Multiple lines of compelling evidence from epidemiological and laboratory studies 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 have compared the anti-proliferative effects of DAS, DADS, and DATS in human breast carcinoma (MCF-7) cells. When MCF-7 cells were treated with each of the aforementioned allylsulfur compounds for 24 h, DATS strongly inhibited the growth of MCF-7 cells compared with other allyl sulfides as determined by the MTT assay. MCF-7 cells treated with DATS (50 μM) underwent apoptotic death as revealed by a progressive increase in the sub-G0/G1 peak, a typical pattern of annexin V/propidium iodide staining, TUNEL staining and perturbation of the mitochondrial transmembrane potential (Δψm). DATS induced phosphorylation of Bcl-2 at Ser 70 and dephosphorylation at Ser 112 of Bad in MCF-7 cells. DATS treatment preferentially inactivated ERK1/2 and Akt. DATS treatment resulted in enhanced accumulation of reactive oxygen spices (ROS), which was attenuated by the antioxidant N-acetyl-L-cysteine (NAC). DATS-induced DNA fragmentation and impairment of mitochondrial transmembrane potential were blocked by NAC treatment. In addition, NAC inhibited the phosphorylation and expression of Bcl-2 as well as proteolytic cleavage of PARP. Moreover, NAC abrogated the DATS-induced suppression of ERK1/2 and Akt phosphorylation. NF-κB as a major down-stream molecular target of ERK1/2 and Akt has been considered to exert anti-apoptotic activity in cancerous or transformed cells. DATS inhibited the DNA binding of NF-κB and catalytic activity of IκB kinase β, which was again blocked by NAC treatment. These findings, taken together, suggest that DATS-induced apoptosis in MCF-7 cells is mediated via generation of ROS. Oral administration of 5 μmole/kg DATS to female Balb/c mice three times a week for 12 weeks inhibited the growth of human MCF-7 cell tumor xenografts by up to 86%, compared with the vehicle control. The Kaplan-Meyer analysis of the survival rates of different treatment groups revealed that 50% animals in the DATS treatment group were alive, while none of the DATS-untreated mice with transplanted tumor survived. Supported by the National Research Laboratory (NRL) Grant (to Y.-J. Surh) from the Ministry of Science and Technology and the grant (KRF08-2003-000-11081-0) from the Korea Research Foundation (H.-K. Na), Republic of Korea.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA