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Carcinogenesis Advance Access published online on August 1, 2003
Carcinogenesis, doi:10.1093/carcin/bgg127
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CARCINOGENESIS

Requirement of a carbon spacer in benzyl isothiocyanate-mediated cytotoxicity and MAPK activation in head and neck squamous cell carcinoma

Vivian W. Y. Lui 1, Abbey L. Wentzel 1, Dong Xiao 2, Karen L. Lew 2, Shivendra V. Singh 2, and Jennifer R. Grandis 3*

1 Department of Otolaryngology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, U.S.A.
2 Department of Pharmacology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, U.S.A.
3 Department of Otolaryngology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, U.S.A.; Department of Pharmacology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, U.S.A.

* Corresponding author. E-mail: jgrandis{at}pitt.edu.

Received 1 June 2003 ; revised 15 July 2003 ; accepted 23 July 2003

Abstract

Cruciferous vegetable derived isothiocyanates (ITCs; chemical structure: R-N=C=S) are highly effective in affording protection against chemically induced cancers in animal models. Here, we studied the antitumor effects of benzyl isothiocyanate (BITC; Ph-CH2-N=C=S), the predominant ITC compound in broccoli, in head and neck squamous cell carcinoma (HNSCC) cell lines. Proliferation, apoptosis and immunoblotting assays were used to determine the effects and mechanism of several ITCs on HNSCC cells. The IC50 for BITC (24 h treatment) in two of the HNSCC cell lines was approximately 22 µM and 17 µM, respectively. Interestingly, phenyl isothiocyanate (PITC; Ph-N=C=S), which is a close structural analogue of BITC but lacks a -CH2- spacer that links the aromatic ring to N=C=S moiety, did not result in significant killing of the HNSCC cells in this dose range. BITC (but not PITC) caused activation of caspase 3 and PARP cleavage. Within 20 minutes of treatment, BITC (but not PITC) induced a rapid activation of p38 MAPK. In addition, BITC (but not PITC) treatment resulted in the activation of p44/42 MAPK. Cotreatment with a p38 MAPK inhibitor, SB203580, or an inhibitor of the MEK/MAPK pathway, U0126, partially rescued cells from BITC-induced killing. Our results show that minor structural differences in ITCs can be crucial for the antiproliferative activity of ITCs and that BITC may be a promising chemopreventive as well as therapeutic agent in HNSCC.

Isothiocyanates, HNSCC, Chemoprevention, Apoptosis, MAPK
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