Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak.
Garlic constituent diallyl trisulfide (DATS) inhibits growth of cancer cells in vitro and in vivo by causing apoptosis, but the sequence of events leading to cell death is not fully understood. We now show that DATS treatment triggers mitochondria-mediated apoptosis program in human prostate cancer cells (LNCaP, LNCaP-C81, LNCaP-C4-2) irrespective of their androgen responsiveness. Interestingly, a normal prostate epithelial cell line (PrEC) is significantly more resistant to apoptosis induction by DATS compared with prostate cancer cells. The DATS-induced apoptosis in LNCaP cells correlated with the collapse of mitochondrial membrane potential, modest increase in protein level of Bak, and down-regulation of Bcl-2 and Bcl-xL protein levels. The DATS-induced apoptosis was significantly attenuated by knockdown of Bax and Bak proteins, but not by ectopic expression of either Bcl-2 or Bcl-xL. The DATS treatment caused generation of reactive oxygen species (ROS) in LNCaP cells, but not in PrEC, which was attenuated by pretreatment with antioxidant N-acetylcysteine. The N-acetylcysteine pretreatment conferred significant protection against DATS-mediated disruption of the mitochondrial membrane potential and apoptosis. In conclusion, the present study reveals that the mitochondria-mediated cell death by DATS is associated with ROS generation and regulated by Bax/Bak but independent of Bcl-2 or Bcl-xL.
Kim
Young-Ae
YA
Department of Pharmacology and Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Xiao
Dong
D
Xiao
Hui
H
Powolny
Anna A
AA
Lew
Karen L
KL
Reilly
Megan L
ML
Zeng
Yan
Y
Wang
Zhou
Z
Singh
Shivendra V
SV
D000111:Acetylcysteine / Q000494:pharmacology; D000498:Allyl Compounds / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species; D013440:Sulfides / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D000498:Allyl Compounds; D000728:Androgens; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013440:Sulfides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C042577:diallyl trisulfide; D000111:Acetylcysteine