To: Pogeu Mahone who wrote (12867 ) 10/20/2015 1:12:45 AM From: E. Charters Respond to "The capacity for apoptosis induction by the ROS generator (ATO), arsenic trioxide (As2O3), in MCF-7 cancer cells was reported to be inversely correlated with the cellular levels of GSH (glutathione), a major intracellular antioxidant in mammalian cells. NAC, a precursor of GSH, is efficiently transported into cells unlike GSH. Impeding cancer cell DNA replication and repair and the induction of oxidative stress by the inhibition of both GSH and thioredoxin (Trx) systems have been advanced as cancer chemotherapeutic strategies."N -acetyl-cysteine (NAC) is an analogue and precursor of glutathione, an intracellular protective reducing equivalent. The antioxidant activity of NAC may have an important role as a chemopreventive agent for cancer progression because of its protective effect against UV-induced cellular damage. 36,37 Several investigations have indicated that NAC prevents the induction and maintenance of DNA damage and progression to cancer in smokers. 38 At the cellular level, NAC has been shown to inhibit endothelial cell invasion and angiogenesis in vitro , presumably because of the inhibition of metalloproteinase activities. 39 Conversely, NAC has been shown to have cytoprotective and anti-genotoxic effects on endothelial cells directly. 40 The chemopreventive activities of NAC have been shown to block tumor growth and angiogenesis in athymic nude mice. 41 Interestingly, NAC therapy was found to be synergistic with doxorubicin in blocking experimental tumorigenesis. 41,42 NAC has also been shown to modulate transcriptional activities through several pathways involving c-fos/c-jun, nuclear factor-?B, STAT, and cyclin inhibitors. 43 Given the possible connection between NAC treatment and reductions in tumor-dependent angiogenesis, it has been reported that one important aspect of NAC effectiveness is to limit the expression of VEGF. 44 This effect seems to be related to possible repression of reactive oxygen species and limiting hypoxia-induced transcription through hypoxia inducible factor-1. 15 Interestingly, it has been shown that the conversion of plasminogen into plasmin by cellular-derived plasminogen activators (uPA, tPA) in the presence of NAC, results in the accumulation of angiostatin in vitro . 45 The possibility that angiostatin formation can be promoted by NAC in which plasminogen activation occurs might provide additional mechanisms whereby antioxidant therapies could affect tumor angiogenesis in vivo ."
