et al (2018) Ellagitannins from pomegranate ameliorates 5-fluorouracil-induced intestinal mucositis in rats while enhancing its chemotoxicity against HT-29 colorectal cancer cells through intrinsic apoptosis induction. J Agric Food Chem 66:7054–7064. https://doi.org/10.1021/acs.jafc.8b02458

    Article  CAS  PubMed  Google Scholar 

  • Cheng X, Gao Y, Yao X, Yu H, Bao J, Guan H et al (2016) Punicalagin induces apoptosis-independent autophagic cell death in human papillary thyroid carcinoma BCPAP cells. RSC Adv 6:72. https://doi.org/10.1039/C6RA13431A

    Article  CAS  Google Scholar 

  • Cheng X, Yaob X, Xua S, Panb J, Yua H, Baoa J et al (2018) Punicalagin induces senescent growth arrest in human papillary thyroid carcinoma BCPAP cells via NF-κB signaling pathway. Biomed Pharmacother 103:490–498. https://doi.org/10.1016/j.biopha.2018.04.074

    Article  CAS  PubMed  Google Scholar 

  • Costantini S, Rusolo F, De Vito V, Moccia S, Picariello G, Capone F et al (2014) Potential anti-inflammatory effects of the hydrophilic fraction of pomegranate (Punica granatum L.) seed oil on breast cancer cell lines. Molecules 19:8644–8660

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • D’Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH (2003) Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 95:1376–1383

    Article  PubMed  Google Scholar 

  • Dahlawi H, Jordan-Mahy N, Clench MR, LeMaitre CL (2012) Bioactive actions of pomegranate fruit extracts on leukemia cell lines in vitro hold promise for new therapeutic agents for leukemia. Nutr Cancer 64:100–110

    Article  PubMed  Google Scholar 

  • Dahlawi H, Jordan-Mahy N, Clench M, McDougall GJ, Maitre CL (2013) Polyphenols are responsible for the proapoptotic properties of pomegranate juice on leukemia cell lines. Food Sci Nutr 2:196–208

    Article  CAS  Google Scholar 

  • Dai Z, Nair V, Khan M, Ciolino HP (2010) Pomegranate extract inhibits the proliferation and viability of MMTV-Wnt-1 mouse mammary cancer stem cells in vitro. Oncol Rep 24:1087–1091

    CAS  PubMed  Google Scholar 

  • Dana N, Javanmard SH, Rafiee L (2016) Role of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract. Iran J Basic Med Sci 19:106–110

    PubMed  PubMed Central  Google Scholar 

  • Davies L, Morris LG, Haymart M, Chen AY, Goldenberg D, Morris J et al (2015) American Association of Clinical Endocrinologists and American College of Endocrinology Disease state clinical review: the increasing incidence of thyroid cancer. Endocr Pract 21:686–696

    Article  PubMed  PubMed Central  Google Scholar 

  • Dawidczyk CM, Russell LM, Searson PC (2014) Nanomedicines for cancer therapy: state-of-the-art and limitations to pre- clinical studies that hinder future developments. Front Chem 2:69. https://doi.org/10.3389/fchem.2014.00069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Vries E, Trakatelli M, Kalabalikis D, Ferrandiz L, Ruiz-de-Casas A, Moreno-Ramirez D et al (2012) Known and potential new risk factors for skin cancer in European populations: a multicentre case-control study. Br J Dermatol 167(Suppl 2):1–13. https://doi.org/10.1111/j.1365-2133.2012.11081.x

    Article  PubMed  Google Scholar 

  • Deng Y, Li Y, Yang F, Zeng A, Yang S, Luo Y et al (2017) The extract from Punica granatum (pomegranate) peel induces apoptosis and impairs metastasis in prostate cancer cells. Biomed Pharmacother 93:976–984

    Article  CAS  PubMed  Google Scholar 

  • DiMarco-Crook C, Xiao H (2015) Diet-based strategies for cancer chemoprevention: the role of combination regimens using dietary bioactive components. Annu Rev Food Sci Technol 6:505–552

    Article  CAS  PubMed  Google Scholar 

  • El-Ashmawy NE, Khedr EG, El-Bahrawy HA, Abd El-Fattah EE (2016) Effect of pomegranate hull extract on liver neoplastic changes in rats: more than an antioxidant. Nutr Cancer 68:1044–1051

    Article  PubMed  Google Scholar 

  • Espín JC, González-Barrio B, Cerdá B, López-Bote C, Rey AI, Tomás-Barberán FA (2007) Iberian pig as a model to clarify obscure points in the bioavailability and metabolism of ellagitannins in humans. J Agric Food Chem 55:10476–10485

    Article  PubMed  CAS  Google Scholar 

  • Espín JC, Larrosa M, García-Conesa M T, Tomás-Barberán FA (2013) Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far. Evid Based Complement Altern Med 270418, 15 p. https://doi.org/10.1155/2013/270418

  • Faria A, Calhau C (2011) The bioactivity of pomegranate: impact on health and disease. Crit Rev Food Sci Nutr 51:626–634

    Article  CAS  PubMed  Google Scholar 

  • Fenaux P, Chomienne C, Degos L (2001) All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol 38:13–25

    Article  CAS  PubMed  Google Scholar 

  • Ferreira LM, Cervi VF, Gehrcke M, da Silveira EF, Azambuja JH, Braganhol E et al (2015) Ketoprofen-loaded pomegranate seed oil nanoemulsion stabilized bypullulan: selective antiglioma formulation for intravenous administration. Colloids Surf B: Biointerfaces 130:272–277

    Article  CAS  PubMed  Google Scholar 

  • Fimognari C, Sestili P, Lenzi M, Bucchini A, Cantelli-Forti G, Hrelia P (2008) RNA as a new target for toxic and protective agents. Mutat Res 648:15–22

    Article  CAS  PubMed  Google Scholar 

  • Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC et al (2005) Risk of prostate cancer–specific mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433–439

    Article  CAS  PubMed  Google Scholar 

  • Freedland SJ, Carducci M, Kroeger N, Partin A, Rao JY, Jin Y et al (2013) A double-blind, randomized, neoadjuvant study of the tissue effects of POMx pills in men with prostate cancer before radical prostatectomy. Cancer Prev Res 6:1120–1127

    Article  CAS  Google Scholar 

  • Frenkel M, Abrams DI, Ladas EJ, Deng G, Hardy M, Capodice JL et al (2013) Integrating dietary supplements into cancer care. Integr Cancer Ther 12:369–384

    Article  CAS  PubMed  Google Scholar 

  • Fu L, Xu BT, Xu XR, Gan RY, Zhang Y, Xia EQ et al (2011) Antioxidant capacities and total phenolic contents of 62 fruits. Food Chem 129:345–350

    Article  CAS  PubMed  Google Scholar 

  • Fuentes VR, Expósito A (1995) Las encuestas etnobotánicas sobre plantas medicinales en Cuba. Rev Jard Bot Nac 16:77–144

    Google Scholar 

  • Ganeshkumar M, Sathishkumar M, Ponrasu T, Dinesh MG, Suguna L (2013) Spontaneous ultrafast synthesis of gold nanoparticles using Punica granatum for cancer targeted drug delivery. Colloids Surf B Biointerfaces 106:208–216

    Article  CAS  PubMed  Google Scholar 

  • Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA (2000) Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 48:4581–4589

    Article  CAS  PubMed  Google Scholar 

  • González-Sarrías A, Giménez-Bastida JA, García-Conesa MT, Gómez-Sánchez MB, García-Talavera NV, Gil-Izquierdo A et al (2010) Occurrence of urolithins, gut microbiota ellagic acid metabolites and proliferation markers expression response in the human prostate gland upon consumption of walnuts and pomegranate juice. Mol Nutr Food Res 54:311–322

    Article  PubMed  CAS  Google Scholar 

  • González-Sarrías A, Núñez-Sánchez MA, Tomé-Carneiro J, Tomás-Barberán FA, García-Conesa MT, Espín JC (2016) Comprehensive characterization of the effects of ellagic acid and urolithins on colorectal cancer and key associated molecular hallmarks: microRNA-cell specific induction on CDKN1A (p21) as a common mechanism involved. Mol Nutr Food Res 60:701–716

    Article  PubMed  CAS  Google Scholar 

  • Gordaliza M (2007) Natural products as leads to anticancer drugs. Clin Trans Oncol 9:767–776

    Article  CAS  Google Scholar 

  • Grossmann ME, Mizuno NK, Schuster T, Cleary MP (2010) Punicic acid is an omega-5 fatty acid capable of inhibiting breast cancer proliferation. Int J Oncol 36:421–426

    CAS  PubMed  Google Scholar 

  • Guo H, Zhang D, Fu Q (2016) Inhibition of cervical cancer by promoting IGFBP7 expression using ellagic acid from pomegranate peel. Med Sci Monit 22:4881–4886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta S, Mukhtar H (2002) Chemoprevention of skin cancer: current status and future prospects. Cancer Metast Rev 21:363–380

    Article  CAS  Google Scholar 

  • Hackshaw-McGeagh LE, Perry RE, Leach VA, Qandil S, Jeffreys M, Martin RM et al (2015) A systematic review of dietary, nutritional, and physical activity interventions for the prevention of prostate cancer progression and mortality. Cancer Causes Control 26:1521–1550

    Article  PubMed  PubMed Central  Google Scholar 

  • Hagiwara Y, Kasukabe T, Kaneko Y, Niitsu N, Okabe-Kado J (2010) Ellagic acid, a natural polyphenolic compound, induces apoptosis and potentiates retinoic acid-induced differentiation of human leukemia HL-60 cells. Int J Hematol 92:136–143

    Article  CAS  PubMed  Google Scholar 

  • Hassanpour Fard M, Ghule AE, Bodhankar SL, Dikshit M (2011) Cardioprotective effect of whole fruit extract of pomegranate on doxorubicin-induced toxicity in rat. Pharm Biol 49:377–382

    Article  PubMed  Google Scholar 

  • He JZ, Ho JJ, Gingerich S, Courtman DW, Marsden PA, Ward ME (2010) Enhanced translation of heme oxygenase-2 preserves human endothelial cell viability during hypoxia. J Biol Chem 285:9452–9461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heinlein CA, Chang C (2004) Androgen receptor in prostate cancer. Endocr Rev 25:276–308

    Article  CAS  PubMed  Google Scholar 

  • Hermeking H (2012) MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer 12:613–626

    Article  CAS  PubMed  Google Scholar 

  • Hilton WM, Svatek RS (2012) Words of wisdom. Re: phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. Eur Urol 61:1062–1063

    Article  PubMed  Google Scholar 

  • Hoensch H, Groh B, Edler L, Kirch W (2008) Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence. World J Gastroenterol 14:2187–2193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong MY, Seeram NP, Heber D (2008) Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor. J Nutr Biochem 19:848–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hora JJ, Maydew ER, Lansky EP, Dwivedi C (2003) Chemopreventive effects of pomegranate seed oil on skin tumor development in CD1 mice. J Med Food 6:157–161

    Article  CAS  PubMed  Google Scholar 

  • Huang WY, Cai YZ, Zhang Y (2010) Natural phenolic compounds from medicinal herbs and dietary plants: potential use for cancer prevention. Nutr Cancer 62:1–20

    Article  PubMed  CAS  Google Scholar 

  • Iguchi T, Wang CY, Delongchamps NB, Kato M, Tamada S, Yamasaki T et al (2015) Association of MnSOD AA genotype with the progression of prostate cancer. PLoS One 10:e0131325

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ito H, Li P, Koreishi M, Nagatomo A, Nishida N, Yoshida T (2014) Ellagitannin oligomers and a neolignan from pomegranate arils and their inhibitory effects on the formation of advanced glycation end products. Food Chem 152:323–330

    Article  CAS  PubMed  Google Scholar 

  • Jeune MAL, Kumi-Diaka J, Brown J (2005) Anticancer activities of pomegranate extracts and genistein in human breast cancer cells. J Med Food 8:469–475

    Article  CAS  PubMed  Google Scholar 

  • Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN (2000) γ-Tocopherol and its major metabolite, in contrast to α-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Nat Acad Sci 97:11494–11499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Q, Wong J, Fyrst H, Saba JD, Ames BN (2004) γ-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. Proc Nat Acad Sci 101:17825–17830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiménez-Escrig A, Santos-Hidalgo AB, Saura-Calixto F (2006) Common sources and estimated intake of plant sterols in the Spanish diet. J Agric Food Chem 54:3462–3471. https://doi.org/10.1021/jf053188k

    Article  CAS  PubMed  Google Scholar 

  • Jurenka JMT (2008) Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern Med Rev 13:123–144

    Google Scholar 

  • Kalaycıoğlu Z, Bedia EF (2017) Total phenolic contents, antioxidant activities, and bioactive ingredients of juices from pomegranate cultivars worldwide. Food Chem 221:496–507

    Article  PubMed  CAS  Google Scholar 

  • Kamiya N, Suzuki H, Endo T, Takano M, Yano M, Naoi M et al (2011) Significance of serum osteoprotegerin and receptor activator of nuclear factor κB ligand in Japanese prostate cancer patients with bone metastasis. Int J Clin Oncol 16:366–372

    Article  CAS  PubMed  Google Scholar 

  • Kapoor R, Ronnenberg A, Puleo E, Chatterton RT Jr, Dorgan JF, Seeram NP et al (2015) Effects of pomegranate juice on hormonal biomarkers of breast cancer risk. Nutr Cancer 67:1113–1119

    Article  CAS  PubMed  Google Scholar 

  • Kasimsetty SG, Bialonska D, Reddy MK, Thornton CK, Willett L, Ferreira D (2009) Effects of pomegranate chemical constituents/intestinal microbial metabolites on CYP1B1 in 22Rv1 prostate cancer cells. J Agric Food Chem 57:10636–10644

    Article  CAS  PubMed  Google Scholar 

  • Kasimsetty SG, Bialonska D, Reddy MK, Ma G, Khan SI, Ferreira D (2010) Colon cancer chemopreventive activities of pomegranate ellagitannins and urolithins. J Agric Food Chem 58:2180–2187

    Article  CAS  PubMed  Google Scholar 

  • Kawaii S, Lansky EP (2004) Differentiation-promoting activity of pomegranate fruit extracts in HL-60 human promyelocytic leukemia cells. J Med Food 7:13

    Article  CAS  PubMed  Google Scholar 

  • Kawasaki BT, Hurt EM, Mistree T, Farrar WL (2008) Targeting cancer stem cells with phytochemicals. Mol Interv 8:174–184

    Article  CAS  PubMed  Google Scholar 

  • Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC (2004) Diet, nutrition and the prevention of cancer. Public Health Nutr 7:187–200

    Article  PubMed  Google Scholar 

  • Khan N, Mukhtar H (2010) Cancer chemoprevention. In: McQueen CA (ed) Comprehensive toxicology, pp 417–431

    Google Scholar 

  • Khan N, Handi N, Afaq F, Syed DN, Kweon MH, Mukhtar H (2007a) Pomegranate fruit extracts inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor growth in athymic nude mice. Carcinogenesis 28:163–173

    Article  CAS  PubMed  Google Scholar 

  • Khan N, Afaq F, Kweon MH, Kim K, Mukhtar H (2007b) Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice. Cancer Res 67:3475–3482

    Article  CAS  PubMed  Google Scholar 

  • Khan N, Afaq F, Mukhtar H (2008) Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal 10:475–510

    Article  CAS  PubMed  Google Scholar 

  • Khan N, Afaq F, Mukhtar H (2010) Lifestyle as risk factor for cancer: evidence from human studies. Cancer Lett 293:133–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim ND, Mehta R, Yu W, Neeman I, Livney T, Amichay A et al (2002) Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Res Treat 71:203–217

    Article  CAS  PubMed  Google Scholar 

  • Kiraz Y, Neergheen-Bhujun VS, Rummun N, Baran Y (2016) Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells. Tumour Biol 37:1803–1815

    Article  PubMed  Google Scholar 

  • Kishore RK, Sudhakar D, Parthasarathy PR (2009) Embryo protective effect of pomegranate (Punica granatum L.) fruit extract in adriamycin-induced oxidative stress. Indian J Biochem Biophys 46:106–111

    CAS  PubMed  Google Scholar 

  • Klempner SJ, Bubley G (2012) Complementary and alternative medicine in prostate cancer: from bench to bedside? Oncologist 17:830–837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohno H, Suzuki R, Yasui Y, Hosokawa M, Miyashita K, Tanaka T (2004) Pomegranate seed oil rich in conjugated linolenic acid suppresses chemically induced colon carcinogenesis in rats. Cancer Sci 95:481–486

    Article  CAS  PubMed  Google Scholar 

  • Lansky EP, Newman RA (2007) Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J Ethnopharmacol 109:177–206

    Article  CAS  PubMed  Google Scholar 

  • Lansky EP, Shubert S, Neeman I (1997) Pharmacological and therapeutic of pomegranate. Ciham Options Mediterr 5:231–235

    Google Scholar 

  • Lansky EP, Jiang W, Mo H, Bravo L, Froom P, Yu W et al (2005a) Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Investig New Drugs 23:11–20

    Article  CAS  Google Scholar 

  • Lansky EP, Harrison G, Froom P, Jiang WG (2005b) Pomegranate (Punica granatum) pure chemicals show possible synergistic inhibition of human PC-3 prostate cancer cell invasion across matrigel™. Investig New Drugs 23:121–122

    Article  CAS  Google Scholar 

  • Larrosa M, González-Sarrías A, García-Conesa MT, Tomás-Barberán FA, Espín JC (2006a) Urolithins, ellagic acid derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. J Agric Food Chem 54:1611–1620

    Article  CAS  PubMed  Google Scholar 

  • Larrosa M, Tomás-Barberán FA, Espíın JC (2006b) The dietary hydrolysable tannin punicalagin releases ellagic acid that induces apoptosis in human colon adenocarcinoma Caco-2 cells by using the mitochondrial pathway. J Nutr Biochem 17:611–625

    Article  CAS  PubMed  Google Scholar 

  • Lazzeroni M, DeCensi A (2013) Breast cancer prevention by antihormones and other drugs: where do we stand? Hematol Oncol Clin North Am 27:657–672

    Article  PubMed  Google Scholar 

  • Lee S-T, Wu Y-L, Chien L-H, Chen S-T, Tzeng Y-K, Wu T-F (2012) Proteomic exploration of the impacts of pomegranate fruit juice on the global gene expression of prostate cancer cell. Proteomics 12:3251–3262

    Article  CAS  PubMed  Google Scholar 

  • Lee ST, Lu MH, Chien LH, Wu TF, Huang LC, Liao GI (2013) Suppression of urinary bladder urothelial carcinoma cell by the ethanol extract of pomegranate fruit through cell cycle arrest and apoptosis. BMC Complement Altern Med 13:364. https://doi.org/10.1186/1472-6882-13-364

    Article  PubMed  PubMed Central  Google Scholar 

  • Li H, Kantoff P, Giovannucci E, Leitzmann MF, Gaziano JM, Stampfer MJ et al (2005) Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinically significant prostate cancer risk. Cancer Res 65:2498–2504

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Yang F, Zheng W, Hu M, Wang J, Ma S et al (2016a) 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 80:227–235

    Article  PubMed  Google Scholar 

  • Li R, Chen XG, Jia K, Liu ZP, Peng HY (2016b) A systematic determination of polyphenols constituents and cytotoxic ability in fruit parts of pomegranates derived from five Chinese cultivars. Springerplus 5:914–922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lisbeth A, Noratto G, Hingorani L, Talcott ST, Mertens-Talcott SU (2008) Protective effects of standardized pomegranate (Punica granatum L.) polyphenolic extract in ultraviolet-irradiated human skin fibroblasts. J Agric Food Chem 56:8434–8441

    Article  CAS  Google Scholar 

  • Liu RH (2003) Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am J Clin Nutr 78:517S–520S

    Article  CAS  PubMed  Google Scholar 

  • Lokina S, Suresh R, Giribabu K, Stephen A, Lakshmi Sundaram R, Narayanan V (2014) Spectroscopic investigations, antimicrobial, and cytotoxic activity of green synthesized gold nanoparticles. Spectrochim Acta A Mol Biomol Spectrosc 129:484–490

    Article  CAS  PubMed  Google Scholar 

  • Longtin R (2003) The pomegranate: Nature’s power fruit? J Natl Cancer Inst 95:346–348

    Article  PubMed  Google Scholar 

  • Lu LY, Liu Y, Zhang ZF, Gou XJ, Jiang JH, Zhang JZ et al (2015) Pomegranate seed oil exerts synergistic effects with trans-resveratrol in a self-nanoemulsifying drug delivery system. Biol Pharm Bull 38:1658–1662

    Article  CAS  PubMed  Google Scholar 

  • Lucci P, Pacetti D, Loizzo MR, Frega NG (2015) Punica granatum cv. Dente di Cavallo seed ethanolic extract: antioxidant and antiproliferative activities. Food Chem 167:475–483

    Article  CAS  PubMed  Google Scholar 

  • Mahaddalkar T, Suri C, Naik PK, Lopus M (2015) Biochemical characterization and molecular dynamic simulation of β-sitosterol as a tubulin-binding anticancer agent. Eur J Pharmacol 760:154–162

    Article  CAS  PubMed  Google Scholar 

  • Malik A, Mukhtar H (2006) Prostate cancer prevention through pomegranate fruit. Cell Cycle 5:371–373

    Article  CAS  PubMed  Google Scholar 

  • Malik A, Afaq F, Sarfaraz S, Adhami VM, Syed DN, Mukhtar H (2005) Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci USA 102:14813–14818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mandal A, Bishayee A (2015) Mechanism of breast cancer preventive action of pomegranate: disruption of estrogen receptor and Wnt/β-catenin signaling pathways. Molecules 20:22315–22328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marquardt JU, Andersen JB, Thorgeirsson SS (2015) Functional and genetic deconstruction of the cellular origin in liver cancer. Nat Rev Cancer 15:653–667

    Article  CAS  PubMed  Google Scholar 

  • Masci A, Coccia A, Lendaro E, Mosca L, Paolicelli P, Cesa S (2016) Evaluation of different extraction methods from pomegranate whole fruit or peels and the antioxidant and antiproliferative activity of the polyphenolic fraction. Food Chem 202:59–69

    Article  CAS  PubMed  Google Scholar 

  • McCarty MF, Hejazi J, Rastmanesh R (2014) Beyond androgen deprivation: ancillary integrative strategies for targeting the androgen receptor addiction of prostate cancer. Integr Cancer Ther 13:386–395

    Article  CAS  PubMed  Google Scholar 

  • Mehta R, Lansky EP (2004) Breast cancer chemopreventive properties of pomegranate (Punica granatum) fruit extracts in a mouse mammary organ culture. Eur J Cancer Prev 13:345–348

    Article  CAS  PubMed  Google Scholar 

  • Melo M, da Rocha AG, Vinagre J, Sobrinho-Simoes M, Soares P (2015) Coexistence of TERT promoter and BRAF mutations in papillary thyroid carcinoma: added value in patient prognosis? J Clin Oncol 33:667–668

    Article  PubMed  Google Scholar 

  • Mertens-Talcott SU, Percival SS (2005) Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells. Cancer Lett 218:141–151

    Article  CAS  PubMed  Google Scholar 

  • Mertens-Talcott SU, Jilma-Stohlawetz P, Rios J, Hingorani L, Derendorf H (2006) Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum L.) polyphenols after ingestion of a standardized extract in healthy human volunteers. J Agric Food Chem 54:8956–8961

    Article  CAS  PubMed  Google Scholar 

  • Ming DS, Pham S, Deb S, Chin MY, Kharmate G, Adomat H et al (2014) Pomegranate extracts impact the androgen biosynthesis pathways in prostate cancer models in vitro and in vivo. J Steroid Biochem Mol Biol 143c:19–28

    Article  CAS  Google Scholar 

  • Modaeinama S, Abasi M, Abbasi MM, Jahanban-Esfahlan R (2015) Antitumoral properties of Punica granatum (pomegranate) peel extract on different human cancer cells. Asian Pac J Cancer Prev 16:5697–5701

    Article  PubMed  Google Scholar 

  • Moon DO, Kim MO, Choi YH, Kim GY (2008) beta-Sitosterol induces G2/M arrest, endoreduplication, and apoptosis through the Bcl-2 and PI3K/Akt signaling pathways. Cancer Lett 264:181–191. https://doi.org/10.1016/j.canlet.2008.01.032

    Article  CAS  PubMed  Google Scholar 

  • Motaal AA, Shaker S (2011) Anticancer and antioxidant activities of standardized whole fruit, pulp, and peel extracts of Egyptian pomegranate. Open Conf Proc J 2:41–45

    Article  Google Scholar 

  • Mukherjee S, Ghosh S, Choudhury S, Adhikary A, Manna K, Dey S et al (2013) Pomegranate reverses methotrexate-induced oxidative stress and apoptosis in hepatocytes by modulating Nrf2-NF-κB pathways. J Nutr Biochem 24:2040–2050. https://doi.org/10.1016/j.jnutbio.2013.07.005

    Article  CAS  PubMed  Google Scholar 

  • Naiki-Ito A, Chewonarin T, Tang M, Pitchakarn P, Kuno T, Ogawa K et al (2015) Ellagic acid, a component of pomegranate fruit juice, suppresses androgen-dependent prostate carcinogenesis via induction of apoptosis. Prostate 75:151–160

    Article  CAS  PubMed  Google Scholar 

  • Nainwani R, Singh D, Soni PK, Gupta A, Gautam R (2013) Chemical constituents of various parts of Punica granatum and their anti-inflammatory activity: a review. Asian J Pharm Res Dev 1:48–53

    Google Scholar 

  • Nair V, Dai Z, Khan M, Ciolino HP (2011) Pomegranate extract induces cell cycle arrest and alters cellular phenotype of human pancreatic cancer cells. Anticancer Res 31:2699–2704

    CAS  PubMed  Google Scholar 

  • National Cancer Institute. Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version. (2016). Retrieved from http://www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq

  • Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477

    Article  CAS  PubMed  Google Scholar 

  • Niedziela M (2014) Thyroid nodules. Best Pract Res Clin Endocrinol Metab 28:245–277

    Article  CAS  PubMed  Google Scholar 

  • No Authors (2013) I’ve been reading about the potential benefits of pomegranates. Should I add this fruit to my diet? Johns Hopkins Med Lett Health After 50 25:7

    Google Scholar 

  • Norman HA, Butrum RR, Feldman E, Heber D, Nixon D, Picciano MF et al (2003) The role of dietary supplements during cancer therapy. J Nutr 133:3794S–3799S

    Article  CAS  PubMed  Google Scholar 

  • Nuñez-Sánchez MA, García-Villalba R, Monedero-Saiz T, García-Talavera NV, Gómez-Sánchez MB, Sánchez-Álvarez C et al (2014a) Targeted metabolic profiling of pomegranate polyphenols and urolithins in plasma, urine and colon tissues from colorectal cancer patients. Mol Nutr Food Res 58:1199–1211

    Article  PubMed  CAS  Google Scholar 

  • Nuñez-Sánchez MA, García-Villalba R, Monedero-Saiz T, García-Talavera NV et al (2014b) Targeted metabolic profiling of pomegranate polyphenols and urolithins in plasma, urine and colon tissues from colorectal cancer patients. Mol Nutr Food Res 58:1199–1211

    Article  PubMed  CAS  Google Scholar 

  • Nuñez-Sánchez MA, Dávalos A, González-Sarrías A, Casas-Agustench P, Visioli F, Monedero-Saiz T et al (2015) MicroRNAs expression in normal and malignant colon tissues as biomarkers of colorectal cancer and in response to pomegranate extracts consumption: critical issues to discern between modulatory effects and potential artefacts. Mol Nutr Food Res 59:1973–1986

    Article  PubMed  CAS  Google Scholar 

  • Núñez-Sánchez MA, González-Sarrías A, Romo-Vaquero M, García-Villalba R, Selma MV, Tomás-Barberán FA, Garcia-Conesa MT, Espín JC (2015) Dietary phenolics against colorectal cancer—from promising preclinical results to poor translation into clinical trials: pitfalls and future needs. Mol Nutr Food Res 59:1274–1291

    Article  PubMed  CAS  Google Scholar 

  • Nuñez-Sánchez MA, Karmokar A, González-Sarrías A, García-Villalba R, Tomás-Barberán FA, García-Conesa MT et al (2016) In vivo relevant mixed urolithins and ellagic acid inhibit phenotypic and molecular colon cancer stem cell features: a new potentiality for ellagitannin metabolites against cancer. Food Chem Toxicol 92:8–16

    Article  PubMed  CAS  Google Scholar 

  • Nuñez-Sánchez MA, González-Sarrías A, García-Villalba R, Monedero-Saiza T, García-Talavera NV, Gómez-Sánchez MB et al (2017) Gene expression changes in colon tissues from colorectal cancer patients following the intake of an ellagitannin-containing pomegranate extract: a randomized clinical trial. J Nutr Biochem 42:126–133

    Article  PubMed  CAS  Google Scholar 

  • Orgil O, Schwartz E, Baruch L, Matityahu I, Mahajna J, Amir R (2014) The antioxidative and anti-proliferative potential of non-edible organs of the pomegranate fruit and tree. LWT-Food Sci Technol 58:571–577

    Article  CAS  Google Scholar 

  • Pacheco-Palencia LA, Noratto G, Hingorani L, Talcott ST, Mertens-Talcott SU (2008) Protective effects of standardized pomegranate (Punica granatum L.) polyphenolic extract in ultraviolet-irradiated human skin fibroblasts. J Agricul Food Chem 56:8434–8441

    Article  CAS  Google Scholar 

  • Paller CJ, Ye X, Wozniak PJ, Gillespie BK, Sieber PR, Greengold RH et al (2013a) A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 16:50–55

    Article  CAS  PubMed  Google Scholar 

  • Paller CJ, Olatoye D, Xie S, Zhou X, Denmeade SR, Eisenberger MA et al (2013b) The effect of the frequency and duration of PSA measurement on PSA doubling time calculations in men with biochemically recurrent prostate cancer. Prostate Cancer Prostatic Dis 17:28–33

    Article  PubMed  PubMed Central  Google Scholar 

  • Paller JC, Pantuck A, Carducci MA (2017) A review of pomegranate in prostate cancer. Prostate Cancer Prostatic Dis 20:265–270. https://doi.org/10.1038/pcan.2017.19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, Hong J, Barnard RJ et al (2006) Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 12:4018–4026

    Article  CAS  PubMed  Google Scholar 

  • Pantuck AJ, Pettaway CA, Dreicer R, Corman J, Katz A, Ho A et al (2015) A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis 18:242–248

    Article  CAS  PubMed  Google Scholar 

  • Paur I, Lilleby W, Bohn SK, Hulander E, Klein W, Vlatkovic L et al (2017) Tomato-based randomized controlled trial in prostate cancer patients: effect on PSA. Clin Nutr 36:672–679

    Article  CAS  PubMed  Google Scholar 

  • Petrelli A, Giordano S (2008) From single- to multi-target drugs in cancer therapy: when a specificity becomes an advantage. Curr Med Chem 15:422–432

    Article  CAS  PubMed  Google Scholar 

  • Pogribny IP, Rusyn I (2013) Environmental toxicants, epigenetics, and cancer. Adv Exp Med Biol 754:215–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prakash CVS, Prakash I (2011) Bioactive chemical constituents from pomegranate (Punica granatum) juice, seed and peel-a review. Int J Res Chem Environ 1:1–18

    Google Scholar 

  • Qasim FK, Qadir FA, Karim KJ (2013) Effects of pomegranate seed oil and tamoxifen on mastectomy breast cancer women. IOSR J Pharm 3:44–51

    Google Scholar 

  • Rahimi HR, Arastoo M, Ostad SN (2012) A comprehensive review of Punica granatum (pomegranate) properties in toxicological, pharmacological, cellular and molecular biology researches. Iran J Pharm Res 11:385–400

    CAS  PubMed  PubMed Central  Google Scholar 

  • Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P et al (2008) Cooperating gene mutations in acutemyeloid leukemia: a review of the literature. Leukemia 22:915–931

    Article  CAS  PubMed  Google Scholar 

  • Rettig MB, Heber D, An J, Seeram NP, Rao JY, Liu H et al (2008) Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-κB-dependent mechanism. Mol Cancer Ther 7:2662–2671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richmond E, Viner JL (2003) Chemoprevention of skin cancer. Semin Oncol Nurs 19:62–69

    Article  PubMed  Google Scholar 

  • Rocha A, Wang L, Penichet M, Martins-Green M (2012) Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer. Breast Cancer Res Treat 136:647–658

    Article  CAS  PubMed  Google Scholar 

  • Roig JT (1974) Plantas medicinales, aromáticas o venenosas de Cuba. Ciencia y Técnica:401–402

    Google Scholar 

  • Sadik NA, Shaker OG (2013) Inhibitory effect of a standardized pomegranate fruit extract on Wnt signalling in 1, 2-dimethylhydrazine induced rat colon carcinogenesis. Dig Dis Sci 58:2507–2517

    Article  PubMed  Google Scholar 

  • Saltz LB (ed) (2007) Colorectal cancer: evidence-based chemotherapy strategies. Current Clinical OncologyTM, Markman M, MD (Series ed). Humana, Totowa. ISBN: 1-58829-751-9, E-ISBN: 1-59745-215-7

    Google Scholar 

  • Sanna V, Pala N, Sechi M (2014) Targeted therapy using nanotechnology: focus on cancer. Int J Nanomedicine 9:467–483

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sartippour MR, Seeram NP, Rao YJ, Moro A, Harris DM, Henning SM et al (2008) Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo. Int J Oncol 32:475–480

    CAS  PubMed  Google Scholar 

  • Scher HI, Helabi S, Tannock I, Morris M, Sternberg CN, Carducci MA et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol 26:1148–1159

    Article  PubMed  Google Scholar 

  • Seeram NP, Lee R, Heber D (2004) Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clin Chim Acta 348:63–68

    Article  CAS  PubMed  Google Scholar 

  • Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG et al (2005) In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem 16:360–367

    Article  CAS  PubMed  Google Scholar 

  • Seeram NP, Henning SM, Zhang Y, Suchard M, Li Z, Heber D (2006) Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours. J Nutr 136:2481–2485

    Article  CAS  PubMed  Google Scholar 

  • Seeram NP, Aronson WJ, Zhang Y, Henning SM, Moro A, Lee RP et al (2007) Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem 55:7732–7737

    Article  CAS  PubMed  Google Scholar 

  • Seeram NP, Zhang Y, McKeever R, Henning SM, Lee RP, Suchard MA et al (2008) Pomegranate juice and extracts provide similar levels of plasma and urinary ellagitannin metabolites in human subjects. J Med Food 11:390–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seidi K, Jahanban-Esfahlan R, Abasi M, Abbasi MM (2016) Antitumoral properties of Punica granatum (pomegranate) seed extract in different human cancer cells. Asian Pac J Cancer Prev 17:1119–1122

    Article  PubMed  Google Scholar 

  • Selma MV, Espín JC, Tomás-Barberán FA (2009) Interaction between phenolics and gut microbiota: role in human health. J Agricu Food Chem 57:6485–6501

    Article  CAS  Google Scholar 

  • Sen V, Bozkurt M, Söker S, Ece A, Güneş A, Uluca Ü et al (2014) The effects of pomegranate and carvacrol on methotrexate-induced bone marrow toxicity in rats. Clin Invest Med 37:E93–E101

    Article  PubMed  Google Scholar 

  • Seoane J (1984) El folklor médico de Cuba. Provincia de Camagüey. Ciencias Sociales, Habana, pp 29, 256, 285, 311, 412, 454, 629, 642

    Google Scholar 

  • Sepehr KS, Baradaran B, Mazandarani M, Yousefi B, Alitappeh MA, Khori V (2014) Growth-inhibitory and apoptosis-inducing effects of Punica granatum L. var. spinosa (Apple Punice) on fibrosarcoma cell lines. Adv Pharm Bull 4(Suppl 2):583–590

    Google Scholar 

  • Shaoul R, Moati D, Schwartz B, Pollak Y, Sukhotnik I (2018) Effect of pomegranate juice on intestinal recovery following methotrexate-induced intestinal damage in a rat model. J Am Coll Nutr 37:406–414. https://doi.org/10.1080/07315724.2017.1413961

    Article  CAS  PubMed  Google Scholar 

  • Sharma M, Li L, Celver J, Killian C, Kovoor A, Seeram NP (2010) Effects of fruit ellagitannin extracts, ellagic acid, and their colonic metabolite, urolithin A, on Wnt signaling. J Agric Food Chem 58:3965–3969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaygannia E, Bahmani M, Zamanzad B, Rafieian-Kopaei M (2016) A review study on Punica granatum L. J Evid Based Complement Altern Med 21:221–227

    Article  CAS  Google Scholar 

  • Shirode AB, Kovvuru P, Chittur SV, Henning SM, Heber D, Reliene R (2014) Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells are associated with reduced DNA repair gene expression and induction of double strand breaks. Mol Carcinog 53:458–470

    Article  CAS  PubMed  Google Scholar 

  • Shirode AB, Bharali DJ, Nallanthighal S, Coon JK, Mousa SA, Reliene R (2015) Nanoencapsulation of pomegranate bioactive compounds for breast cancer chemoprevention. Int J Nanomedicine 10:475–484

    PubMed  PubMed Central  Google Scholar 

  • Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212–236

    Article  PubMed  Google Scholar 

  • Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64:9–29

    Article  PubMed  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30

    Article  PubMed  Google Scholar 

  • Sreeja S, Santhosh Kumar TR, Lakshmi BS, Sreeja S (2012) Pomegranate extract demonstrate a selective estrogen receptor modulator profile in human tumor cell lines and in vivo models of estrogen deprivation. J Nutr Biochem 23:725–732

    Article  CAS  PubMed  Google Scholar 

  • Sreekumar S, Sithul H, Muraleedharan P, Azeez JM, Sreeharshan S (2014) Pomegranate fruit as a rich source of biologically active compounds. Biomed Res Int 686921. https://doi.org/10.1155/2014/686921

  • Srinivas NR (2013) Is pomegranate juice a potential perpetrator of clinical drug-drug interactions? Review of the in vitro, preclinical and clinical evidence. Eur J Drug Metab Pharmacokinet 38:223–229

    Article  CAS  PubMed  Google Scholar 

  • Stenner-Liewen F, Liewen H, Cathomas R, Renner C, Petrausch U, Sulser T et al (2013) Daily pomegranate intake has no impact on PSA levels in patients with advanced prostate cancer – results of a phase IIb randomized controlled trial. J Cancer 4:597–605

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sturgeon SR, Ronnenberg AG (2010) Pomegranate and breast cancer: possible mechanisms of prevention. Nutr Rev 68:122–128

    Article  PubMed  Google Scholar 

  • Suzuki R, Noguchi R, Ota T, Abe M, Miyashita K, Kawada T (2001) Cytotoxic effect of conjugated trienoic fatty acids on mouse tumor and human monocytic leukemia cells. Lipids 36:477–482

    Article  CAS  PubMed  Google Scholar 

  • Syed DN, Malik A, Hadi N, Sarfaraz S, Afaq F, Mukhtar H (2006) Photochemopreventive effect of pomegranate fruit extract on UVA-mediated activation of cellular pathways in normal human epidermal keratinocytes. Photochem Photobiol 82:398–405

    Article  CAS  PubMed  Google Scholar 

  • Syed DN, Chamcheu J-C, Adhami VM, Mukhtar H (2013) Pomegranate extracts and cancer prevention: molecular and cellular activities. Anti Cancer Agents Med Chem 13:1149–1161

    Article  CAS  Google Scholar 

  • Takigawa Y, Brown AMC (2008) Wnt signaling in liver cancer. Curr Drug Targets 9:1013–1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang JM, Min J, Li BS, Hong SS, Liu C, Hu M et al (2016) Therapeutic effects of punicalagin against ovarian carcinoma cells in association with β-Catenin signaling inhibition. Int J Gynecol Cancer 26:1557–1563

    Article  PubMed  Google Scholar 

  • Tezcan F, Gültekin- Özgüven M, Diken T, Özcelik B, Erim FB (2009) Antioxidant activity and total phenolic, organic acid and sugar content in commercial pomegranate juices. Food Chem 115:873–877

    Article  CAS  Google Scholar 

  • Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P (2014) 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 17:180–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tibullo D, Caporarello N, Giallongo C, Anfuso CD, Genovese C, Arlotta C et al (2016) Antiproliferative and antiangiogenic effects of Punica granatum juice (PGJ) in Multiple Myeloma (MM). Nutrients 8(10):E611

    Article  PubMed  CAS  Google Scholar 

  • Toi M, Bando H, Ramachandran C, Melnick SJ, Imai A, Fife RS et al (2003) Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis 6:121–128

    Article  CAS  PubMed  Google Scholar 

  • Tomás-Barberán FA, Seeram NP, Espín JC (2006) Bioavailability of pomegranate polyphenols. In: Seeram NP, Schulman RN, Heber D (eds) Pomegranates. Ancient roots to modern medicine. CRC, Boca Raton, pp 45–60

    Google Scholar 

  • Tomás-Barberán FA, Espín JC, García-Conesa MT (2009) Bioavailability and metabolism of ellagic acid and ellagitannins. In: Quideau S (ed) Chemistry and biology of ellagitannins. World Scientific, Hackensack, pp 293–297

    Google Scholar 

  • Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108

    Article  PubMed  Google Scholar 

  • Tran HNA, Bae S-Y, Song B-H, Lee B-H, Bae Y-S, Kim Y-H et al (2010) Pomegranate (Punica granatum) seed linolenic acid isomers: concentration-dependent modulation of estrogen receptor activity. Endocr Res 35:1–16

    Article  CAS  PubMed  Google Scholar 

  • Turk G, Ateshahin A, Sonmez M, Cheribashi AO, Yuce A (2008) Improvement of cisplatin-induced injuries to sperm quality, the oxidant-antioxidant system, and the histologic structure of the rat testis by ellagic acid. Fertil Steril 89:1474–1481

    Article  CAS  PubMed  Google Scholar 

  • Turrini E, Ferruzzi L, Fimognari C (2015) Potential effects of pomegranate polyphenols in cancer. Prevention and therapy. Oxid Med Cell Longev 938475, 19 p. https://doi.org/10.1155/2015/938475

  • Valadares MC, Pereira ERT, Benfica PL, Paula JR (2010) Assessment of mutagenic and antimutagenic effects of Punica granatumin mice. Braz J Pharm Sci 46:121–127

    Article  Google Scholar 

  • Valko M, Rhodes CJ, Moncol J, Izakovic MM, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:1–40

    Article  CAS  PubMed  Google Scholar 

  • van Die MD, Bone KM, Emery J, Williams SG, Pirotta MV, Paller CJ (2016) Phytotherapeutic interventions in the management of biochemically recurrent prostate cancer: a systematic review of randomised trials. BJU Int 117(Suppl 4):17–34

    PubMed  PubMed Central  Google Scholar 

  • Van Elswijk DA, Schobel UP, Lansky EP, Irth H, Van Der Greef J (2004) Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Phytochemistry 65:233–241

    Article  PubMed  CAS  Google Scholar 

  • Van Ryswyk K, Villeneuve PJ, Johnson KC (2016) Dietary patterns and the risk of female breast cancer among participants of the Canadian National Enhanced Cancer Surveillance System. Can J Public Health 107:49–55

    Article  Google Scholar 

  • Vanella L, Barbagallo I, Acquaviva R, di Giacomo C, Cardile V, Abraham NG et al (2013a) Ellagic acid: cytodifferentiating and antiproliferative effects in human prostatic cancer cell lines. Curr Pharm Design 19:2728–2736

    Article  CAS  Google Scholar 

  • Vanella L, di Giacomo C, Acquaviva R, Barbagallo I, Li Volti G, Cardile V et al (2013b) Effects of ellagic acid on angiogenic factors in prostate cancer cells. Cancers 5:726–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vargas AJ, Thompson PA (2012) Diet and nutrient factors in colorectal cancer risk. Nutr Clin Pract 27:613–623

    Article  PubMed  Google Scholar 

  • Vasudev SS, Ahmad FJ, Khar RK, Bhatnagar A, Kamal YT, Talegaonkar S et al (2012) Validated HPLC method for the simultaneous determination of taxol and ellagic acid in a Punica granatum fruit extract containing combination formulation. Pharmazie 67:834–838

    CAS  PubMed  Google Scholar 

  • Vini R, Sreeja S (2015) Punica granatum and its therapeutic implications on breast carcinogenesis: a review. Biofactors 41:78–89

    Article  CAS  PubMed  Google Scholar 

  • Vini R, Juberiya AM, Sreeja S (2016) Evidence of pomegranate methanolic extract in antagonizing the endogenous SERM, 27-hydroxycholesterol. IUBMB Life 68:116–121

    Article  CAS  PubMed  Google Scholar 

  • Vinod BS, Maliekal TT, Anto RJ (2013) Phytochemicals as chemosensitizers: from molecular mechanism to clinical significance. Antioxid Redox Signal 18:1307–1348

    Article  CAS  PubMed  Google Scholar 

  • Viuda-Martos M, Fernandez-Lopez J, Perez–Alvarez JA (2010) Pomegranate and its many functional components as related to human health: a review. Compr Rev Food Sci Food Saf 9:635–654

    Article  CAS  PubMed  Google Scholar 

  • Vlachojannis C, Zimmermann BF, Chrubasik-Hausmann S (2015) Efficacy and safety of pomegranate medicinal products for cancer. Evid Based Complement Altern Med 2015:258598, 15 p. https://doi.org/10.1155/2015/258598

  • von Holtz RL, Fink CS, Awad AB (1998) beta-Sitosterol activates the sphingomyelin cycle and induces apoptosis in LNCaP human prostate cancer cells. Nutr Cancer 32:8–12. https://doi.org/10.1080/01635589809514709

    Article  Google Scholar 

  • Waly MI, Ali A, Guizani N, Al-Rawahi AS, Farooq SA, Rahman MS (2012) Pomegranate (Punica granatum) peel extract efficacy as a dietary antioxidant against azoxymethane-induced colon cancer in rat. Asian Pac J Cancer Prev 13:4051–4055

    Article  PubMed  Google Scholar 

  • Waly MI, Al-Rawahi AS, Al-Riyami M, Al-Kindi MA, Al-Issaei HK, Farooq SA, Al-Alawi A, Rahman MS (2014) Amelioration of azoxymethane induced-carcinogenesis by reducing oxidative stress in rat colon by natural extracts. BMC Comp Alter Med 14:60–69

    Article  CAS  Google Scholar 

  • Wang L, Martins-Green M (2014) Pomegranate and its components as alternative treatment for prostate cancer. Int J Mol Sci 15:14949–14966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang SG, Huang MH, Li JH, Lai FI, Lee HM, Hsu YN (2013) Punicalagin induces apoptotic and autophagic cell death in human 87MG glioma cells. Acta Pharmacol Sin 34:1411–1419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Zhang S, Iqbal S, Chen Z, Wang X, Wang YA et al (2014) Pomegranate extract inhibits the bone metastatic growth of human prostate cancer cells and enhances the in vivo efficacy of docetaxel chemotherapy. Prostate 74:497–508

    Article  CAS  Google Scholar 

  • Weinberg HD, Robert A (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  PubMed  CAS  Google Scholar 

  • Wu TF, Hsu LT, Tsang BX, Huang LC, Shih WY, Chen LY (2016) Clarification of the molecular pathway of Taiwan local pomegranate fruit juice underlying the inhibition of urinary bladder urothelial carcinoma cell by proteomics strategy. BMC Complement Altern Med 16:96. https://doi.org/10.1186/s12906-016-1071-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu X, Ho W, Zhang X, Bertrand N, Farokhzad O (2015) Cancer nanomedicine: from targeted delivery to combination therapy. Trends Mol Med 21:223–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yaseen NJ, Mustafa Al-Attar MS (2014) Protective effects of Punica granatum seed extract against ifosfamide induced sperm abnormalities in male albino mice. Zanco J Pure Appl Sci 26:97–104

    Article  Google Scholar 

  • Yazici ZM, Meric A, Midi A, ArInc YV, Kahya V, HafIz G (2012) Reduction of cisplatin ototoxicity in rats by oral administration of pomegranate extract. Eur Arch Otorhinolaryngol 269:45–52

    Article  PubMed  Google Scholar 

  • Yildirim NC, Kandemir FM, Ceribasi S, Ozkaraca M, Benzer F (2013) Pomegranate seed extract attenuates chemotherapy-induced liver damage in an experimental model of rabbits. Cell Mol Biol (Noisy-le-Grand) 59(Suppl):OL1842–OL1847

    CAS  Google Scholar 

  • Yoshimura M, Watanabe Y, Kasai K, Yamakoshi J, Koga T (2005) Inhibitory effect of an ellagic acid-rich pomegranate extract on tyrosinase activity and ultraviolet-induced pigmentation. Biosci Biotechnol Biochem 69:2368–2373

    Article  CAS  PubMed  Google Scholar 

  • Zahin M, Ahmad I, Gupta RC, Aqil F (2014) Punicalagin and ellagic acid demonstrate antimutagenic activity and inhibition of benzo[a]pyrene induced DNA adducts. BioMed Res Intern 467465, 10 p. https://doi.org/10.1155/2014/467465

  • Zaid MA, Afaq F, Khan N, Mukhtar H (2007) Protective effects of pomegranate derived products on UVB-induced DNA damage, PCNA expression and MMPs in human reconstituted skin. J Invest Dermatol 127:143–153

    Article  CAS  Google Scholar 

  • Zhou B, Yi H, Tan J, Wu Y, Liu G, Qiu Z (2015) Anti-proliferative effects of polyphenols from pomegranate rind (Punica granatum L.) on EJ bladder cancer cells via regulation of p53/miR-34a axis. Phytother Res 29:415–422

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Li Y, Zhou T, Zheng J, Li S, Li HB (2016) Dietary natural products for prevention and treatment of liver cancer. Nutrients 8:156. https://doi.org/10.3390/nu8030156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Genotoxicology and Antitumor Research Laboratory, Center for Pharmaceutical Research and Development (CIDEM), BioCubaFarma, Havana, Cuba

    Julio César Rodríguez González

  2. Center for Research and Drug Biological Evaluation, Institute of Food and Pharmacy, University Havana, Havana, Cuba

    René Delgado Hernández

  3. Laboratory of Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp (UA), Antwerp, Belgium

    Wim Vanden Berghe

Authors
  1. Julio César Rodríguez González
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. René Delgado Hernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wim Vanden Berghe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wim Vanden Berghe .

Editor information

Editors and Affiliations

  1. Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA

    John M. Pezzuto

  2. Department of Science, Systems & Models, Roskilde University, Roskilde, Denmark

    Ole Vang

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Rodríguez González, J.C., Delgado Hernández, R., Vanden Berghe, W. (2020). Punica granatum L. Constituents for Cancer Prevention, Chemosensitisation and Therapeutic Treatment. In: Pezzuto, J., Vang, O. (eds) Natural Products for Cancer Chemoprevention. Springer, Cham. https://doi.org/10.1007/978-3-030-39855-2_13

Download citation

Publish with us

Policies and ethics

Search

Navigation