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Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity
R Yu1, S Mandlekar, K J Harvey
1Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, 60607-7173, USA.
Abstract:
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.
Insights
Certain isothiocyanates, like phenethyl isothiocyanate, induce apoptosis (programmed cell death) in cancer cells via a caspase-3-dependent pathway, offering potential chemopreventive benefits.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Isothiocyanates show anticancer effects in animal models.
- Their mechanism involves modulating xenobiotic-metabolizing enzymes.
- Potential roles include cytochrome P-450 inhibition and phase II enzyme induction.
Purpose of the Study:
- To investigate the effect of specific isothiocyanates on apoptosis in HeLa cells.
- To elucidate the role of caspase-3 in isothiocyanate-induced apoptosis.
- To explore the chemopreventive potential of isothiocyanates through apoptosis induction.
Main Methods:
- Treatment of HeLa cells with various isothiocyanates (phenethyl, phenylmethyl, phenylbutyl, phenylhexyl, and phenyl isothiocyanate).
- Assay of caspase-3/CPP32-like activity and poly(ADP-ribose) polymerase cleavage.
- Assessment of DNA fragmentation and inhibition studies using a caspase-3 inhibitor (acetyl-Asp-Glu-Val-Asp-aldehyde).
Main Results:
- Phenethyl and related isothiocyanates induced apoptosis in a time- and dose-dependent manner.
- Apoptosis-inducing concentrations led to rapid, transient caspase-3-like activity.
- Isothiocyanates stimulated poly(ADP-ribose) polymerase cleavage, followed by DNA fragmentation.
- Caspase-3 inhibition blocked isothiocyanate-induced apoptosis.
Conclusions:
- Isothiocyanates, except phenyl isothiocyanate, induce apoptosis in HeLa cells.
- The process is mediated by a caspase-3-dependent mechanism.
- Isothiocyanate-induced apoptosis represents a potential mechanism for their chemopreventive effects.