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Research Articles: Therapeutics, Targets, and Development

Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak

Department of Pharmacology and Urology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Requests for reprints: S.V. Singh, 2.32A Hillman Cancer Center Research Pavilion, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-3263; Fax: 412-623-7828. E-mail: singhs{at}upmc.edu

Abstract

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. [Mol Cancer Ther 2007;6(5):1599–609]

Grant support: U.S. Public Health Service grant CA113363 awarded by the National Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/ 6/06; revised 2/24/07; accepted 3/27/07.

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