Abstract A36: Topoisomerase II-dependent apoptosis induced by dietary isothiocyanates

Abstract Cruciferous vegetables, such as broccoli and watercress, have been studied extensively for their chemopreventive activities in animal models. It has been demonstrated that the thiol-reactive isothiocyanates (ITCs) are primarily responsible for their chemopreventive activity. While ITCs are known to induce Phase II enzymes and hence detoxification of certain carcinogens to prevent initiation of carcinogenesis, they also exhibit antitumor activity at a post-initiation phase, suggesting their additional role(s) in cancer prevention. In vitro studies have demonstrated that ITCs induce apoptosis which could be linked to their chemopreventive activity in the post-initiation phase. A number of studies have suggested that IKK inhibition, NF-κB suppression and/or STAT3 down-regulation may contribute to ITC-induced apoptosis. Here, we provide evidence that topoisomerase II (Top2) is involved in ITC-induced apoptosis in cultured tumor cells: (1) BITC (benzyl isothiocyanate) and PEITC (phenethyl isothiocyanate) induced much reduced apoptosis in HL-60 cells and T-antigen transformed MEFs transfected with Top2α siRNA. (2) Similarly, the induction of the DSB signal, γ-H2AX, was also reduced in HL-60 cells transfected with Top2α siRNA. (3) BITC and PEITC induced Top2-mediated DNA damage in vitro through the formation of topoisomerase II-DNA covalent complexes. Together, these results suggest a possible role of Top2 in ITC-induced cell death, presumably through the formation of topoisomerase II-DNA cleavage complexes. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A36.