Induction of apoptosis by As2O3 could be caused by the production of intra-cellular ROS.43 The generation of ROS appears to occur consistently after arsenic exposure,10,44 46 and the generated ROS subsequently initiates the programmed cell death.45 The generation of ROS from the As2O3-induced apoptosis in U937 myeloid cells could be prevented by the anti-oxidant N-acetyl-L-cysteine (NAC).44 The ROS generated in response to arsenic exposure leads to the accumulation of intracellular hydrogen peroxide (H2O2) through activation of flavoprotein-dependent superoxide-producing enzymes such as NADPH oxidase.45 H2O2 acts as a mediator to induce apoptosis through release of cytochrome c to cytosol, activation of CPP32 protease (caspase 3), and PARP (poly (ADP-ribose) polymerase) degradation.45 H2O2 has been suggested to mediate As2O3-induced apoptosis in APL-derived NB4 cells. In these cells, apoptosis was preceded by mitochondrial membrane potential disruption, increased H2O2 content, and followed by cytochrome c release and caspase-3 activation.46 Elevating the intracellular ROS levels would sensitize the cells to As2O3-induced apoptosis, and the inherent intracellular ROS levels would also determine the tumor cells' susceptibility to As2O3.47,48 Nevertheless, there are controversies in the literature regarding the role of ROS in the arsenic-induced apoptosis. It has been reported that the increased intracellular peroxide levels accompanied with As2O3-induced apoptosis could be significantly inhibited by NAC (a thiol-containing anti-oxidant), diphenylene iodonium (an inhibitor of NADPH oxidase), 4,5-dihydro-1,3-benzene disulfonic acid (a selective scavenger of O2~) and catalase.45 However, another study showed that dithiothreitol (DTT) a reducing agent blocked the As2O3-induced apoptosis, but did not antagonize the As2O3-induced ROS production.49 Butylated hydroxy-anisole, a potent anti-oxidant that can inhibit the production of free radicals, has been shown to exert no effects on the As2O3-mediated cytotoxicity in ovarian and prostate cancer cells. It was then suggested that As2O3-mediated cytotoxicity in these cancer cells is not related to As2O3-mediated superoxide radical genera-tion.50
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