Implications of flavonoids as potential modulators of cancer neovascularity

Abstract

Purpose: The formation of new blood vessels from previous ones, angiogenesis, is critical in tissue repair, expansion or remodeling in physiological processes and in various pathologies including cancer. Despite that, the development of anti-angiogenic drugs has great potential as the treatment of cancer faces many problems such as development of the resistance to treatment or an improperly selected therapy approach. An evaluation of predictive markers in personalized medicine could significantly improve treatment outcomes in many patients.

Methods: This comprehensive review emphasizes the anticancer potential of flavonoids mediated by their anti-angiogenic efficacy evaluated in current preclinical and clinical cancer research.

Results and conclusion: Flavonoids are important groups of phytochemicals present in common diet. Flavonoids show significant anticancer effects. The anti-angiogenic effects of flavonoids are currently a widely discussed topic of preclinical cancer research. Flavonoids are able to regulate the process of tumor angiogenesis through modulation of signaling molecules such as VEGF, MMPs, ILs, HIF or others. However, the evaluation of the anti-angiogenic potential of flavonoids within the clinical studies is not frequently discussed and is still of significant scientific interest.

Keywords: Anti-cancer therapy; Cancer; Flavonoids; Neovascularity; Tumor angiogenesis; VEGF.

Fig. 1

Complex process of tumor angiogenesis. ANG angiopoietin, FGF fibroblast growth factor, MMP matrix metallopeptidase, PDGF platelet-derived growth factor, VEGF, vascular endothelial growth factor. An activation of endothelial cells (growth factors-receptors binding) → local degradation of basement membrane and extracellular matrix and migration of endothelial cells (proteases, MMPs, angiopoietins, chymases, heparanases) → organization of endothelial cells into tubes → new basement membranes → lumen formation → blood flow

Fig. 2

a Selected signaling involved in tumor angiogenesis (based on Qin et al. ; Lugano et al. ; Hillen and Griffioen ; Huang ; Khan and Kerbel ; Siamakpour-Reihani et al. ; Mancini and Toker ; Narayanan et al. ; Lee et al. ; Natori et al. ; Garcia and Kandel ; Yu et al. ; Tang et al. ; Zhao et al. ; Schlüter et al. ; Minder et al. 2015). AKT serine/threonine protein kinase B, Ang1 angiopoietin1, Ang2 angiopoietin2, ATOX copper chaperone antioxidant, bFGF basic fibroblast growth factor, Ca²⁺ calcium ion, CD31 cluster of differentiation 31, COX-2 cyclooxygenase-2, CTR1 copper transporter 1, EGF epidermal growth factor, EGFR epidermal growth factor receptor, EphA ephrin protein A, erbB receptor tyrosine kinases, ERK extracellular-signal-regulated kinase, ETS-1 protein C-Ets-1, G-CSF granulocyte colony-stimulating factor, HIF-1α hypoxia-inducible factor 1-alpha, HRE hypoxia-regulated element, HSPGs heparan sulfate proteoglycans, IL-8 interleukin-8, MAPK the mitogen-activated protein kinase, Mdm2 murine double minute 2, MEK member of MAPK, MMP matrix metallopeptidase, MMP-9 matrix metallopeptidase 9, NFAT nuclear factor of activated T-cells, NF-κB nuclear factor kappa B, PDGF platelet-derived growth factor, PDGFR platelet-derived growth factor receptor, PDK-1 pyruvate dehydrogenase kinase 1, PI3K phosphoinositide 3-kinase, PI3K phosphoinositide 3-kinase, PLCγ phospholipase Cγ, PTN pleiotrophin, RAF RAF kinases, RLIP76 oncoprotein Ral-interacting protein of 76 kDa, TGF-β transforming growth factor beta, Tie-2 tyrosine-protein kinase receptor 2, TNF-α tumor necrosis factor alpha, TSP1 thrombospondin 1, Ub ubiquitination, VEGF vascular endothelial growth factor, VEGFR-2 vascular endothelial growth factor receptor 2, vHL Hippel-Lindau protein. b Contribution of immune cells in the process of tumor angiogenesis (based on Keith and Simon ; Lugano et al., ; Ren et al. 2006). Ang1 angiopoietin-1, Ang2 angiopoietin-2, bFGF basic fibroblast growth factor, COX-2 cyclooxygenase-2, CXCL10 C-X-C Motif Chemokine Ligand 10, CXCL11 C-X-C Motif Chemokine Ligand 11, CXCL2 C-X-C Motif Chemokine Ligand 2, CXCL8 C-X-C Motif Chemokine Ligand 8, CXCL9 C-X-C Motif Chemokine Ligand 9, EGF epidermal growth factor, GM-CSF granulocyte–macrophage colony-stimulating factor, HB-EGF heparin-binding EGF-like growth factor, IL-1β interleukin 1 beta, iNOS inducible nitric oxide synthase, MCP-1 monocyte chemoattractant protein-1, MDSC myeloid-derived suppressor cell, MMP-9 matrix metallopeptidase 9, MMPs matrix metallopeptidases, TGFβ transforming growth factor beta, TNF tumor necrosis factor, TNFα tumor necrosis factor alpha, VEGF vascular endothelial growth factor, VEGFC vascular endothelial growth factor C, VEGFD vascular endothelial growth factor D. The contribution of immune cells in tumor angiogenesis: a Macrophages (tumor-associated macrophages) resemble M2 macrophages and release number of molecules that modulate angiogenesis such as VEGFs, EGF, FGF2, CXCL6, CXCL12, TNFα, MCP-1, semaphorin 4D, adrenomedullin, thymidine phosphorylase, MMPs. b Myeloid-derived suppressor cells (MDSC) regulate tumor angiogenesis primarily by secretion of MMPs; in the presence of VEGF, MDSCs secrete CCL2, CXCL8, CXCL2, IL-1β, Ang1, Ang2, GM-CSF. c STAT3 activation in neutrophils triggers angiogenic switch through signaling molecules such as VEGF, TNFα or MMPs. d Lymphocytes: T-cells promote angiogenesis by secretion of FGF-2, HB-EGF. Most prominent angiogenic factors derived from T cells including TNF, TGFβ, interferons have anti-angiogenic potential. Interferon-induced CXC family chemokines inhibit endothelial cell proliferation, promote Th1 type T cell, natural killer cells and dendritic cell infiltration (inhibition of tumor growth). CXCL9, CXCL10 and CXCL11 can directly inhibit angiogenesis (binding to CXCR3 on endothelial cells)

Fig. 3

Selected dietary flavonoids

Fig. 4

Selected flavonoids obtained from medicinal plants

Fig. 5

The role of flavonoids in anti-angiogenic strategy of cancer management. 2HF 2′-hydroxyflavanone, 3βmWi-A 2,3-dihydro-3β-methoxy analogue of Wi-A, 4HW 4′-hydroxywogonin, AMT amentoflavone, API apigenin, CAT catechin, EGCG epigallocatechin-3-gallate, EU eupatilin, FIS fisetin, GEN genistein, HES hesperidin, ISL isoliquiritigenin, KAEM kaempferol, LUT luteolin, MK Murraya koenigii leaf extract, MOR morusin, MYR myricetin, OSE Abelmoschuc esculentus (L.) Moench seed extract (okra), Pol E Polyphenon E, Pro-EGCG EGCG prodrug, QDG Quingdu granule, Qu quercetin, SF Scutellaria flavonoids, SIL silibinin, TQ thymoquinone, VIT vitexicarpine, XAN xantohumol