Apoptosis Induction in Human Lung Adenocarcinoma Cells by Oil-Soluble Allyl Sulfides: Triggers, Pathways, and Modulators

DAS (diallyl sulfide), DADS (diallyl disulfide), and DATS (diallyl trisulfide) are major oil-soluble allyl sulfides (OAS) that represent major garlic constituents. The anticarcinogenic and antimutagenic effects of these substances have been extensively studied during the last decades. Previous reports suggest that induction of apoptosis by OASs might contribute to their chemopreventive effects. In this study, we report that OASs DADS and DATS induce significant apoptosis in human lung adenocarcinoma A549 cells, whereas DAS does not. Differential modulation of reactive oxygen intermediates (ROI) and mitochondria membrane potential (MMP) may account for the apoptotic effects of DADS and DATS. The underlying molecular mechanisms of apoptosis induction by both compounds include activation of C-Jun N-terminal kinase (JNK), up-regulation of p53, and down-regulation of bcl-2 expression. In our test series, upregulation of extracellular signal-regulated protein kinase (ERK) was dispensable for apoptosis induction; DAS, DADS, or DATS did not modify expression of MAPK p38, box, and bcl-xL. Further investigation revealed that the specific JNK inhibitor SP6001 25 and the antioxidant NAC blocked DADS and DATS-induced apoptosis, whereas ERK inhibitors did not. Additionally, our data provide the first evidence that Fas-mediated cell death pathway is partly involved in DADS but not DATS-mediated cell death. Taken together, our work has elucidated the triggers, important modulators, and signal transduction pathways in DADS and DATS-mediated apoptosis. Environ. Mal. Mutagen. 50:266-275, 2009. (C) 2009 Wiley-Liss, Inc.