Antitumor activities of synthetic and natural stilbenes through antiangiogenic action

Abstract

We reported that the antitumor and antimetastatic actions of resveratrol might be due to the inhibition of tumor-induced angiogenesis. To search for anticancer agents with stronger activity than resveratrol, we examined the antiangiogenic effects of 21 synthetic and/or natural stilbenes. Among these 21 stilbenes, 2,3-, 3,4-, and 4,4′-dihydroxystilbene inhibited the pro-matrix metalloproteinase (pro-MMP)-9 production in colon 26 cells at 5-25 mM, vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) migration at 10 and 25 mM, and VEGFinduced angiogenesis at 5-50 mM. Resvertarol inhibited the pro-MMP-9 production and VEGF-induced angiogenesis at 25 or 50 mM. Thus, the inhibition of pro-MMP-9 production in colon 26 cells and VEGF-induced angiogenesis by three dihydroxystilbenes were greater than those of resveratrol. The three dihydroxystilbenes (8 mg/kg, intraperitoneal injection) inhibited the tumor-induced neovascularization in colon 26-packed chamber-bearing mice and the tumor growth in colon 26-bearing mice. Furthermore, the three dihydroxystilbenes inhibited VEGF-induced VEGFR-2 phosphorylation. On the other hand, the three dihydroxystilbenes had no effect on VEGFR-1 and-2 expression, and VEGF-induced VEGFR-1 phosphorylation in HUVECs. These findings suggest that the inhibition of tumor-induced neovascularization by these three dihydroxystilbenes may be due (1) They stimulate cancer cell growth, migration, invasion, angiogenesis, and metastasis. (2) When MMPs are secreted from tumor cells, the invasion of tumor cells is facilitated by increased intravasation and extravasation through the degradation of the ECM and basement membranes.

Resveratrol Inhibits Monocytic Cell Chemotaxis to MCP-1 and Prevents Spontaneous Endothelial Cell Migration Through Rho Kinase-Dependent Mechanism

“…In spite of these promising in vivo studies, clinical attempts to inhibit neovascularization in the atherosclerotic arterial wall have been few thus far 25) . Resveratrol was implicated in the inhibition of tumor neovascularization by recent studies 12) , but the mechanisms of its anti-angiogenic effect are far from understood. Resveratrol was shown to activate SIRT1, the main endothelial sirtuin 26) , which is known to control vessel growth under ischemic conditions 27) ; however, as SIRT1-dependent deacetylation either inhibits anti-angiogenic effects of FoxO1 28) , or activates pathways inducing cell migration, such as cortactin 29) , SIRT1 is unlikely to be involved in the resveratrolinduced inhibition of migration.…”

“…Moreover, as shown in our previous study, treatment with resveratrol significantly prevented TNF--induced adhesion molecule expression and monocytic cell adhesion to ECs exposed to non-uniform shear stress 10) . Apart from the inhibition of inflammatory pathways, resveratrol was previously implicated in the inhibition of cancer cell migration 11) and tumor angiogenesis 12) indicating its ability to interfere with signal transduction pathways regulating cell motility. In the context of atherosclerosis, inhibition of vascular cell migration, in particular with regard to monocytes and endothelial cells, may contribute to reduced plaque progression.…”

Water-Soluble Components of Pinus pinaster Wood

“…A wide scope of applications has been suggested or pinosylvins including antifungal and antibacterial agents (Lindberg et al 2004;Lee et al 2005;Celimene et al 1999;Gref et al 2000;Venäläinen et al 2004) with activity towards Listeria monocytogenes (Gözü et al 2010), cytotoxicity against a murine hepatic carcinoma cell line (Välimaa et al 2007), antimetastatic activity (Park et al 2012), antiinflammatory action based on the reduction of blood reactive species (Jančinová et al 2012;Bauerova et al 2011), and angiogenic effects (Kimura and Sumiyoshi 2011).…”

Discovery of genes from feces correlated with colorectal cancer progression

“…CHIA-LONG LEE 1,2,5 , CHI-JUNG HUANG 3,4,5 , SHUNG-HAUR YANG 6,7 , CHUN-CHAO CHANG 1,8 , CHI-CHENG HUANG 1,5,9,10 , CHIH-CHENG CHIEN 3,5,11 and RUEY-NENG YANG poor specificity (15). In addition to the fecal occult blood test, the molecular detection of CRC using human feces has attracted attention in recent years (16)(17)(18).…”

“…Markers of CRC may provide the basis for decision-making regarding intensive chemotherapy or molecule-targeting drugs in CRC patients (5-7). Therefore, the identification of markers may assist in cancer prevention, detection and prognostic prediction (5,8,9), thereby increasing survival rates (10). Molecular markers (11) have their own clinical significance in CRC (12).…”