Diallyl Trisulfide Suppresses Growth of PC-3 Human Prostate Cancer Xenograft In vivo in Association with Bax and Bak Induction

Abstract

Purpose: The present study was undertaken to determine the effect of garlic constituent diallyl trisulfide (DATS) on growth of PC-3 human prostate cancer xenograft in vivo. Experimental Design: DATS was given orally (6 AmoL, thrice weekly) to male athymic mice s.c. implanted with PC-3 cells. Tumor sections from control and DATS-treated mice were examined for apoptotic bodies by terminal deoxynucleotidyl transferase^mediated dUTP nick end labeling assay. Protein levels of apoptosis and cell cycle regulating proteins in tumor tissues of control and DATS-treated mice were determined by immunoblotting. The effect of DATS treatment on in vivo angiogenesis was determined by immunohistochemical analysis of CD31in tumors. Results: Oral gavage of DATS significantly retarded growth of PC-3 xenografts in athymic mice without causing weight loss. For instance, 20 days after starting therapy, the average tumor volume in control mice was f3-fold higher compared with DATS-treated mice. Tumors from DATS-treated mice exhibited a markedly higher count of apoptotic bodies compared with control tumors. Consistent with the results in cultured PC-3 cells, the DATS-mediated suppression of PC-3 xenograft growth correlated with induction of proapoptotic proteins Bax and Bak. Although DATS treatment inhibited migration of cultured PC-3 cells in association with down-regulation of vascular endothelial growth factor receptor-2 protein, formation of new blood vessels was comparable in tumors of control and DATS-treated mice as judged by CD31immunostaining. Conclusions: The present study indicates that DATS administration inhibits growth of PC-3 xenografts in vivo in association with induction of Bax and Bak.

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

“…Second, the PrEC normal prostate epithelial cell line is significantly more resistant to growth inhibition and apoptosis induction by DATS even at concentrations that are highly cytotoxic to the prostate cancer cells. Third, we have shown recently that oral administration of DATS (6 Amol, thrice per week) significantly retards growth of PC-3 xenografts in vivo in athymic mice in association with apoptotic cell death (42).…”

“…The present study indicates that Bax and Bak proteins play an important role in the regulation of DATS-induced apoptosis because (a) the SV40-immortalized MEFs derived from DKO mice are significantly more resistant toward DATS-induced cell death compared with the WT MEFs; (b) the DATS-mediated cytosolic release of cytochrome c and cleavage of procaspase-3 is relatively more pronounced in the MEFs derived from WT mice than in the MEFs derived from DKO mice; and (c) Bax and Bak knockdown in LNCaP cells confers statistically significant protection against DATS-induced apoptosis. We have shown recently that the DATS-mediated inhibition of PC-3 xenograft growth in athymic mice in vivo correlates not only with increased apoptosis but also induction of Bax and Bak proteins in the tumor tissues (42). It is important to point out, however, that Bax and Bak cannot fully explain the cell death caused by DATS because combined knockdown of these proteins confers only partial protection against DATS-induced apoptosis.…”

“…Because ROS generation is implicated in the pathogenesis of many chronic diseases including cancer, the potential side effects of DATS-mediated ROS production cannot be ignored. However, we are tempted to speculate that ROS generation by DATS may not be deleterious because (a) DATS is derived from vegetables consumed by humans on a daily basis, yet epidemiologic studies continue to support the premise that dietary intake (1 -3); (b) the DATS-treated athymic mice do not exhibit weight loss or any other signs of toxicity (42); and (c) a normal prostate epithelial cell line (PrEC) seems resistant to DATS-mediated ROS generation, mitochondrial membrane potential collapse, and apoptosis induction (present study). It is possible that the DATS-mediated ROS generation in cancer cells is transient and serves to trigger the apoptosis signaling cascade.…”

An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells

“…In previous studies, Bak1 and Bax were reported to regulate apoptotic signaling in CaP synergistically. Knockdown of Bak1 and Bax completely prevented the apoptosis induced by a variety of biological molecules and chemical compounds (33)(34)(35)(36). Bak1 expression has also been reported to be associated with the progression of CaP.…”

Mechanisms of apoptosis resistance and treatment strategies to overcome them in hormone‐refractory prostate cancer

“…Diallyl trisulfide-mediated inhibition of PC-3 xenograft growth was accompanied by induction of proapoptotic Bcl-2 proteins Bak and Bax. 35 Garlic has been explored in prostate cancer prevention studies, and a relative decreased risk of prostate cancer was noted in consumers of garlic in an Asian population, supporting its possible use as an interesting agent in future studies. 36 In summary, initial anti-Bcl-2 approaches have been attempted in prostate cancer.…”