Piceatannol, a Natural Analog of Resveratrol, Exerts Anti-angiogenic Efficiencies by Blockage of Vascular Endothelial Growth Factor Binding to Its Receptor

Abstract

Piceatannol is also named as trans-3,4,3′,5′-tetrahydroxy-stilbene, which is a natural analog of resveratrol and a polyphenol existing in red wine, grape and sugar cane. Piceatannol has been proved to possess activities of immunomodulatory, anti-inflammatory, antiproliferative and anticancer. However, the effect of piceatannol on VEGF-mediated angiogenesis is not known. Here, the inhibitory effects of piceatannol on VEGF-induced angiogenesis were tested both in vitro and in vivo models of angiogenesis. In human umbilical vein endothelial cells (HUVECs), piceatannol markedly reduced the VEGF-induced cell proliferation, migration, invasion, as well as tube formation without affecting cell viability. Furthermore, piceatannol significantly inhibited the formation of subintestinal vessel in zebrafish embryos in vivo. In addition, we identified the underlying mechanism of piceatannol in triggering the anti-angiogenic functions. Piceatannol was proposed to bind with VEGF, thus attenuating VEGF in activating VEGF receptor and blocking VEGF-mediated downstream signaling, including expressions of phosphorylated eNOS, Erk and Akt. Furthermore, piceatannol visibly suppressed ROS formation, as triggered by VEGF. Moreover, we further determined the outcome of piceatannol binding to VEGF in cancer cells: piceatannol significantly suppressed VEGF-induced colon cancer proliferation and migration. Thus, these lines of evidence supported the conclusion that piceatannol could down regulate the VEGF-mediated angiogenic functions with no cytotoxicity via decreasing the amount of VEGF binding to its receptors, thus affecting the related downstream signaling. Piceatannol may be developed into therapeutic agents or health products to reduce the high incidence of angiogenesis-related diseases.

Rhus coriaria L. (Sumac) Demonstrates Oncostatic Activity in the Therapeutic and Preventive Model of Breast Carcinoma

“…Analyses focused on the therapeutic possibilities of new drugs affecting cell signaling of neovascularization (e.g., VEGF, FGF, EGF, HGF, neuropilins, integrins, tyrosine kinases receptors) represent an important area in oncology research [ 55 ]. Natural plant foods rich in bioactive molecules that significantly affect the activity of VEGF/VEGFR complex and subsequent cell neoangiogenesis signalizations have been shown to suppress carcinogenesis [ 56 , 57 , 58 ]. However, we did not observe any significant alterations in the expression levels of VEGF and VEGFR-2 induced by sumac in our in vivo studies.…”

CCL4‐mediated targeting of spleen tyrosine kinase (Syk) inhibitor using nanoparticles alleviates inflammatory bowel disease

“…Piceatannol, a natural hydroxylated stilbene analog and metabolite of resveratrol, has been demonstrated to exhibit anti‐inflammatory, antioxidative, antiaging, antiobesity, and anticancer effects similar to resveratrol, but has better bioavailability and stability than resveratrol 40 . Piceatannol is mainly generated during the process of fruit ripening and microbial β‐glucosidases‐triggered fermentation 41 . There has been accumulating evidence to reveal a crucial role of piceatannol in participating multiple physiological and pathophysiological by modulation of a range of signaling pathways 42 .…”

Toxicological Evaluation of Piceatannol, Pterostilbene, and ε-Viniferin for Their Potential Use in the Food Industry: A Review

“…In general, although high concentrations were required to obtain an IC 50 value up to 400 µM, a decrease in cell proliferation was recorded in a time- and dose-dependent manner. This effect was even observed at lower concentrations such as 30 µM for piceatannol [ 28 ], 40 µM for pterostilbene [ 29 ], and 20 µM for ε-viniferin [ 30 ]. These findings are relevant since non-cancerous cells are usually more sensitive, and the results could be easily extrapolated to human systems [ 31 ].…”

“…In general, most of the authors stated that piceatannol has cytotoxic effects in a dose- and time-dependent manner in cancer cells lines at concentrations between 20–100 µM after 24 and 48 h of exposure. Moreover, cytotoxic effects have also been reported in non-cancerous cells treated with piceatannol [ 28 , 32 , 46 ]. Similar to that observed in cancer cells, concentrations from 30 µM affected the cell viability of normal HUVEC cells after 48 h [ 28 ].…”

“…Moreover, cytotoxic effects have also been reported in non-cancerous cells treated with piceatannol [ 28 , 32 , 46 ]. Similar to that observed in cancer cells, concentrations from 30 µM affected the cell viability of normal HUVEC cells after 48 h [ 28 ]. In contrast, higher concentrations were necessary to observe toxic effects in the two non-tumor oral human cells, HGF (gingival fibroblast) and HPC (pulp cells), reaching CC 50 values at 364 µM and 414 µM after 24 h of exposure [ 32 ].…”