Arom & at al ic in P l ic a n d t Kadioglu et al., Med Aromat Plants 2013, 2:5 e s M Medicinal & Aromatic Plants DOI: 10.4172/2167-0412.1000134 ISSN: 2167-0412 ResearchReview Article Article OpenOpen Access Access Targeting Angiogenesis By Phytochemicals Onat Kadioglu, Ean Jeong Seo and Thomas Efferth* Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany Abstract Cancer is a major cause of death worldwide and angiogenesis is critical in cancer progression. Development of new blood vessels and nutrition of tumor cells are heavily dependent on angiogenesis. Thus, angiogenesis inhibition might be a promising approach for anticancer therapy. Anti-angiogenic small molecule and phytochemicals as a cancer treatment approach are focused in these main points; modes of action, adverse effects, mechanisms of resistance and new developments. Treatment with anti-angiogenic compounds might be advantageous over conventional chemotherapy due to the fact that those compounds mainly act on endothelial cells, which are genetically more stable and homogenous compared to tumor cells and they show lower susceptibility to acquired drug resistance (ADR). Targeting the VEGF (vascular endothelial growth factor) signalling pathway with synthetic small molecules inhibiting Receptor Tyrosine Kinases (RTKs) in addition to antagonizing VEGF might be a promising approach. Moreover, beneficial effect of phytochemicals were proven on cancer-related pathways especially concerning anti-angiogenesis. Plant phenolics being an important category of prominent phytochemicals affect different pathways of angiogenesis. Green tea polyphenols (epigallocatechin gallate) and soy bean isoflavones (genistein) are two examples involving an anti-angiogenic effect. Keywords: Blood vessel formation; Angiogenesis; Cancer biology; Vascular Endothelial Growth Factor; VEGFR: Vascular Endothelial Inhibitors; Natural products; Phytochemicals; Nutraceuticals; Targeted Growth Factor Receptor; VSMC: Vascular Smooth Muscle Cell chemotherapy Introductıon Abbreviations: AADR: Acquired Drug Resistance; AITC: Allyl Angiogenesis is the growth of new blood vessels to ensure wound Isothiocyanate; ANG2: Angiopoietin 2; AP-1: Activator Protein 1; healing, reproduction and development of cells. It is strictly regulated APN: Aminopeptidase N; ARE: Antioxidant Response Element; BAEC: and various inhibitors and stimulators play role to maintain it in Bovine Aortic Endothelial Cells; BPGF-1: Bone-Derived Growth balance [1]. Tumor growth and metastasis depend on angiogenesis Factor-1; bFGF: Basic Fibroblast Growth Factor; BRCA1: Breast and stimulators are upregulated disrupting the angiogenesis balance Cancer 1, early onset; CAM: Chicken Chorioallantoic Membrane; [1,2]. Tumor blood vessels have a different structure with irregular CD31: Cluster of Differentiation 31; COX: Cyclooxygenase; CREB: branches and they are more heterogenous compared to normal blood cAMP Response Element Binding; DHA: Docosahexenoic Acid; vessels [3]. Various pathways such as VEGF, EGF, FGF and HGF ensure EGCG: Epiallocatechin Gallate; EGF: Epidermal Growth Factor; EGFR: the heterogeneity of tumor blood vessel structure and upregulated Epidermal Growth Factor Receptor; EPA: Eicosapentaenoic Acid; angiogenesis. ERK: Extracellular Signal-Regulated Kinase; FAK: Focal Adhesion Kinase; FGFR: Fibroblast Growth Factor Receptor; HER: Human Secondary plant metabolites are valuable sources of small Epidermal Growth Factor Receptor; HGF: Hepatocyte Growth Factor; molecules and various drugs were identified from plants. Combined HIF: Hypoxia-Inducible Factor; HUVEC: Human Umbilical Vein therapy approach targeting multiple components of angiogenesis with Endothelial Cells; IκB: Inhibitor of Kappa B; IL: Interleukin; iNOS: phytochemicals might be promising to achieve an effective anti-cancer Inducible Nitric Oxide Synthase; JAK2: Janus Kinase 2; JNK: Janus therapy [4]. Kinase; KDR: Kinase Insert Domain Receptor; LOX: Lysyl Oxidase; Therapy wıth phytochemıcals MAP-Kinase: Mitogen-Activated Protein Kinase; MCP-1: Monocyte Chemoattractant Protein1; MIF: Migration Inhibitory Factor; MMP: Natural products from botanical sources (phytochemicals) Matrix Metalloproteinase; MT1-MMP: Membrane-Type 1 Matrix continue to attract interest for various applications including cancer Metalloproteinase; MVD: Microvessel Density; NFκB: Nuclear Factor treatment with their effect on cancer-related biological pathways such Kappa B; NO: Nitric Oxide; NOS: Nitric Oxide Synthase; Nrf2: Nuclear as angiogenesis [5,6]. Throughout nature in flora, marine wildlife and Factor (erythroid-derived 2)-like 2; PAI-1: Plasminogen Activator microbial products might involve effective active principles which Inhibitor-1; pAKT: Phosphorylated Akt; PAR: Protease Activated contain a multitude of diverse molecular entities. For natural products Receptor; PDGF: Platelet-Derived Growth Factor; PEITC: Phenethyl Isothiocyanate; PGC-1a: Peroxisome Proliferator- Activated Receptor Coactivator-1a; PGE2: Prostaglandin E2; PGG: Penta-1,2,3,4,6-O- *Corresponding author: Thomas Efferth,Department of Pharmaceutical Galloyl-beta-d-Glucose; PI3: Phosphatidylinositide 3; PIGF: Platelet- Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Inhibitor Growth Factor; PKC: Protein Kinase C; PTK: Protein Tyrosine Staudinger Weg 5, 55128 Mainz, Germany, E-mail: [email protected] Kinase; RA: Rosmarinic Acid; ROS: Reactive Oxygen Species; RTK: Received May 24, 2013; Accepted August 26, 2013; Published August 29, 2013 Receptor Tyrosine Kinase; RWPC: Red Wine Polyphenolic Compound; SC: Shark Cartilage; SFN: Sulforaphane; Sirt1: Silent Information Citation: Kadioglu O, Seo EJ, Efferth T (2013) Targeting Angiogenesis By Phytochemicals. Med Aromat Plants 2: 134. doi: 10.4172/2167-0412.1000134 Regulator 1; Src: V-Src Sarcoma; STAT-3: Signal Transducer And Activator of Transcription 3; TGF: Transforming Growth Factor; Copyright: © 2013 Kadioglu O, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits TIMP1: Tissue Inhibitor of MMP-1; TNF: Tumor Necrosis Factor; unrestricted use, distribution, and reproduction in any medium, provided the uPAR: Urokinase-Type Plasminogen Activator Receptor; VEGF: original author and source are credited. Med Aromat Plants ISSN: 2167-0412 MAP, an open access journal Volume 2 • Issue 5 • 1000134 Citation: Kadioglu O, Seo EJ, Efferth T (2013) Targeting Angiogenesis By Phytochemicals. Med Aromat Plants 2: 134. doi: 10.4172/2167-0412.1000134 Page 2 of 8 from marine or microorganisms, three reviews are helpful in that in matrix turnover) and VEGF expressions are decreased whereas an regard [7-9]. increase in expression of TIMP1 (tissue inhibitor of MMP) have been observed upon green tea catechin treatments [14,20]. EGCG degrades Herbal ingredients have been used for more than 10000 years by the basement membrane via MMP inhibition and facilitates cell mankind to influence body functions and curing diseases [10]. Indian invasion in tumor cells. It also deregulate the expression of membrane- Ayurveda and Traditional Chinese Medicine are successful examples type 1 matrix metalloproteinase (MT1-MMP) which generates an for traditional therapeutic paradigms. active form of MMP-2 from proMMP-2 [10]. Phytochemicals are mostly classified as secondary plant metabolites. MAP kinase family members Erk-1 and Erk-2 influence VEGF Various anti-angiogenic effects of phytochemicals including flavonoids, expression. Thus, inhibition of them leads to lower expression of sulphated carbohydrates, triterpenoids, catechols, tannins and aromatic VEGF. EGCG might exert its effect by chelation of divalent cations substances have been reported [9,10]. Wholesome herbal extracts essential for the activity of some receptor kinases that are involved have been investigated in terms of anti-angiogenic activities [11] in Erk-1 and -2 activation. Moreoever, EGCG downregulates VEGF identifying molecules targeting different pathways of angiogenesis. expression via inhibition of activator protein 1 (AP-1) which binds to Nitric oxide synthase (NOS) and VEGF are of special importance for the promoter region of VEGF. Inhibition of VEGFR-1 and -2 tyrosine their interaction with well-known secondary plant metabolites from phosphorylation has also been reported [21]. EGCG is able to influence different botanical sources [12]. COX-2 expression since COX-2 promoter involve binding sites for Anti-angiogenic Phytochemicals NFκB and AP-1. Reduced COX-2 level leads to a reduced activation of MMP and angiogenic PGE2 expression [21]. In vitro studies serve as the main source of evidence for anti- angiogenic activities of phytochemicals. Single steps of angiogenesis EGCG has an inhibitory activity against platelet-induced growth such as apoptosis, proliferation, migration and protease production factor-BB (PIGFBB) induced intracellular signalling transduction in addition to complex cascades leading to neovascularization have pathway in vascular smooth muscle cells (VSMCs), several MAP- been investigated [11]. Culturing of microvascular endothelium cells kinase isoforms in VSMCs after PDGF-BB activation and the tyrosine can be difficult for such experiments [13]. VEGF and MMPs are phosphorylation of various kinases. EGCG exerts its interference prominent angiogenic effectors and the effect of phytochemicals on the with angiogenesis by targeting