Prostate cancer (PCA) is the second leading cause of cancer-related deaths in men in the U.S. The standard of care for advanced disease remains androgen ablation, but despite strong initial responses in most cases, therapies inevitably fail in nearly all patients. Our group has designed a novel therapeutic, designated VN/124-1, which offers a distinct advantage over current therapies in that it globally inhibits androgen production and inhibits the androgen receptor directly. To test whether or not VN/124-1 also had an effect on androgen independent PCA (AIPC), the AIPC cell lines PC-3 and DU-145 were treated with increasing concentrations of VN/124-1, and it was found that the compound inhibits the growth of both cell lines at concentrations previously shown to be physiologically relevant. Microarray technology was employed to analyze gene expression changes in PC-3 cells treated with VN/124-1 and revealed the up-regulation of genes involved in cellular stress and amino acid metabolism as well as the down-regulation of genes involved in DNA replication and cell cycle progression. These results led to the hypothesis that VN/124-1 was inhibiting cell growth via induction of the endoplasmic reticulum stress response (ERSR). Quantitative real-time PCR and western blot analyses confirmed that VN/124-1 induced the expression and activation of genes involved in the ERSR in PC-3 cells. Activation of the ERSR resulted in the growth arrest of PC-3 cells in the G1/G0 phase of the cell cycle. VN/124-1 was found to induce the ERSR by causing disruptions in ER Ca2+ homeostasis. In-vivo studies using PC-3 xenografts demonstrated VN/124-1 also significantly inhibits the growth of androgen-independent tumors. VN/124-1’s diverse mechanisms of action may offer an advantage over other androgen ablative therapies, demonstrated by its improved efficacy over leading lyase inhibitor, abiraterone, in mouse LAPC-4 xenograft models. VN/124-1 was also compared to the compounds VNLG/21-1 (3-fluoro VN/124-1) and VN/124-1 Sulfamate which were designed to increase the stability and oral bioavailability of VN/124-1, respectively in-vivo. However, these molecules failed to demonstrate any clear advantage over VN/124-1 treatment. Together these studies demonstrate the potential efficacy of VN/124-1 and aid in the understanding of the molecule’s complex pharmacology.
|Advisor:||Njar, Vincent C.O.|
|Commitee:||Brodie, Angela MH, Pei, Feng, Renty, Franklin, Ross, Douglas|
|School:||University of Maryland, Baltimore|
|School Location:||United States -- Maryland|
|Source:||DAI-B 70/04, Dissertation Abstracts International|
|Subjects:||Molecular biology, Pharmacology, Physiology|
|Keywords:||Androgen deprivation therapy, Antiandrogen, Cyp17, Prostate cancer|
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