CHEMOPREVENTIVE ISOTHIOCYANATES INDUCE APOPTOSIS AND CASPASE-3-LIKE PROTEASE ACTIVITY

Isothiocyanates exert strong anticarcinogenic effects in a number of a nimal models of cancer, presumably by modulation of xenobiotic-metabol izing enzymes, such as by inhibition of cytochrome P-450 and/or by ind uction of phase II detoxifying enzymes. Here, we report that phenethyl isothiocyanate and other structurally related isothiocyanates, phenyl methyl isothiocyanate, phenylbutyl isothiocyanate, and phenylhexyl iso thiocyanate, but not phenyl isothiocyanate induced apoptosis in HeLa c ells in a time-and dose-dependent manner. Treatment with apoptosis-ind ucing concentrations of isothiocyanates also caused rapid and transien t induction of caspase-3/CPP32-like activity. Furthermore, these isoth iocyanates, except phenyl isothiocyanate, stimulated proteolytic cleav age of poly(ADP-ribose) polymerase, which followed the appearance of c aspase activity and preceded DNA fragmentation, Pretreatment with a po tent caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde inhibited iso thiocyanate-induced caspase-3-like activity and apoptosis. These resul ts suggest that isothiocyanates may induce apoptosis through a caspase -3-dependent mechanism. The induction of apoptosis by isothiocyanates may provide a distinct mechanism for their chemopreventive functions.