Cargando…
Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases
Peroxynitrite (ONOO ‐), which is generated from nitric oxide (NO) and superoxide anion (O(2)‐) under pathological conditions, plays an important role in pathophysiological processes. Activation of matrix metalloproteinases (MMPs) contributes to tumor angiogenesis and metastasis. NO mediates the enha...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2001
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926730/ https://www.ncbi.nlm.nih.gov/pubmed/11346467 http://dx.doi.org/10.1111/j.1349-7006.2001.tb01114.x |
_version_ | 1783318964643823616 |
---|---|
author | Wu, Jun Akaike, Takaaki Hayashida, Kazuyuki Okamoto, Tatsuya Okuyama, Akira Maeda, Hiroshi |
author_facet | Wu, Jun Akaike, Takaaki Hayashida, Kazuyuki Okamoto, Tatsuya Okuyama, Akira Maeda, Hiroshi |
author_sort | Wu, Jun |
collection | PubMed |
description | Peroxynitrite (ONOO ‐), which is generated from nitric oxide (NO) and superoxide anion (O(2)‐) under pathological conditions, plays an important role in pathophysiological processes. Activation of matrix metalloproteinases (MMPs) contributes to tumor angiogenesis and metastasis. NO mediates the enhanced vascular permeability and retention (EPR) effect in solid tumors, and ONOO‐ activates proMMP to MMP in vitro. In this study, we examined the role of ONOO‐ in the EPR effect in solid tumors and normal tissues as related to MMP activation. Authentic ONOO‐, at 50 nmol or higher concentrations, induced the enhanced vascular permeability in normal dorsal skin of mice. ONOO‐ scavengers ebselen and uric acid significantly suppressed the EPR effect in mouse sarcoma 180 (S‐180) tumors. Indirect evidence for formation of ONOO‐ in S‐180 and mouse colon adenocarcinoma (C‐38) tumors included strong immunostaining for nitrotyrosine in the tumor tissue, predominantly surrounding the tumor vessels. MMP inhibitor BE16627B (66.6 mg/kg i.v., given 2 tunes) or SI‐27 (10 mg/kg i.p., given 2 times) significantly suppressed the ONOO‐induced EPR effect in S‐180 tumors and in normal skin. Soybean trypsin inhibitor (Kunitz type), broad‐spectrum proteinase inhibitor ovomacroglobulin, and bradykinin receptor antagonist HOE 140 also significantly suppressed the ONOO‐induced EPR effect in normal skin tissues. These data suggest that ONOO‐ may be involved in and promote the EPR effect in tumors, which could be mediated partly through activation of MMPs and a subsequent proteinase cascade to generate potent vasoactive mediators such as bradykinin. |
format | Online Article Text |
id | pubmed-5926730 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2001 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-59267302018-05-11 Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases Wu, Jun Akaike, Takaaki Hayashida, Kazuyuki Okamoto, Tatsuya Okuyama, Akira Maeda, Hiroshi Jpn J Cancer Res Article Peroxynitrite (ONOO ‐), which is generated from nitric oxide (NO) and superoxide anion (O(2)‐) under pathological conditions, plays an important role in pathophysiological processes. Activation of matrix metalloproteinases (MMPs) contributes to tumor angiogenesis and metastasis. NO mediates the enhanced vascular permeability and retention (EPR) effect in solid tumors, and ONOO‐ activates proMMP to MMP in vitro. In this study, we examined the role of ONOO‐ in the EPR effect in solid tumors and normal tissues as related to MMP activation. Authentic ONOO‐, at 50 nmol or higher concentrations, induced the enhanced vascular permeability in normal dorsal skin of mice. ONOO‐ scavengers ebselen and uric acid significantly suppressed the EPR effect in mouse sarcoma 180 (S‐180) tumors. Indirect evidence for formation of ONOO‐ in S‐180 and mouse colon adenocarcinoma (C‐38) tumors included strong immunostaining for nitrotyrosine in the tumor tissue, predominantly surrounding the tumor vessels. MMP inhibitor BE16627B (66.6 mg/kg i.v., given 2 tunes) or SI‐27 (10 mg/kg i.p., given 2 times) significantly suppressed the ONOO‐induced EPR effect in S‐180 tumors and in normal skin. Soybean trypsin inhibitor (Kunitz type), broad‐spectrum proteinase inhibitor ovomacroglobulin, and bradykinin receptor antagonist HOE 140 also significantly suppressed the ONOO‐induced EPR effect in normal skin tissues. These data suggest that ONOO‐ may be involved in and promote the EPR effect in tumors, which could be mediated partly through activation of MMPs and a subsequent proteinase cascade to generate potent vasoactive mediators such as bradykinin. Blackwell Publishing Ltd 2001-04 /pmc/articles/PMC5926730/ /pubmed/11346467 http://dx.doi.org/10.1111/j.1349-7006.2001.tb01114.x Text en |
spellingShingle | Article Wu, Jun Akaike, Takaaki Hayashida, Kazuyuki Okamoto, Tatsuya Okuyama, Akira Maeda, Hiroshi Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases |
title | Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases |
title_full | Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases |
title_fullStr | Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases |
title_full_unstemmed | Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases |
title_short | Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases |
title_sort | enhanced vascular permeability in solid tumor involving peroxynitrite and matrix metalloproteinases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926730/ https://www.ncbi.nlm.nih.gov/pubmed/11346467 http://dx.doi.org/10.1111/j.1349-7006.2001.tb01114.x |
work_keys_str_mv | AT wujun enhancedvascularpermeabilityinsolidtumorinvolvingperoxynitriteandmatrixmetalloproteinases AT akaiketakaaki enhancedvascularpermeabilityinsolidtumorinvolvingperoxynitriteandmatrixmetalloproteinases AT hayashidakazuyuki enhancedvascularpermeabilityinsolidtumorinvolvingperoxynitriteandmatrixmetalloproteinases AT okamototatsuya enhancedvascularpermeabilityinsolidtumorinvolvingperoxynitriteandmatrixmetalloproteinases AT okuyamaakira enhancedvascularpermeabilityinsolidtumorinvolvingperoxynitriteandmatrixmetalloproteinases AT maedahiroshi enhancedvascularpermeabilityinsolidtumorinvolvingperoxynitriteandmatrixmetalloproteinases |