Affiliations: Department of Biofunctional Chemistry, Division of
Bioscience, Graduate School of Natural Science and Technology, Okayama
University, Okayama, 700-8530, Japan | Laboratory of Biochemistry, National Heart, Lung and
Blood Institute, National Institutes of Health, Bethesda, MD 20892-8012,
USA
Note: [] Address for correspondence: Yoshimasa Nakamura, Graduate School
of Natural Science and Technology, (Faculty of Agriculture), Okayama
University, Okayama 700-8530, Japan. Tel./Fax: +81 86 251 8300; E-mail:
[email protected]
Abstract: An important and promising group of compounds that have a
chemopreventive property are organosulfur compounds, such as isothiocyanates
(ITCs). In recent years, it has been shown that ITCs induce apoptosis in
various cancer cell lines and experimental rodents. During the course of
apoptosis induction by ITC, multiple signal-transduction pathways and apoptosis
intermediates are modulated. We have also clarified the molecular mechanism
underlying the relationship between cell cycle arrest and apoptosis induced by
benzyl isothiocyanate (BITC), a major ITC compound isolated from papaya. The
exposure of cells to BITC resulted in the inhibition of the
G_{2}/M progression that coincided with not only the
up-regulated expression of the G_{2}/M cell cycle
arrest-regulating genes but also the apoptosis induction. The experiment using
the phase-specific synchronized cells demonstrated that the
G_{2}/M phase-arrested cells are more sensitive to
undergoing apoptotic stimulation by BITC than the cells in other phases. We
identified the phosphorylated Bcl-2 as a key molecule linking the p38
MAPK-dependent cell cycle arrest with the JNK activation by BITC. We also found
that BITC induced the cytotoxic effect more preferentially in the proliferating
normal human colon epithelial cells than in the quiescent cells. Conversely,
treatment with an excessive concentration of BITC resulted in necrotic cell
death without DNA ladder formation. This review addresses the biological impact
of cell death induction by BITC as well as other ITCs and the involved signal
transduction pathways.
