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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...

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Autores principales: Wu, Jun, Akaike, Takaaki, Hayashida, Kazuyuki, Okamoto, Tatsuya, Okuyama, Akira, Maeda, Hiroshi
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
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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.
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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
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