Antiangiogenic Potential of Pomegranate Extracts

Abstract

Pomegranate (Punica granatum L.) has long been recognised for its rich antioxidant profile and potential health benefits. Recent research has expanded its therapeutic potential to include antiangiogenic properties, which are crucial for inhibiting the growth of tumours and other pathological conditions involving aberrant blood vessel formation. This review consolidates current findings on the antiangiogenic effects of pomegranate extracts. We explore the impact of pomegranate polyphenols, including ellagic acid, punicalagin, anthocyanins, punicic acid and bioactive polysaccharides on key angiogenesis-related pathways and endothelial cell function. Emphasis is placed on the effects of these extracts as phytocomplexes rather than isolated compounds. Additionally, we discuss the use of pomegranate by-products, such as peels and seeds, in the preparation of extracts within a green chemistry and circular economy framework, highlighting their value in enhancing extract efficacy and sustainability. By primarily reviewing in vitro and in vivo preclinical studies, we assess how these extracts modulate angiogenesis across various disease models and explore their potential as adjunctive therapies for cancer and other angiogenesis-driven disorders. This review also identifies existing knowledge gaps and proposes future research directions to fully elucidate the clinical utility of pomegranate extracts in therapeutic applications.

Keywords: Punica granatum L.; VEGF; angiogenesis; cancer; ellagic acid; ellagitannins; extraction methods; punicalagin; punicic acid; supplement.

Figure 1

Schematic illustration of key steps in angiogenesis and multicellular interactions during new vessel development. (a) In rapidly growing tumours, severe hypoxia leads to the stabilisation of HIF proteins (HIF-1α and HIF-2α), triggering the synthesis and release of proangiogenic factors like VEGFs. These factors are initially sequestered by the basement membrane (BM) and cannot reach their target receptors on endothelial cell (EC) membranes. Cancer cells recruit macrophages and mast cells from the nearby stroma, which release matrix metalloproteinases (MMPs) that start degrading BM. (b) Degradation of BM releases sequestered proangiogenic factors, allowing them to bind to their receptors and activate the MAPK/ERK signalling pathway. Phosphorylated ERK translocates to the nucleus to regulate transcription, promoting EC proliferation and migration. Additionally, increased endothelial permeability releases more MMPs and urokinase plasminogen activators (UPAs), participating in activating pericellular proteolysis and releasing additional proangiogenic factors (e.g., bFGF, TGF-β, PDGF, angiogenin and angioprotein). Activin receptor-like kinases (ALK1/5) work together to regulate angiogenesis, with ALK1 promoting the formation of new vessels and ALK5 contributing to their maturation and stabilisation. VEGF-DLL4/Notch signalling regulates the formation of tip and stalk cells: VEGF induces DLL4 expression in tip cells, activating Notch1 signalling and suppressing tip cell formation in adjacent stalk cells. Tip cells adhere to the extracellular matrix via integrins, start to form lamellipodia and filopodia and migrate toward guidance signals like semaphorins and ephrins. (c) Stalk cells proliferate behind the tip cell, elongating the sprout along the VEGF gradient towards the tumour microenvironment and initiating lumen formation. Growth factors also decrease the levels of antiangiogenic molecules (e.g., thrombospondins, angiostatin, endostatin), while eNOS and NO synthesis in endothelial cells under shear stress enhance blood flow, vascular permeability, and endothelial cell proliferation and migration. NO also interacts with VEGF, amplifying its angiogenic effects. (d) Proangiogenic signals recruit endothelial progenitor cells from the bone marrow, accelerating vascularisation. As sprouting continues, stalk cells deposit BM and recruit pericytes, stabilising the forming vessel. Pericyte precursors are attracted by endothelial cell-expressed PDGF and differentiate into mature pericytes in response to TGF-β, reducing endothelial cell migration, proliferation, and vascular leakage, leading to vessel stabilisation and the formation of mature vasculature. HIFs, Hypoxia-Inducible Factors; VEGFs, Vascular Endothelial Growth Factor; ERK, Extracellular signal-Regulated Kinase; bFGF, basic Fibroblast Growth Factor; TGF-β, Transforming Growth Factor beta; PDGF, Platelet-Derived Growth Factor; DLL4, Delta-Like ligand 4; eNOS, endothelial Nitric Oxide Synthase; NO, Nitric Oxide.

Figure 2

Potential inhibitory mechanisms of pomegranate juice and extracts on cancer initiation and progression. Processes that are upregulated or activated are shown in green, while those that are downregulated or inhibited are shown in red. Bad, Bcl-2-associated death promoter; Bak, Bcl-2 homologous antagonist/killer; Bax, Bcl-2-associated X protein; Bcl-2; B-cell lymphoma 2 protein; Bcl-XL, B-cell lymphoma-Extra Large protein; CCL5, C-C motif chemokine ligand 5; CDK, Cyclin-dependent kinase; CXCR4, C-X-C chemokine receptor type 4; E-caderin, Epithelial caderin; HIF-1α, Hypoxia-Inducible Factor 1-alpha; HMMR, Hyaluronan-Mediated Motility Receptor; ICAM1, Intercellular Adhesion Molecule 1; ILs, interleukins; LDL, Low-Density Lipoprotein; KIP1/P27, Cyclin-dependent kinase inhibitor 1B; MGO, methylglyoxal; miRs, microRNAs; MMPs, Matrix metalloproteinases, PON, Paraoxonase; PECAM1, Platelet Endothelial Cell Adhesion Molecule; SOD, Superoxide Dismutase; VEGF, Vascular Endothelial Growth Factor; CDKNs, Cyclin-dependent kinase inhibitors.

Figure 3

Pomegranate fruit anatomy and key chemical constituents identified in the juice, peel and kernel fractions.

Figure 4

Valorisation of bioactive compounds from pomegranate peels and seed kernels using conventional and green extraction methods.

Figure 5

Metabolic pathway of punicalagin to urolithins in the human digestive system. Ingested punicalagin is initially hydrolysed in the stomach and small intestine to produce punicalin and ellagic acid. These compounds are then transformed by the gut microbiota through a series of reactions, leading to the formation of various urolithins, with urolithin-A and urolithin-B being two key final products.

Figure 6

Schematic illustration of the primary molecular targets of pomegranate juice and extracts in relation to angiogenesis and their interactions. ADMA, Asymmetric dimethylarginine; ALKs, Activin receptor-like kinases; AKT, Protein Kinase B; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma-2; Bcl-XL, B-cell lymphoma-extra-large; bFGF, basic Fibroblast Growth Factor; COX1, Cyclooxygenase 1; COX2; Cyclooxygenase 2; eNOS, endothelial Nitric Oxide Synthase; ERK, Extracellular Signal-Regulated Kinase; HIF-1α, Hypoxia Inducible Factor 1-alpha; ILs, Interleukins; JNK, c-Jun N-terminal kinase; MAPK, Mitogen-Activated Protein Kinase; MIF, Macrophage Migration Inhibitory Factor; miR126, MicroRNA 126; MMPs, Matrix metalloproteinases; mPGES-1, Microsomal Prostaglandin E Synthase-1; mTOR, mechanistic Target of Rapamycin; NF-kB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; Nrf2, Nuclear factor erythroid 2-related factor 2; NO, Nitric oxide; p53, protein 53; PI3K, Phosphoinositide 3-kinase; PGE2, Prostaglandin E 2; PPAR, Peroxisome Proliferator-Activated Receptor; Sp, Specificity proteins; TGF-β, Transforming Growth Factor beta; TIMPs, tissue inhibitors of metalloproteinases; TNFα, Tumor Necrosis Factor alpha; TRL4, Toll-like receptor-4; VEGF, Vascular Endothelial Growth Factor; VCAM1, Vascular Cell Adhesion Molecule 1; VEGFR-2, Vascular Endothelial Growth Factor Receptor-2.