Document Detail


Inhibition of aldose reductase prevents angiogenesis in vitro and in vivo.
MedLine Citation:
PMID:  21409599     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 PI3 K/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.
Authors:
Ravinder Tammali; Aramati B M Reddy; Satish K Srivastava; Kota V Ramana
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-03-16
Journal Detail:
Title:  Angiogenesis     Volume:  14     ISSN:  1573-7209     ISO Abbreviation:  Angiogenesis     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-27     Completed Date:  2011-09-30     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  9814575     Medline TA:  Angiogenesis     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  209-21     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Reductase / antagonists & inhibitors*,  metabolism
Angiogenesis Inducing Agents / pharmacology
Animals
Capillaries / drug effects,  growth & development
Cell Adhesion Molecules / secretion
Cell Movement / drug effects
Cell Proliferation / drug effects
Collagen
Drug Combinations
Endothelial Cells / drug effects,  enzymology,  pathology,  secretion
Humans
Imidazolidines / pharmacology
Interleukin-6 / secretion
Laminin
Matrix Metalloproteinases / secretion
Mice
NF-kappa B / metabolism
Neovascularization, Pathologic / enzymology*
Neovascularization, Physiologic / drug effects
Phosphatidylinositol 3-Kinases / metabolism
Proteoglycans
Proto-Oncogene Proteins c-akt / metabolism
Rats
Spheroids, Cellular / drug effects,  pathology
Umbilical Veins / cytology
Grant Support
ID/Acronym/Agency:
CA129383/CA/NCI NIH HHS; DK36118/DK/NIDDK NIH HHS; GM71036/GM/NIGMS NIH HHS; R01 CA129383/CA/NCI NIH HHS; R01 CA129383-04/CA/NCI NIH HHS; R01 GM071036/GM/NIGMS NIH HHS; R01 GM071036-06/GM/NIGMS NIH HHS; R37 DK036118/DK/NIDDK NIH HHS; R37 DK036118-23/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Angiogenesis Inducing Agents; 0/Cell Adhesion Molecules; 0/Drug Combinations; 0/Imidazolidines; 0/Interleukin-6; 0/Laminin; 0/NF-kappa B; 0/Proteoglycans; 119978-18-6/matrigel; 8SH8T1164U/fidarestat; 9007-34-5/Collagen; EC 1.1.1.21/Aldehyde Reductase; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.24.-/Matrix Metalloproteinases
Comments/Corrections

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