Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases

Wu, Jun; Akaike, Takaaki; Hayashida, Kentaro; Okamoto, Tatsuya; Okuyama, Atsushi; Maeda, Hiroshi

doi:10.1111/j.1349-7006.2001.tb01114.x

Cited by 135 publications

(78 citation statements)

References 57 publications

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“…This result suggests an important role of peroxynitrite as a potential mediator of oxidative tissue injury through MMPdependent ECM destruction. This idea is further supported by our recent study showing involvement of peroxynitrite-dependent proMMP activation in enhanced vascular permeability in the skin of mice and guinea pigs and in an experimental murine solid tumor in vivo (42).…”

Section: Characterization Of S-glutathiolation Of Prommps By Maldi-tosupporting

confidence: 72%

Activation of Matrix Metalloproteinases by Peroxynitrite-induced Protein S-Glutathiolation via Disulfide S-Oxide Formation

Okamoto¹,

Akaike²,

Sawa³

et al. 2001

Journal of Biological Chemistry

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413

299

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Oxidative stress may cause tissue injury through activation of the precursors of matrix metalloproteinase (proMMPs). In this study, we observed glutathione (GSH)-dependent proMMP activation induced by peroxynitrite, a potent oxidizing agent formed during inflammatory processes. Peroxynitrite strongly activated all three types of purified human proMMPs (proMMP-1, -8, and -9) in the presence of similar concentrations of GSH. Of the potential reaction products between peroxynitrite and GSH, only S-nitroglutathione (GSNO 2 ) caused proMMP activation. Extensive S-glutathiolation of the proMMP protein occurred during activation of proMMP by peroxynitrite and GSH, as shown by radiolabeling studies with [ S]GSH or [3 H]GSH. Evidence of appreciable S-glutathiolation persisted even after dithiothreitol and proteindenaturing treatment, however, suggesting that some Sglutathiolation did not occur through formation of simple mixed disulfide. Matrix-assisted laser-desorption ionization-time-of-flight mass spectrometry indicated that not only peroxynitrite plus GSH but also synthetic GSNO 2 produced dithiothreitol-resistant S-glutathiolation of the synthetic peptide PRCGVPD, which is a well conserved Cys-containing sequence of the propeptide autoinhibitory domain of proMMPs. PRCGVPD S-glutathiolation is presumed to be formed through glutathione disulfide Soxide (GS(O)SR), based on the m/z 1064. Our results illustrate a unique mechanism of oxidative proMMP activation and oxidative tissue injury during inflammation.

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Section: Characterization Of S-glutathiolation Of Prommps By Maldi-tosupporting

confidence: 72%

Activation of Matrix Metalloproteinases by Peroxynitrite-induced Protein S-Glutathiolation via Disulfide S-Oxide Formation

Okamoto¹,

Akaike²,

Sawa³

et al. 2001

Journal of Biological Chemistry

Self Cite

413

299

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“…Although it can be cytotoxic to tumor cells, 16 NO could facilitate metastasis by increasing vasodilation and permeability. 17 NO is synthesised by both constitutive (eNOS) and inducible (iNOS) nitric oxide synthase enzymes. iNOS is induced in response to a range of stimuli, including LPS.…”

mentioning

confidence: 99%

Lipopolysaccharide‐induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion

Harmey

Bucana

Wang

et al. 2002

Intl Journal of Cancer

238

202

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Endotoxin/lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, is a potent inflammatory stimulus. We previously reported that LPS increased the growth of experimental metastases in a murine tumor model. Here, we examined the effect of LPS exposure on key determinants of metastasis-angiogenesis, tumor cell invasion, vascular permeability, nitric oxide synthase (NOS) and matrix metalloproteinase 2 (MMP2) expression. BALB/c mice bearing 4T1 lung metastases were given an intraperitoneal (i.p.) injection of 10 g LPS or saline. LPS exposure resulted in increased lung weight and incidence of pleural lesions. LPS increased angiogenesis both in vivo and in vitro. Most cancer patients ultimately succumb to metastatic disease, and up to 50% of cancer patients already have metastatic deposits at the time of diagnosis. 1 In many cases, the primary tumor can be successfully treated by surgery, radiotherapy, chemotherapy or a combination but the subsequent growth of previously dormant or clinically undetectable metastatic deposits presents a serious obstacle to the complete eradication of the disease. Elucidating factors that influence the development and progression of metastatic disease is critical to the development of effective therapies for patients with metastatic deposits.Metastatic tumor growth involves a complex series of sequential events involving a number of cell types, cytokines and pathways. After the initial transformation event, growth of a primary tumor is accompanied by extensive angiogenesis. Cells with a metastatic phenotype invade the tissue stroma and penetrate the blood vessels to enter the circulation. The majority of tumor cells entering the circulation are rapidly destroyed but those that do survive can then become trapped in organ capillary beds and extravasate into the organ parenchyma. Cell proliferation and vascularization of the secondary deposit completes the metastatic process. 2 Endotoxin/lipopolysccharide (LPS), a cell wall constituent of Gram-negative bacteria, is released during growth or lysis of bacteria and acts as a potent inflammatory stimulus, eliciting a range of cytokines, growth factors and inflammatory mediators. LPS and some bacteria have been shown to have angiogenic activity. [3][4][5] Inflammation has been linked with angiogenesis, resulting in changes in permeability, activation of endothelium and vessel remodeling. 6 In support of a link between inflammation and tumor progression, there is a growing body of evidence that anti-inflammatory agents such as the nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclo-oxygenase activity, inhibit both tumorigenesis and growth of colon and mammary tumors. 7 Endotoxin is ubiquitously present in air, and we previously implicated endotoxin in surgically induced tumor growth. 8,9 Endogenous gut bacteria are a major source of endotoxin, which can translocate across the gut into the circulation following surgical trauma or thermal injury. 10 -12 Vascular endothelial growth factor (VEGF), also known as va...

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“…Low NOs facilitate blood flow, ensuring the efficient delivery of nutrients and oxygen to the tumor (16)(17)(18)(19). They also enhance vascular permeability (10,20) and stimulate angiogenesis, facilitating the development of the tumor neovasculature (21,22). These effects promote tumor growth and assist metastatic spread.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Actions of Ruthenium(III)-Based Nitric Oxide Scavengers and Nitric Oxide Synthase Inhibitors

Flitney

Pritchard²,

Kennovin³

et al. 2011

Molecular Cancer Therapeutics

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The role of endogenous nitric oxide (NO) in the growth and vascularization of a rat carcinosarcoma (P22) has been investigated. Tumor-bearing animals were treated with (i) nitric oxide synthase (NOS) inhibitors, administered via the drinking water, including N G -nitro-L-arginine methyl ester (L-NAME), a nonisoform-selective inhibitor, and 2 others that target the inducible (NOS II) enzyme preferentially, namely 1-amino-2-hydroxyguanidine or N-[3-(aminomethyl)benzyl]acetamidine hydrochloride; or (ii) daily injections (intraperitoneally) of 2 Ru(III) polyaminocarboxylates, AMD6221 and AMD6245, both of which are effective NO scavengers. L-NAME, AMD6221, and AMD6245 reduced tumor growth by approximately 60% to 75% of control rates. Tumor sections stained with abs to CD-31/platelet endothelial cell adhesion molecule-1 or NOS III showed that this was associated with a marked reduction (60%-77%) of tumor microvascular densitiy (MVD). Tumors resumed growing promptly when treatment was discontinued, accompanied by partial or complete restoration of MVDs. In contrast, NOS-II selective inhibitors had no effect on tumor growth or vascularization, indicating that both responses require complete blockade of NO production. The results corroborate the view that endogenous NO facilitates tumor development. We suggest that NO deprivation causes tumor feeder vessels to constrict, reducing tumor blood flow. The delivery of oxygen and essential nutrients to the developing tumor is impaired as a consequence, hampering further growth. Normalizing NO levels by withholding treatment causes tumor feeder vessels to dilate, increasing tumor perfusion and reestablishing conditions that allow tumors to begin growing again.

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Enhanced Vascular Permeability in Solid Tumor Involving Peroxynitrite and Matrix Metalloproteinases

Cited by 135 publications

References 57 publications

Activation of Matrix Metalloproteinases by Peroxynitrite-induced Protein S-Glutathiolation via Disulfide S-Oxide Formation

Activation of Matrix Metalloproteinases by Peroxynitrite-induced Protein S-Glutathiolation via Disulfide S-Oxide Formation

Lipopolysaccharide‐induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion

Antitumor Actions of Ruthenium(III)-Based Nitric Oxide Scavengers and Nitric Oxide Synthase Inhibitors

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