N-acetyl-cysteine promotes angiostatin production and vascular collapse in an orthotopic model of breast cancer.
The antioxidant N-acetyl-cysteine (NAC) has been shown to be chemopreventive in clinical studies, and in recent studies, has shown promise in preventing tumor progression. Although the effects of NAC on tumorigenesis have been associated with decreased angiogenesis, the mechanism of the anti-angiogenic activity has not been determined. In the following study, we describe a novel mechanism whereby NAC therapy blocks MDA-MB-435 breast carcinoma cell proliferation and metastasis in an in vivo tumorigenic model. Athymic nude mice bearing MDA-MB-435 xenografts were treated with systemic NAC daily for 8 weeks. NAC treatment resulted in endothelial cell apoptosis and reduction of microvascular density within the core of the tumor leading to significant tumor cell apoptosis/necrosis. Angiostatin accumulated in tumors from NAC-treated but not control animals. Additional studies using a vascular endothelial growth factor-dependent chicken chorioallantoic membrane angiogenic assay recapitulated NAC-induced endothelial apoptosis and coordinate production of angiostatin, a potent endothelial apoptotic factor. In vitro studies showed angiostatin was formed in endothelial cultures in a vascular endothelial growth factor- and NAC-dependent manner, a process that requires endothelial cell surface plasminogen activation. These results suggest that systemic NAC therapy promotes anti-angiogenesis through angiostatin production, resulting in endothelial apoptosis and vascular collapse in the tumor.
Agarwal
Anshu
A
Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501, USA.
Muñoz-Nájar
Ursula
U
Klueh
Ulrike
U
Shih
Shu-Ching
SC
Claffey
Kevin P
KP
D000111:Acetylcysteine / Q000494:pharmacology*; D043168:Angiostatins / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002645:Chickens; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D049452:Green Fluorescent Proteins; D006801:Humans; D020287:In Situ Nick-End Labeling; D008164:Luminescent Proteins / Q000378:metabolism; D008207:Lymphatic Metastasis; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009336:Necrosis; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000975:Antioxidants; D018076:DNA, Complementary; D016166:Free Radical Scavengers; D008164:Luminescent Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D012313:RNA; D043168:Angiostatins; D000111:Acetylcysteine