MP16-15 METABOLOMIC PROFILING TO EVALUATE THE PHARMACODYNAMIC OF PROXALUTAMIDE, A NOVEL ANDROGEN RECEPTOR ANTAGONIST

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP16)1 Apr 2020MP16-15 METABOLOMIC PROFILING TO EVALUATE THE PHARMACODYNAMIC OF PROXALUTAMIDE, A NOVEL ANDROGEN RECEPTOR ANTAGONIST Feng Qu*, Yue Gu, Qi-zhi Wang, Ming-zhe He, Guang-ji Wang, Fang Zhou, Hong-qian Guo, and Ying Peng Nanjing Feng Qu*Feng Qu* More articles by this author , Yue GuYue Gu More articles by this author , Qi-zhi WangQi-zhi Wang More articles by this author , Ming-zhe HeMing-zhe He More articles by this author , Guang-ji WangGuang-ji Wang More articles by this author , Fang ZhouFang Zhou More articles by this author , Hong-qian GuoHong-qian Guo More articles by this author , and Ying Peng NanjingYing Peng Nanjing More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000841.015AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Proxalutamide is a newly developed androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer and has now entered Phase III clinical trials. It has been reported to have potent anti-tumor efficacy and multiple abilities to intervene the AR signaling pathway. We now tried to further elucidate the pharmacodynamic mechanism of proxalutamide from metabolic reprogramming on prostate cancer (PCa) cells. METHODS: We investigated the anti-proliferative effects of proxalutamide on AR-positive cells (22RV1 and LNCaP ) and AR-negative cells (PC3 and DU145) by quantitating the amount of ATP present. LC-Q/TOF-MS was then used for analyzing intracellular metabolites in the four PCa cells before or after administration of proxalutamide and two other AR antagonists (bicalutamide and enzalutamide). RESULTS: Cell viability assay indicated that proxalutamide showed potent anti-proliferative effects on AR-positive cells but weak on AR-negative cells. The changes of content of intracellular metabolites in the four PCa cells caused by proxalutamide and the other two AR antagonists showed obvious differences in metabolomics analysis (Fig.1a and 1b). In AR-positive PCa cells, proxalutamide significantly reduced the intracellular content of certain important amino acids, such as glutamine, glutamate, cysteine, glycine and aspartate (p<0.05). Results showed that proxalutamide significantly down-regulated the intracellular levels of GSH, GSSG and the ratio of GSH to GSSG (p<0.01)(Fig.1e). The intracellular contents of uridine, cytidine and thymidine were also decreased significantly (p<0.01) by proxalutamide. The similar changes were observed after administration of bicalutamide and enzalutamide, but there was no significant difference or lesser degree of difference compared to untreated cells. However, these changes on intracellular metabolites were not reflected in AR-negative cells. CONCLUSIONS: Proxalutamide influenced the glutamate metabolism, redox homeostasis and pyrimidine synthesis in PCa cells (Fig.1c and 1d), and these changes may be associated with the blockade of AR signaling pathways. Source of Funding: Supported by National Nature Science Foundation of China (81703608) and Nanjing Medical Science and Technique Development Foundation(QRX17049) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e221-e221 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Feng Qu* More articles by this author Yue Gu More articles by this author Qi-zhi Wang More articles by this author Ming-zhe He More articles by this author Guang-ji Wang More articles by this author Fang Zhou More articles by this author Hong-qian Guo More articles by this author Ying Peng Nanjing More articles by this author Expand All Advertisement PDF downloadLoading ...