Garlic-derived organosulfides (OSCs) including
diallyl trisulfide (DATS) are highly effective in affording protection against chemically induced
cancer in animals. Evidence is also mounting to indicate that some naturally occurring OSCs can suppress proliferation of
cancer cells by causing apoptosis, but the sequence of events leading to proapoptotic effect of OSCs is poorly defined. Using PC-3 and DU145 human
prostate cancer cells as a model, we now demonstrate that DATS is a significantly more potent apoptosis inducer than
diallyl sulfide (
DAS) or
diallyl disulfide (DADS). DATS-induced apoptosis in PC-3 cells was associated with phosphorylation of Bcl-2, reduced Bcl-2 : Bax interaction, and cleavage of
procaspase-9 and -3. Bcl-2 overexpressing PC-3 cells were significantly more resistant to apoptosis induction by DATS compared with vector-transfected control cells. DATS treatment resulted in activation of
extracellular-signal regulated kinase 1/2 (ERK1/2) and
c-jun N-terminal kinase 1 (JNK1) and/or JNK2, but not
p38 mitogen-activated protein kinase. Phosphorylation of Bcl-2 in DATS-treated PC-3 cells was fully blocked in the presence of JNK-specific inhibitor
SP600125. Moreover, JNK inhibitor afforded significant protection against DATS-induced apoptosis in both cells. DATS-induced Bcl-2 phosphorylation and apoptosis were partially attenuated by pharmacological inhibition of ERK1/2 using
PD98059 or
U0126. Overexpression of
catalase inhibited DATS-mediated activation of JNK1/2, but not ERK1/2, and apoptosis induction in DU145 cells suggesting involvement of
hydrogen peroxide as a second messenger in DATS-induced apoptosis. In conclusion, our data point towards important roles for Bcl-2, JNK and ERK in DATS-induced apoptosis in human
prostate cancer cells.