Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2.

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.

Xiao D ，Choi S ，Johnson DE ，Vogel VG ，Johnson CS ，Trump DL ，Lee YJ ，Singh SV ... -  《ONCOGENE》

Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells.

Xiao D ，Singh SV 《CARCINOGENESIS》

Apoptosis induction in human lung adenocarcinoma cells by oil-soluble allyl sulfides: triggers, pathways, and modulators.

Wu XJ ，Hu Y ，Lamy E ，Mersch-Sundermann V ... -  《-》

c-Jun NH(2)-terminal kinase signaling axis regulates diallyl trisulfide-induced generation of reactive oxygen species and cell cycle arrest in human prostate cancer cells.

Antosiewicz J ，Herman-Antosiewicz A ，Marynowski SW ，Singh SV ... -  《CANCER RESEARCH》

Diallyl trisulfide induces apoptosis in human breast cancer cells through ROS-mediated activation of JNK and AP-1.

Multiple lines of evidence support an inverse association between consumption of garlic and the risk of cancer. Chemopreventive effects of garlic have been attributed to its oil-soluble sulfur ingredients, such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), but their underlying molecular mechanisms remain largely unresolved. In the present study, we found that DATS showed the most potent anti-proliferative effects in human breast cancer MCF-7 cells. MCF-7 cells treated with DATS underwent apoptotic death as revealed by a progressive increase in the proportion of the sub-G0/G1 cell population and a typical pattern of annexin V/propidium iodide staining. DATS induced phosphorylation of the antiapoptotic Bcl-2 and proteolytic cleavage of poly(ADP-ribose)polymerase (PARP) in MCF-7 cells. DATS treatment activated c-Jun N-terminal kinase (JNK). DATS-induced apoptosis was blunted in MCF-7 cells treated with a specific JNK inhibitor SP600125 or transiently transfected with dominant negative JNK. DATS treatment resulted in accumulation of reactive oxygen species (ROS). DATS-induced apoptosis as well as activation of JNK was abrogated by N-acetyl-l-cysteine (NAC). Furthermore, DATS induced phosphorylation and expression of c-Jun, which were attenuated by NAC. MCF-7 cells treated with DATS also exhibited increased DNA binding activity of AP-1, which was blocked by NAC and the JNK inhibitor. Proteolytic cleavage of PARP induced by DATS was abrogated in the cells transfected with c-jun siRNA. Oral administration of 5μmol/kg DATS to female Balb/c mice inhibited the growth of human MCF-7 cell tumor xenografts. These results suggest that DATS-induced apoptosis is mediated through ROS generation and subsequent activation of JNK and AP-1.

Na HK ，Kim EH ，Choi MA ，Park JM ，Kim DH ，Surh YJ ... -  《-》