Angiogenesis Inhibition by Antioxidants

Abstract

Reducing cancer morbidity and mortality requires several synergic approaches target on tumoural cells and their environment. Angiogenesis is the development of new blood vessels from the pre-existing vasculature. This process is normally observed only transiently during embryogenesis, and in adulthood, during wound healing and uterus function. However, pathologic angiogenesis is involved in some diseases, including cancer. Tumoural angiogenesis favors cancer invasion and metastasis emission. Normally, endothelial cells are maintained in a latent state, but under determined stimulus they suffer activation, a process called “angiogenic switch”. Among stimulatory angiogenic factors are vascular endothelial growth factor (VEGF), angiopoetin-1 and 2, interleukin-8 (IL-8), fibroblast growth factor basic (bFGF), platelet-derived growth factor (PDGF) and angiotensin II. Furthermore, matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, play role in angiogenesis. Reactive oxygen species (ROS), as hydrogen peroxide (H2O2), participates in angiogenesis signaling through VEGF receptors, mainly VEGFR2 (Flk-1/KDR), and angiopoietin-I/Tie-2 receptors. The major source of ROS in endothelial cells is the enzyme NAD(P)H oxidase, but the role of nitric oxide (NO•), from endothelial nitric oxide synthase (eNOS), should not be neglected. Moreover, oxidized phospholipids and products from arachidonic acid metabolism can participate in angiogenesis induction. Then, it would be likely that antioxidants could inhibit angiogenesis. Really, a number of studies demonstrated that several antioxidants found in natural products (catechins from teas, resveratrol, polyphenols, flavonoids, isoflavones, lycopene, pigment epithelium-derived factor, glutathione); nutritional components (vitamins C, D, E, β-carotene and selenium); and semi-synthetic and synthetic compounds (N-acetylcysteine, L-NAME, L-NIO, sodium piruvate, pyrrolidine dithiocarbamate, and organoselenium compounds) were able to inhibit angiogenesis. These compounds were tested in several in vitro assays and in vivo animal models and inhibited angiogenesis via redox-sensitive and insensitive mechanisms. Thus, the consumption of antioxidants from natural sources can be recommended in face to benefic effects related to angiogenesis inhibition, while high fat diet can be undesired. In addition, some semi-synthetic and synthetic compounds has potential as future drugs for inhibiting tumoural angiogenesis, but it needs more detailed studies in terms of efficacy and security.