Carcinogenesis Advance Access originally published online on April 29, 2004
Carcinogenesis 2004 25(9):1701-1709; doi:10.1093/carcin/bgh179
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Carcinogenesis vol.25 no.9 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Cell cycle arrest, apoptosis induction and inhibition of nuclear factor kappa B activation in anti-proliferative activity of benzyl isothiocyanate against human pancreatic cancer cells
Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
1 To whom correspondence should be addressed Email: srivastavask{at}msx.upmc.edu
Benzyl isothiocyanate (BITC), a cruciferous vegetable-derived compound, has been shown to inhibit chemically induced cancer in animal models. Moreover, epidemiological studies have provided compelling evidence to suggest that cruciferous vegetables may be protective against cancer risk. Here, we report that BITC significantly inhibits growth of human pancreatic cancer BxPC-3 cells in a concentration-dependent manner with an IC50 of 
8 µM, a concentration that can be generated through dietary intake of cruciferous vegetables. Treatment of BxPC-3 cells with growth suppressive concentrations of BITC resulted in G2/M phase cell cycle arrest that was associated with a marked decline in protein levels of G2/M regulatory proteins including cyclin-dependent kinase 1 (Cdk1), cyclin B1 and cell division cycle 25B (Cdc25B). Further, BITC-mediated growth inhibition of BxPC-3 cells correlated with apoptosis induction that was characterized by an increase in Bax/Bcl-2 ratio, cleavage of procaspase-3 and poly(ADP-ribose)polymerase (PARP), and an increase in cytoplasmic histone-associated DNA fragmentation. Interestingly, BITC treatment caused inhibition of nuclear factor 
B (NF-B) activation, which is constitutively activated in human pancreatic cancer. Western blotting revealed concentration-dependent decrease in NF-B/Rel-p65 protein level in BxPC-3 cells upon exposure to BITC. An increase in protein level of inhibitory subunit B (IBa) in association with reduced serine-32 phosphorylation was also observed in BITC-treated BxPC-3 cells. Consistent with these findings, BITC treatment caused a decrease in nuclear translocation of NF-B as reflected by reduced DNA-binding capacity of NF-B. Furthermore, the protein level of cyclin D1, a transcriptional target of NF-B, was reduced significantly in BITC-treated BxPC-3 cells. To the best of our knowledge, this study is the first published report to implicate suppression of NF-B activation as a potential mechanism for anti-proliferative activity of BITC against human pancreatic cancer cells.
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