title: Diallyl trisulfide induces apoptosis in human breast cancer cells through ROS-mediated activation of JNK and AP-1.
abstract: 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.
authors.affiliation: Department of Food & Nutrition, College of Human Ecology, Sungshin Women's University, Seoul, South Korea. nhkdec28@gmail.com
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Na
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Min-Ah
authors.initials: MA
authors.lastname: Choi
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Park
authors.forename: Do-Hee
authors.initials: DH
authors.lastname: Kim
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013440:Sulfides / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000498:Allyl Compounds; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013440:Sulfides; D018808:Transcription Factor AP-1; C042577:diallyl trisulfide; D048055:Mitogen-Activated Protein Kinase 8