Abstract
Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10−9 M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing unilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine, to reach plasma concentrations equivalent to 10–9 M. Laser Doppler analysis showed that recovery of blood flow was 1.5 fold higher in ethoxidine-treated mice in comparison with control mice. Furthermore, CD31 staining and angiographic studies confirmed an increase of vascular density in ethoxidine-treated mice. This ethoxidine-induced recovery was associated with an increase of NO production through an enhancement of eNOS phosphorylation on its activator site in skeletal muscle from ischemic hindlimb. Moreover, real-time RT-PCR and western blots have highlighted that ethoxidine has pro-angiogenic properties by inducing a significant enhancement in vegf transcripts and VEGF expression, respectively. These findings suggest that ethoxidine could contribute to favor neovascularization after an ischemic injury by promoting the NO pathway and VEGF expression.
Highlights
DNA topoisomerases I are essential enzymes that control DNA supercoiling and torsional strain during processes such as replication, transcription and DNA repair [1] whose inhibition is involved in the treatment of many cancers
During the significant change has been reported between control mice (22.83 ± 0.20 g) and ethoxidine-treated protocol, no weight change has been shown in each group
Before the experimental protocol, no difference has been shown significant change has been reported between control mice (22.83 ± 0.20 g) and ethoxidine-treated mice in each group of mice
Summary
DNA topoisomerases I are essential enzymes that control DNA supercoiling and torsional strain during processes such as replication, transcription and DNA repair [1] whose inhibition is involved in the treatment of many cancers. Molecules 2017, 22, 627 molecule is not currently used in cancer treatment, many studies have confirmed its anti-proliferative properties on various in vitro models of tumor cells (HT-29, A-549, MCF-7, Caov3) at concentrations between 10−9 to 10−5 M [3,4]. Topoisomerase I is highly expressed in endothelial cells [5,6] and various studies haveproperties suggestedonbeneficial properties of topoisomerase. Various in vitro models of tumor cells (HT-29, A-549, MCF-7, Caov3) at concentrations. Topoisomerase is highly expressed in endothelial cells splicing [5,6] andof various studiesnitric that inhibition of topoisomerase. In another study in a model of human venous endothelial (HUVEC), has been shown performed on HUVEC treated with umbilical topoisomerase
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