Efeitos do resveratrol e derivados sintéticos na angiogênese tumoral: revisão sistemática da literatura e ensaio angiogênico em modelo tumoral singênico de melanoma cutâneo

Abstract

Resveratrol (Resv; 3,4,5-trans-trihydroxystilbene) is a polyphenolic phytoalexin found naturally in plants. Resv has demonstrated anti-neoplastic effects in cancer cells and peritumoral stroma, by modulating diverse molecular signaling pathways. Among these pathways, the anti-angiogenic effects promoted by Resv and some of its derivatives in cancer cells and peritumoral stromal endothelial cells have been highlighted. Tumor angiogenesis is the formation of new blood vessels from the preexisting peritumoral vascular network, and is related to the favoring of tumor growth and the occurrence of metastases, which, in turn, lead to a worse survival of individuals with cancer. Thus, the objective of this study was to perform a systematic review of the literature on the anti-angiogenic effects promoted by Resv and some of its derivatives on cancer cells and murine tumor models, as well as to measure caliber and vascular resistance. For this systematic review, we investigated the anti- angiogenic effects promoted by Resveratrol (Resv) and its derivatives (ResvSD) in in vitro cancer cell and murine tumor model in vivo assays. In our experimental study, a syngeneic MC tumor model was established with subcutaneous inoculation of B16F10 murine MC cells. Resv was administered by gavage at concentrations of 200 and 400 mg / kg body weight over the 12 day period. Animals with CM and treated with PBS alone were used as controls. The effect of resveratrol on angiogenesis was evaluated by measurement of vessel area and intratumoral vascular resistance index, both measured with the aid of high frequency Doppler ultrasound. In vitro studies have shown that the administration of Resv and analogues in cancer cells has promoted a decrease in the expression of pro-angiogenic factors, increased intracellular degradation of these factors and inhibition of protein stabilization of pro- angiogenic ligands and receptors. In vivo studies, Resv and analogs promoted inhibitory effects for the development of the peritumoral neovascular network and, consequently, for tumor progression. Resveratrol analogues exhibited better absorption characteristics by the body and, functionally, appear to exhibit better anti-angiogenic activities compared to the natural Resv isoforms. In our experimental study, animals treated with resveratrol (Resv200 mg / kg and Resv400 mg / kg) showed a decrease in the area of the intratumor vessels (p <0.05). The findings showed that Resv and some of its derivatives promoted anti-angiogenic effects on various cancer cells and experimental murine tumors. Specifically in the murine CM model, Resv showed vascular caliber effect, suggesting an anti-angiogenic effect. Further studies are needed to better understand the effects of resveratrol, especially on cutaneous melanoma angiogenesis.