Table 1.

Pomegranate's molecular targets in malignancies.

Cancers	Cellular Targets	In vitro/in vivo/clinical	Extract/Phytochemical	Mechanism	References
Skin	MAPK activation (UVB-mediated), STAT3, and NFκB signaling pathway inhibition	In vitro, in vivo	Galactomannan (PSP001) isolated from the fruit rind, Fruit extract	Down-regulation of VEGF & MMPs	[[17], [18], [19], [20], [21]]
Breast	Anti-estrogenic and anti-aromatase properties are shown by this compound	In vitro	Extract (peel)	Decreased expression of β-catenin & EMT markers	[22,23]
	Estrogen-responsive genes inhibition	In vitro	Extract (peel oil)	Down-regulation of metastasis-related genes	[24,25]
	Pro-inflammatory cytokines, as well as chemokines and vascular endothelial growth factors, are reduced	In vitro	Extract (seed)	Reduced secretion of inflammatory cytokines	[[26], [27], [28], [29], [30]]
Prostate	Reduce the serum PSA ranges	In vitro, in vivo	Fruit extract	NF-κB blockade	[31,32]
	NF-κB activation and STAT3 phosphorylation is regulated and reduced	In vitro, in vivo	Fruit extract	Decreased expression of HIF-1α &VEGF	[[32], [33], [34], [35]]
	IGF-1/Akt/mTOR signaling inhibition	in vivo	Luteolin Ellagic acid + Punicic acid	Decreased expression of oncogenic miRNAs & inhibition of the CXCR4/SDF1α chemotaxis axis, changes in the expression of cell adhesion & cytoskeletal proteins	[[36], [37], [38]]
Lung	Reduce p27 and p21 protein transformation PCNA, Ki-67, and cyclins/CDKs transformation downregulation PI3K/Akt, MAPK, and NF-κB signaling pathways inhibition	In vitro	Extract (leaves)	Reduction of MMP-2 & MMP-9 expression	[39,40]
	It prevents the production of DNA adducts.	In vitro	Galactomannan (PSP001) isolated from the fruit rind	Down-regulation of VEGF & MMPs	[21,41,42]
	Proliferative, inflammation, and angiogenesis-related indicators are all reduced. c-Met and MAPK phosphorylation prevention	In vivo	Fruit extract	Information not available	[43,44]
Colon	Cyclooxygenase-2 transformation, the binding activity of NFκB DNA, and Akt phosphorylation prevention	In vitro, In vivo	Juice	Targeting miR-126-regulated pathways which contribute in anti-inflammatory & anti-angiogenic mechanisms	[42,45]
	Hepatic GST action is reduced	In vitro, in vivo	Juice, Tannin, Punicalagin	Abolish TNFα-induced AKT activation resulting modulation of inflammatory cell signaling	[46,47]
	miR-18a-3p, miR-181c-3p, miR-1249, miR-765, miR-646, miR-496 modulation	Information not available	Information not available	Information not available	[48]

MAPK: Mitogen-activated protein kinase; GST: Glutathione-S-transferase; TNFα: tumor necrosis factor alpha; VEGF: Vascular endothelial growth factor; MMPs: Matrix metalloproteinases; HIF-1α: Hypoxia-inducible factor 1-alpha; PSA: Prostate-specific antigen; IGF-1: insulin-like growth factor 1; PCNA: Proliferating cell nuclear antigen; CDKs: Cyclin-dependent kinases; DNA: Deoxyribonucleic acid.