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Chemopreventive Isothiocyanates Induce Apoptosis and Caspase-3-like Protease Activity¹

Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60607-7173 [R. Y., S. M., A-N. T. K.]; and Department of Microbiology and Immunology, College of Medicine [K. J. H., D. S. U.], University of Illinois at Chicago, Chicago, Illinois 60612

Isothiocyanates exert strong anticarcinogenic effects in a number of animal models of cancer, presumably by modulation of xenobiotic-metabolizing enzymes, such as by inhibition of cytochrome P-450 and/or by induction of phase II detoxifying enzymes. Here, we report that phenethyl isothiocyanate and other structurally related isothiocyanates, phenylmethyl isothiocyanate, phenylbutyl isothiocyanate, and phenylhexyl isothiocyanate, but not phenyl isothiocyanate induced apoptosis in HeLa cells in a time- and dose-dependent manner. Treatment with apoptosis-inducing concentrations of isothiocyanates also caused rapid and transient induction of caspase-3/CPP32-like activity. Furthermore, these isothiocyanates, except phenyl isothiocyanate, stimulated proteolytic cleavage of poly-(ADP-ribose) polymerase, which followed the appearance of caspase activity and preceded DNA fragmentation. Pretreatment with a potent caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde inhibited isothiocyanate-induced caspase-3-like activity and apoptosis. These results 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.

¹ This work was supported by NIH Grants R29-GM49172 and R01-ES06887 (to A-N. T. K.) and R01-GM38800 (to D. S. N.).

² To whom requests for reprints should be addressed, at Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology MC870, College of Pharmacy, University of Illinois at Chicago, 900 South Ashland Avenue, MBRB Room 3102, Chicago, IL 60607-7173. Phone: (312) 413-9646; Fax: (312) 413-9303.

Received 11/14/97. Accepted 12/17/97.

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