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, up-regulation of extracellular signal-regulated protein kinase (ERK) was dispensable for apoptosis induction; DAS, DADS, or DATS did not modify expression of MAPK p38, bax, and bcl-xL. Further investigation revealed that the specific JNK inhibitor SP600125 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.
Wu
Xin-Jiang
XJ
University Medical Center Freiburg, Institute of Environmental Medicine and Hospital Hygiene, Freiburg, Germany. toxwu@hotmail.com
Hu
Ying
Y
Lamy
Evelyn
E
Mersch-Sundermann
Volker
V
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000498:Allyl Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005737:Garlic / Q000737:chemistry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009821:Oils / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012995:Solubility; D013440:Sulfides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D009821:Oils; D017382:Reactive Oxygen Species; D013440:Sulfides; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D019938:Cyclin D1; C038491:allyl sulfide; D048031:JNK Mitogen-Activated Protein Kinases