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N-acetylcysteine inhibits endothelial cell invasion and angiogenesis
Abstract:
The thiol N-acetylcysteine (NAC) is a chemopreventive agent that acts through a variety of mechanisms and can prevent in vivo carcinogenesis. We have previously shown that NAC inhibits invasion and metastasis of malignant cells as well as tumor take. Neovascularization is critical for tumor mass expansion and metastasis formation. We investigated whether a target of the anti-cancer activity of NAC could be the inhibition of the tumor angiogenesis-associated phenotype in vitro and in vivo using the potent angiogenic mixture of Kaposi's sarcoma cell products as a stimulus. Two endothelial (EAhy926 and human umbilical vein endothelial [HUVE]) cell lines were utilized in a panel of assays to test NAC ability in inhibiting chemotaxis, invasion, and gelatinolytic activity in vitro. NAC treatment of EAhy926 and HUVE cells in vitro dose-dependently reduced their ability to invade a reconstituted basement membrane, an indicator of endothelial cell activation. Invasion of HUVE cells was inhibited with an ID50 of 0.24 mM NAC, whereas inhibition of chemotaxis required a 10 fold higher doses, indicating that invasion is a preferential target. NAC inhibited the enzymatic activity and conversion to active forms of the gelatinase produced by endothelial cells. The matrigel in vivo assay was used for the evaluation of angiogenesis; NAC strongly inhibited neovascularization of the matrigel sponges in response to Kaposi's sarcoma cell products. NAC prevented angiogenesis while preserving endothelial cells, implying that it could be safely used as an anti-angiogenic treatment.
Insights
N-acetylcysteine (NAC) inhibits tumor angiogenesis, a key process for tumor growth and metastasis. This chemopreventive agent prevents endothelial cell invasion and neovascularization, suggesting potential as a safe anti-angiogenic therapy.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- N-acetylcysteine (NAC) is a known chemopreventive agent with multiple anticancer mechanisms.
- Tumor angiogenesis, the formation of new blood vessels, is crucial for tumor expansion and metastasis.
- Previous studies demonstrated NAC's ability to inhibit cancer cell invasion and metastasis.
Purpose of the Study:
- To investigate N-acetylcysteine's potential to inhibit tumor angiogenesis.
- To evaluate NAC's effect on endothelial cell phenotype associated with angiogenesis.
- To assess NAC's anti-angiogenic activity in vitro and in vivo.
Main Methods:
- Utilized EAhy926 and human umbilical vein endothelial (HUVE) cell lines for in vitro assays.
- Assessed NAC's impact on endothelial cell chemotaxis, invasion, and gelatinolytic activity.
- Employed a matrigel in vivo assay to evaluate angiogenesis stimulated by Kaposi's sarcoma cell products.
Main Results:
- NAC dose-dependently inhibited endothelial cell invasion, with a preferential effect over chemotaxis.
- NAC reduced the enzymatic activity and activation of gelatinases produced by endothelial cells.
- In vivo, NAC significantly inhibited neovascularization in response to angiogenic stimuli, without apparent toxicity to endothelial cells.
Conclusions:
- N-acetylcysteine effectively inhibits key aspects of tumor angiogenesis, including endothelial cell invasion and neovascularization.
- NAC targets the angiogenesis-associated phenotype of endothelial cells.
- NAC demonstrates potential as a safe and effective anti-angiogenic therapeutic agent.