Sensitization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Resistant Primary Prostate Cancer Cells by Isoegomaketone from Perilla frutescens

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a cancer treatment due to its ability to induce apoptosis selectively in cancer cells. Nevertheless, the risk of developing resistance warrants the development of sensitizers that can overcome resistan...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2014-11, Vol.77 (11), p.2438-2443
Main Authors: Lee, Ju-Hye, Cho, Hyun-Dong, Jeong, Il-Yun, Lee, Mi-Kyung, Seo, Kwon-Il
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Apoptosis Regulatory Proteins - metabolism
Caspase 8 - metabolism
Furans - chemistry
Furans - isolation & purification
Furans - pharmacology
Humans
Ketones - chemistry
Ketones - isolation & purification
Ketones - pharmacology
Male
Molecular Structure
Perilla frutescens - chemistry
Prostatic Neoplasms - drug therapy
TNF-Related Apoptosis-Inducing Ligand - metabolism
Up-Regulation
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Summary:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a cancer treatment due to its ability to induce apoptosis selectively in cancer cells. Nevertheless, the risk of developing resistance warrants the development of sensitizers that can overcome resistance to TRAIL. In this study, isoegomaketone (1) acted as a synergistic TRAIL sensitizer by mediating up-regulation of DR5 expression in primary prostate cancer RC-58T/h/SA#4 cells. Combined with 1, TRAIL exhibited enhanced apoptotic activity in a human prostate cancer cell line designated RC-58T/h/SA#4, as indicated by increases in annexin V-positive and sub-G1 cell populations as well as condensation of chromatin or apoptotic bodies. Combined treatment also activated caspases-8, -9, and -3; increased the protein levels of Bax, AIF, and cytosolic cytochrome c; and induced PARP cleavage while reducing Bcl-2 protein expression. Human recombinant DR5 Fc chimera efficiently attenuated 1-induced apoptosis, thereby demonstrating the critical role of DR5 in 1-mediated apoptotic cell death. Furthermore, DR5 expression induced by 1 was mediated via a ROS-independent pathway that required CHOP and p53. Overall, these findings provide evidence that 1 potentiates TRAIL-mediated apoptosis through up-regulation of DR5 via a ROS-independent pathway. This suggests that 1 has potential for increasing the effectiveness of prostate cancer therapy with TRAIL.
ISSN:0163-3864
1520-6025
DOI:10.1021/np500452e