Table 1. Summary of the anti-carcinogenic effects of pomegranate-derived products.

Organ	Study Model	Pomegranate Formulation	Target/ Mechanism(s)	Reference
Prostate
	Monolayer cell cultures	Cold-pressed or CO2-extracted seed oil, fermented juice polyphenols, and pericarp polyphenols	Inhibits proliferation and invasion Inhibits secretory phospholipase	[26, 27]
		Standardized extract (POMx, POM Wonderful) containing ellagitannins (37-40%) and ellagic acid (3.4%) but no anthocyanins; Juice (POM Wonderful) containing ellagitannins (1 mg/ml), ellagic acid (0.97 mg/ml) and anthocyanins; ellagitannins and ellagic acid	Suppresses androgen receptor expression Inhibits androgen-synthesizing enzymes	[29]
		Acetone extract of pomegranate fruit	Induces apoptosis Increases Bax/ Bcl-2 ratio Increases p21 & p27 Down-regulates cyclins and cdks	[13]
		POMX prepared from skin and arils minus seeds and standardized to ellagitannins (37%)	Induces apoptosis & inhibits cell growth Increases JNK phosphorylation Suppresses AKT/mTOR signaling Decreases IGF-1 mRNA levels	[34]
		Fruit extract (POMX; POM Wonderful) standardized to ellagitannins [punicalagins] (37–40%), and ellagic acid (3.4%); Juice concentrate (POM Wonderful) containing punicalagins (1,561 mg/L), ellagic acid (121 mg/L), anthocyanins (387 mL/L), other hydrolysable tannins (417 mg/L)	Inhibits NF-κB activity	[30]
		Juice (POM Wonderful) with flavonoids (anthocyanins, catechins, and phenols) constituting 40% of total polyphenols	Antiproliferative, proapoptotic effects, increase in nitric oxide and reduction in oxidative state in exploratory bioassays	[37]
		Pomegranate juice; ellagitannins extracted from POMX, urolithins	Inhibits CYP enzyme activity	[40, 41]
		Pomegranate juice	Up-regulates anti-invasive mi-RNAs (−335,−205,−200, & −126) Down-regulates pro-invasive mi-RNA (−21 and −373) Reduces pro-inflammatory cytokines (IL-6,-12p40,-1β and Rantes)	[36]
	Athymic nude mice	Ellagitannin-rich fruit extract (POM Wonderful) standardized to ellagitannins [punicalagin] (37%) and ellagic acid (3.5%); acetone fruit extract	Inhibits tumor growth & multiplicity Decreases serum PSA levels	[32, 13]
		Fruit extract (POMX; POM Wonderful) standardized to ellagitannins [punicalagins] (37–40%), and ellagic acid (3.4%); juice concentrate (POM Wonderful) containing punicalagins (1,561 mg/L), ellagic acid (121 mg/L), anthocyanins (387 mL/L), and other hydrolysable tannins (417 mg/L)	Delays emergence of androgen independence Decreases NF-κB activity	[30]
	TRAMP mice	Acetone extract of pomegranate fruit	Reduces tumor formation Decreases metastasis Increases survival Inhibits IGF-I/AKT/mTOR signaling	[33]
	Human trials	Juice (POM Wonderful) with flavonoids (anthocyanins, catechins, and phenols) constituting 40% of total polyphenols; pomegranate extract (POMX)	Increases PSA doubling time Disease stabilization	[37, 38]
	Monolayer cell cultures	Acetone extract of pomegranate fruit	Inhibits UVA-mediated phosporylation of STAT3, AKT, ERK1/2, mTOR & p70S6K Decreases PCNA & Ki-67 expression Up-regulates Bax & Bad Down-regulates Bcl-XL	[42]
		Acetone extract of pomegranate fruit	Inhibits UVB-mediated MAPK phosphorylation; NF-κB/p65 activation	[43]
		Pomegranate extract POMX (POM Wonderful) with 135000 ppm polyphenols with major constituents gallic acid equivalent and ellagitannins	Protects keratinocytes from UV-B-induced oxidative stress and photo-aging Inhibits UV-B-mediated decrease in cell viability and intracellular GSH content; increase in lipid peroxidation & up-regulation of MMPs −1,−2,−7 and −9 Inhibits MAPKs; c-Jun	[44]
Skin
		Pomegranate fruit extract standardized to ellagitannins [gallic acid & punicalagins] (37.5%) and ellagic acid (2.7%)	Protects fibroblasts from cell death post UV Decreases NF-κB activity	[45]
		Aqueous extracts of pomegranate juice, peel and seed (POM Wonderful)	Facilitates skin repair Stimulates type I procollagen synthesis Inhibits MMP-1 production	[54]
	3-D EpiDerm	Pomegranate extract POMX (POM Wonderful) with 135000 ppm polyphenols with major constituents gallic acid equivalent and ellagitannins; POMx juice (POM Wonderful) contains anthocyanins, ellagitannins and hydrolyzable tannins; POM seed oil (POM Wonderful)	Inhibits UVB-induced CPDs & 8-OHdG formation; PCNA expression Increases p21 Inhibits UVB-induced MMPs-1,-2,-3,-7,-8,-9,-11,-12; c-Jun and c-Fos; tropoelastin expression	[46]
	SKH-1 mice	Acetone extract of pomegranate fruit	Inhibits UVB-induced skin edema, hyperplasia, leukocytic infiltration; lipid peroxidation; CPDs & 8-OHdG formation; PCNA, ODC & COX-2 expressions; MAPK phosporylation; NF-κB/p65 activation, phosporylation of c-Jun; MMPs -2,-3,-9 expression Increases p53 and p21 expressions	[47, 48]
	CD-1 mice SKH-1 mice	Pomegranate seed oil; Acetone extract of pomegranate fruit	Decreases tumor incidence & multiplicity Inhibits TPA-mediated increase in skin edema and hyperplasia; ODC activity, COX-2 expression; phosphorylation of MAPKs and NF-κB activity	[52, 31]
	Balb/c mice	Pomegranate fruit extract	Delays onset and incidence of tumor Suppresses MAPKs and NF-κB activity	[53]
	Wistar rats	Methanolic extract of dried pomegranate peel	Accelerates wound healing Increases hydroxyproline content	[55]
	Guinea pigs	Methanolic pomegranate peel extract based- ointment	Accelerates wound healing	[56]
Colon
	Monolayer cell cultures	Punicalagin, ellagic acid, standardized pomegranate tannin extract (punicalagin 85%, ellagic acid 1.3% and ellagitannins 12%) and pomegranate juice; POMX (POM Wonderful)	Induces apoptosis, cell cycle arrest Inhibits growth	[35, 64]
		Pomegranate fruit extract standardized to ellagitannins [punicalagin α and β] (25%) and ellagic acid (3.5%)	Inhibits Wnt signaling	[67]
		Ellagic acid; urolithins	Inhibits migration and adhesion Inhibits activation of NF-κB & MAPKs Down-regulates COX-2, PGE2, PAI-1 and IL-8	[58]
		Pomegranate juice (POM Wonderful) (punicalagin 1.74 g/L), pomegranate tannin extract and punicalagins	Suppresses TNFα-induced COX-2 expression, AKT & NF-κB activity	[65]
	F344/Ducrj rats	Pomegranate seed oil	Inhibits the incidence and multiplicity of azoxymethane-induced colonic adenocarcinomas Increases PPAR expression	[68]
	TNBS mouse model	Ellagic acid	Attenuates morphologic alterations associated with cellular injury Maintains glandular architecture Decreases inflammatory cells infiltrate Represses COX-2 and iNOS Inhibits MAPKs and NF-κB signaling	[59]
		Punicic acid	Down-regulates neutrophil hyper-activation Decreases ROS-induced tissue damage	[60]
	DSS mouse model	Pomegranate extract standardized to punicalagins (35%), punicalin (13%), ellagic acid glucoside (4.5%) and ellagic acid (8.9%); urolithin A	Decreases inflammation markers (iNOS, COX-2, PTGES and PGE2)	[61]
		Pomegranate flower extract; ellagic acid rich fraction from pomegranate extract	Attenuates oxidative stress and subsequent colonic inflammation	[63]
Lung
	Monolayer cell cultures	Aqueous extract of pomegranate peel	Anti-oxidant Inhibits myeloperoxidase activity	[70]
		Acetone extract of pomegranate fruit	Decreases cell viability Induces p21 and p27 protein expressions Down-regulates cyclins/cdks Decreases PCNA & Ki67 expression Inhibits MAPKs; PI3K/AKT pathway, NF-κB activity	[71]
	Athymic nude mice	Acetone extract of pomegranate fruit	Inhibits tumor growth	[71]
	A/J mice	Acetone extract of pomegranate fruit	Decreases tumor incidence & multiplicity Inhibits phosphorylation of MAPKs; PI3K/ AKT/mTOR pathway; NF- κB/p65 activation Inhibits c-Met phosphorylation Decreases Ki-67 & PCNA; iNOS, CD31 & VEGF	[14]
Breast
	Monolayer cell cultures	Urolithins	Inhibits aromatase activity Inhibits proliferation	[72]
		Punicic acid; Cold-pressed or CO2-extracted seed oil, fermented juice polyphenols, and aqueous pericarp extract	Inhibits proliferation Induces apoptosis dependent on lipid peroxidation and the PKC pathway	[74, 73]
		Pomegranate fruit extract	Suppresses NF-κB Decreases RhoC and RhoA	[78]
		Pomegranate seed oil; fermented juice polyphenols	Down-regulates VEGF and MIF	[79]
	Organ culture	Fermented juice polyphenols	Reduces DMBA-induced lesions	[73, 76]
Blood
	Monolayer cell cultures	PSP001polysaccharide from pomegranate rind	Inhibits leukemia cell growth	[80]
		Pomegranate juice; pomegranate ellagitannin nanoparticles	Induces apoptosis; cell cycle arrest	[81, 82]
		Pomegranate ellagitannin nanoparticles	Promotes differentiation in promyelocytic leukemia cells	[82]