N-Acetylcysteine interacts with copper to generate hydrogen peroxide and selectively induce cancer cell death

Abstract

A variety of metal-binding compounds have been found to exert anti-cancer activity. We postulated that N-acetylcysteine (NAC), which is a membrane-permeable metal-binding compound, might have anti-cancer activity in the presence of metals. We found that NAC/Cu(II) significantly alters growth and induces apoptosis in human cancer lines, yet NAC/Zn(II) and NAC/Fe(III) do not. We further confirmed that this cytotoxicity of NAC/Cu(II) is attributed to reactive oxygen species (ROS). These findings indicate that the combination of Cu(II) and thiols generates cytotoxic ROS that induce apoptosis in cancer cells. They also indicate a fourth class of anti-neoplastic metal-binding compounds, the “ROS generator”.

Trolox Enhances Curcumin's Cytotoxicity through Induction of Oxidative Stress

“…In contrast, the cytotoxicity induced by 1 mM NAC plus 10 µM Cu (II) was enhanced by exogenous SOD1, and attenuated by exogenous catalase, which is consistent with toxicity due to extracellular ROS generation (data not shown, [23]). …”

“…We recently reported that NAC plus copper generates extracellular ROS, which is cytotoxic to cancer cells [23] in a manner similar to that reported for vitamin C [24]. The concept of extracellular and intracellular ROS generation and its influence on cell function has been recognized [25].…”

Zinc and calcium modulate mitochondrial redox state and morphofunctional integrity

“…We, for the first time using real-time flow cytometry, measured mitochondrial redox state by monitoring H 2 DCFDA oxidation to DCF [35] and its attenuation by known anti-oxidants, NAC and vitamin E. Unexpectedly, we found that low doses of both NAC and vitamin E had pro-oxidant activity. While pro-oxidant effects of NAC [36,37] and vitamin E [38] have previously been reported, our study conclusively linked these effects with the mitochondria. In general, antioxidants may act as pro-oxidants when reducing equivalents are depleted [39] or by interacting with redox active transition metals, e.g., Cu and Fe (both occur in substantial amounts in the mitochondria), yielding the superoxide anion and H 2 O 2 [37,40].…”

“…While pro-oxidant effects of NAC [36,37] and vitamin E [38] have previously been reported, our study conclusively linked these effects with the mitochondria. In general, antioxidants may act as pro-oxidants when reducing equivalents are depleted [39] or by interacting with redox active transition metals, e.g., Cu and Fe (both occur in substantial amounts in the mitochondria), yielding the superoxide anion and H 2 O 2 [37,40]. Moreover, the oxidation of thiol groups present in NAC by ROS can result in the formation of thiyl radicals due to insufficient regenerative reduction [36].…”

Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline)

“…The cytotoxicity of clioquinol and its six analogues were examined using the MTS reagent as previously described [13]. Briefly, Raji, DHL-4 and HL-60 cells were plated in 96-well plates at 10,000 cells/well, and A2780 and Panc-1 cells at 5,000/well.…”