Inhibition of aldose reductase prevents angiogenesis in vitro and in vivo

Abstract

We have recently shown that aldose reductase (AR, EC 1.1.1.21) a nicotinamide adenine dinucleotide phosphate-dependent aldo-keto reductase, known to be involved in oxidative stress-signaling, prevents human colon cancer cell growth in culture as well as in nude mice xenografts. Inhibition of AR also prevents azoxymethane-induced aberrant crypt foci formation in mice. In order to understand the chemopreventive mechanism(s) of AR inhibition in colon cancer, we have investigated the role of AR in the mediation of angiogenic signals in vitro and in vivo models. Our results show that inhibition of AR significantly prevented the VEGF- and FGF -induced proliferation and expression of proliferative marker Ki67 in the human umbilical vein endothelial cells (HUVEC). Further, AR inhibition or ablation with siRNA prevented the VEGF-and FGF –induced invasion and migration in HUVEC. AR inhibition also prevented the VEGF-and FGF- induced secretion/expression of IL-6, MMP2, MMP9, ICAM, and VCAM. The anti-angiogenic feature of AR inhibition in HUVEC was associated with inactivation of PI3K/AKT and NF-κB (p65) and suppression of VEGF receptor 2 protein levels. Most importantly, matrigel plug model of angiogenesis in rats showed that inhibition of AR prevented infiltration of blood cells, invasion, migration and formation of capillary like structures, and expression of blood vessels markers CD31 and vWF. Thus, our results demonstrate that AR inhibitors could be novel agents to prevent angiogenesis.

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

“…Blockade or genetic deficiency of aldose reductase reverses the excessive angiogenesis associated with vascular retinopathy (Fu et al, 2012;Obrosova and Kador, 2011). Interestingly, aldose reductase inhibitors also decrease VEGFstimulated angiogenesis, suggesting a role for polyol pathway flux in normal angiogenic functions (Tammali et al, 2011).…”

Prevention of VEGF-induced growth and tube formation in human retinal endothelial cells by aldose reductase inhibition

“…Various investigators have presented evidence that antioxidants and natural polyphenolic compounds with antioxidant properties could prevent neovascularization in experimental animals (Dorrell et al, 2009; Chen, Li, Xing, & Cao, 2008; Tan et al, 2008; Kim et al, 2007; Kim et al, 2009; Keshavarz et al, 2009). Recently our lab has demonstrated that inhibition of aldose reductase (AR), a glucose and lipid aldehyde metabolizing enzyme, has anti-inflammatory and anti-oxidative properties and could prevent cancer angiogenesis in-vitro and in-vivo (Tammali, Reddy, Srivastava, & Ramana, 2011; Yadav et al, 2009a; Yadav et al, 2009b; Yadav, Srivastava, & Ramana, 2010). However, role of AR inhibition in diabetes-induced retinal neovascularization is not known.…”

Antidepressant fluoxetine and its potential against colon tumors

“…This idea was abetted by the discovery of a small subset of stromal spindle cells expressing CD133 and CD34 in angiofibromas, which suggests tumors promoting subepithelial resident cells to transit towards endothelial cell phenotypes [72] . Endothelial progenitor cells were then shown to lose, in a process related to high proliferation [73] , the expression of CD133 during their differentiation into vascular cells, while the expression of CD34 was increased [74][75][76] . Considering that CD31-positive cells have been designated as mature endothelial lineage promoting microvessels [77] , vascular smooth muscle cells were found to increase the expression of CD31 during their differentiation process, whilst a simultaneous decrease of CD133 and CD34 progenitor markers was previously observed [78,79] .…”