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.
Highlights
Cancer is a major cause of death worldwide and angiogenesis is critical in cancer progression
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)
Further anti-angiogenic effects include; inhibition of NFκB, inhibition of TGF-β signaling being an important feature in upregulating angiogenesis, inhibition of protein tyrosine kinase (PTK) and PTK-mediated signaling pathways, modulation of the Akt signaling pathway, down-regulation of several genes relevant for angiogenesis pathways (Type IV collagenases, protease M, VEGF, uPAR, neuropilin, bone-derived growth factor-1 (BPGF-1), lysophosphatidic acid receptor, aminopeptidase, thrombospondin-1, proteinase-activated receptor), suppression of activator protein 1 (AP-1)/CREB-binding to the COX-2 promoter leading to lower COX-2 levels (COX-2 increases cell proliferation and VEGF production), dose-dependent inhibition of expression/excretion of VEGF, PDGF, tissue factor, urokinase plasminogen activator, matrix metalloproteinases (MMPs)-2 and -9 as well as up-regulation of angiogenesis inhibitors: plasminogen activator inhibitor-1, endostatin, angiostatin, thrombospondin-2 [2527]
Summary
Cancer is a major cause of death worldwide and angiogenesis is critical in cancer progression. Expression of vascular endothelial cell antigens, e.g.CD31 are downregulated [22] protein kinase C (PKC) [11,22] together with angiogenic factors MMP-2 and -9, VEGF, CD31 [23] activities are reduced and EGFR signalling is suppressed [24].
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