Diallyl trisulfide selectively causes Bax- and Bak-mediated apoptosis in human lung cancer cells.
Garlic-derived organosulfur compounds (OSCs) are highly effective in affording protection against chemically induced pulmonary carcinogenesis in animal models. We now demonstrate that garlic constituent diallyl trisulfide (DATS) suppresses viability of cultured human lung cancer cell lines H358 (anon-small cell lung cancer cell line) and H460 (a large cell lung cancer cell line) by causing G2-M phase cell cycle arrest and apoptotic cell death. On the other hand, a normal human bronchial epithelial cell line BEAS-2B was significantly more resistant to growth inhibition and apoptosis induction by DATS compared with lung cancer cells. We also found that even a subtle change in the OSC structure could have a significant impact on its biological activity. For example, DATS was significantly more effective than either diallyl sulfide or diallyl disulfide against proliferation of lung cancer cells. The DATS-mediated G2-M phase cell cycle arrest was explained by down-regulation of cyclin-dependent kinase 1 (Cdk1) and cell division cycle 25C protein expression leading to accumulation of Tyr15 phosphorylated (inactive) Cdk1. The DATS-induced apoptosis correlated with induction of pro-apoptotic proteins Bax, Bak and BID, and a decrease in the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL in lung cancer cells but not in BEAS-2B. Knockdown of Bax and Bak proteins conferred significant protection against DATS-induced apoptotic cytoplasmic histone-associated DNA fragmentation. On the other hand, BID protein was dispensable for DATS-induced apoptosis. In conclusion, the present study indicates that Bax and Bak proteins are critical targets of DATS-induced apoptosis in human lung cancer cells.
Xiao
Dong
D
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Zeng
Yan
Y
Hahm
Eun-Ryeong
ER
Kim
Young-Ae
YA
Ramalingam
Suresh
S
Singh
Shivendra V
SV
D000498:Allyl Compounds / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics; D001980:Bronchi / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005737:Garlic / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D013440:Sulfides / Q000302:isolation & purification / Q000494:pharmacology*; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000502:physiology*
D000498:Allyl Compounds; C494772:BAK1 protein, human; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D013440:Sulfides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C042577:diallyl trisulfide
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