Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cance
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PRECLINICAL STUDIES
Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells Feng Qu 1 & Yue Gu 2 & Qizhi Wang 2 & Mingzhe He 2 & Fang Zhou 2 & Jianguo Sun 2 & Guangji Wang 2 & Ying Peng 2 Received: 20 November 2019 / Accepted: 17 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Proxalutamide is a newly developed androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (PCa) that has entered phase III clinical trials. In the present study, we intended to elucidate the antitumor efficacy of proxalutamide through the metabolomic profiling of PCa cells. Two AR-positive PCa cell lines and two AR-negative PCa cell lines were investigated. Cell viability assays based on ATP quantitation were conducted. LC-Q/TOF-MS was used to analyze intracellular metabolites before or after the administration of proxalutamide and two other clinical AR antagonists (bicalutamide and enzalutamide). The results of this study showed that the inhibitory effect of proxalutamide on PCa cell proliferation was better than that of bicalutamide and enzalutamide, and proxalutamide preferentially affected AR-positive PCa cells over ARnegative cells. The metabolic composition of PCa cells changed significantly after proxalutamide administration, and these changes in response to proxalutamide were significantly different from those in the presence of the two other AR antagonists. In AR-positive cells, proxalutamide significantly decreased the intracellular levels of glutamine, glutamate, glutathione, cysteine, glycine, aspartate, uridine, cytidine and thymidine. However, the effects of the two other antagonists on these discriminant metabolites were ambiguous, and no changes in these metabolites were found in AR-negative cells. Our findings indicate that proxalutamide has inhibitory effects on glutamine metabolism, redox homeostasis and de novo pyrimidine synthesis in ARpositive PCa cells that enhance the cellular sensitivity to proxalutamide. Keywords Proxalutamide . Prostate cancer . Metabolomics . Glutamine . Glutathione . Pyrimidine synthesis
Introduction Prostate cancer (PCa) has become one of the most common malignancies in men, with over 174,000 new cases per year [1]. PCa is an androgen-driven disease, and the natural Feng Qu and Yue Gu contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00901-w) contains supplementary material, which is available to authorized users. * Ying Peng [email protected] 1
Department of Urology, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu 210008, People’s Republic of China
2
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, Jiangsu 210009, People’s Republic of China
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