Activation of JNK by benzyl isothiocyanate causes G₂/M cell cycle arrest and induction of apoptosis in human pancreatic cancer cells

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In our previous studies, we have shown that benzyl isothiocyanate (BITC), a naturally occurring anticancer agent present in cruciferous vegetables inhibits the proliferation of Capan-2 human pancreatic cancer cells. Nevertheless, the exact mechanism of the growth suppressive effects of BITC was not clear. Here we demonstrate that BITC treatment results in the increased level of reactive oxygen species (ROS), G₂/M cell cycle arrest and induction of apoptosis in Capan-2 cells. We also observed that BITC-induced apoptosis was associated with the disruption of mitochondrial membrane potential, activation of capsase-8, and caspase-3. However, treatment of cells with 5 mM N-acetyl cysteine (NAC) completely protected the cells from above-mentioned BITC mediated deleterious effects. In addition, our results demonstrate that BITC treatment results in the significant activation of c-Jun N-terminal kinase (JNK), which is known to play pivotal role in the generation of ROS, mitochondrial depolarization and induction of apoptosis in other cellular models. Moreover, JNK-specific inhibitor SP600125 offered significant protection against BITC-induced G₂/M cell cycle arrest and apoptosis. Taken together, our data suggest that BITC-induced ROS generation, G₂/M cell cycle arrest and apoptosis are mediated by the activation of JNK in Capan-2 cells. [Supported in part by RO1 grant CA 106953 (to S.K.S.) awarded by the National Cancer Institute].