Mancozeb selectively induces mitochondrial-mediated apoptosis in human gastric carcinoma cells through ROS generation

Mancozeb (Manganese ethylene bis-dithiocarbamate with zinc salt) is a dithiocarbamate fungicide used to control fungal disease in many fruit plants, flowers and the maintenance of field crops. The effect of mancozeb on cell viability of human gastric adenocarcinoma AGS, SNU-1 cells and human normal FHs 74 Int cells were investigated. This study demonstrated that mancozeb was able to inhibit cell proliferation by 56-82% at 5-10 μM concentrations after 48 h. Mancozeb treatment for 48 h resulted in 33% (P < 0.05) and 61% (P < 0.001) increase in apoptotic cells at 5 and 10 μM concentrations in AGS cells, respectively. Treatment with mancozeb did not cause cell cycle arrest, while modulated the expression level of cleaved caspase-3, and cleavage of poly-(ADP-ribose) polymerase. Furthermore, treatment with mancozeb caused a rapid stimulation of reactive oxygen species (ROS) and loss of mitochondrial transmembrane potential. The results also showed that mancozeb-induced apoptosis was accompanied by up-regulation of Bax and down-regulation of Bcl-2 and Bcl-xL. Overall, our data suggested that mancozeb caused ROS generation which induced significant (P < 0.05) apoptosis in AGS cells that was attenuated with pretreatment of NAC. More importantly, same concentration of mancozeb did not show any considerable effect on cell growth, death, cell cycle arrest and ROS generation in normal FHs 74 Int cells. Overall, for the first time these results suggest that mancozeb has selective anticancer activity at lower concentrations against gastric cancer cells.