Abstract Title

TETRANDRINE INDUCES ROS-DRIVEN CASPASE-DEPENDENT APOPTOSIS OF PROSTATE CANCER CELLS VIA MITOCHONDRIAL AND CELL DEATH RECEPTOR PATHWAY

Presenter Name

Pankaj Chaudhary

Abstract

Androgen deprivation is still the standard systemic therapy for prostate cancer, but patients invariably relapse with a more aggressive form of prostate cancer termed hormone refractory, androgen independent, or castration resistant prostate cancer. Once prostate cancer becomes castration-resistant, metastasis is a significant problem and treatment options are limited. Therefore, identification of novel agents that can selectively kill tumor cells with no additional toxicity to normal tissue would have significant impact on prostate cancer therapy.

Presentation Type

Poster

Purpose (a):

Tetrandrine, a bisbenzylisoquinoline alkaloid, isolated from the root of Stephania tetrandra is used in traditional Chinese medicine as an anti-rheumatic, anti-inflammatory, and anti-hypertensive agent for the past several years. During recent years, increasing number of studies have focused on the potential of tetrandrine in cancer therapy. Despite its great potential as an anti-cancer agent, the effect of tetrandrine in prostate cancer has not been studied. Therefore, in the present study, we demonstrate the cytotoxic efficacy of tetrandrine in human androgen-independent prostate cancer cells, PC3 and DU145, and delineate the mechanism of this effect.

Methods (b):

Prostate cancer cell lines, PC3 and DU145, and normal prostate PWR-1E cells were cultured in ATCC recommended medium. The toxicity of tetrandrine was analyzed by MTT assay and Vybrant Apoptosis Assay Kit. Western blotting was used to detect the expression of proteins involved in apoptosis.

Results (c):

Our results indicate that tetrandrine selectively inhibits the growth of PC3 and DU145 cancer cells compared to normal prostate PWR-1E cells. Treatment of cancer cells with tetrandrine caused the upregulation of Fas and Bax, downregulation of Bcl-2, cleavage of Bid, and release of cytochrome c, which were accompanied by activation of caspases-9, -3 and -8 and subsequently poly(ADP-ribose) polymerase cleavage. Pre-incubation with caspase-8 inhibitor significantly blocked the tetrandrine-induced Bid cleavage, reduction in mitochondrial membrane potential, and activation of caspase 3, and cell death. Together, these results suggest that the mitochondrial pathway is primarily involved in tetrandrine-induced apoptosis. Additionally, our results demonstrated that tetrandrine-induced apoptosis was caused by the generation of reactive oxygen species (ROS) and most of the signaling effects were attenuated with the preincubation of cells with N-acetylcysteine, thereby further confirming the involvement of ROS in these events.

Conclusions (d):

Our results demonstrated that treatment of prostate cancer cells with tetrandrine induces caspase-dependent apoptosis via Fas-mediated Bid cleavage and cytochrome c release.

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TETRANDRINE INDUCES ROS-DRIVEN CASPASE-DEPENDENT APOPTOSIS OF PROSTATE CANCER CELLS VIA MITOCHONDRIAL AND CELL DEATH RECEPTOR PATHWAY

Androgen deprivation is still the standard systemic therapy for prostate cancer, but patients invariably relapse with a more aggressive form of prostate cancer termed hormone refractory, androgen independent, or castration resistant prostate cancer. Once prostate cancer becomes castration-resistant, metastasis is a significant problem and treatment options are limited. Therefore, identification of novel agents that can selectively kill tumor cells with no additional toxicity to normal tissue would have significant impact on prostate cancer therapy.