Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells.

Abstract

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 AR-negative 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 AR-positive PCa cells that enhance the cellular sensitivity to proxalutamide.

• Authors: Feng Qu, Yue Gu, Qizhi Wang, Mingzhe He, Fang Zhou, Jianguo Sun, Guangji Wang, Ying Peng
• Journal: Investigational new drugs (Invest New Drugs) Vol. 38 Issue 5 Pg. 1292-1302 (10 2020) ISSN: 1573-0646 [Electronic] United States
• PMID: 32008178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Androgen Receptor Antagonists
• Anilides
• Benzamides
• Nitriles
• Nucleosides
• Oxazoles
• Thiohydantoins
• Tosyl Compounds
• Phenylthiohydantoin
• enzalutamide
• bicalutamide
• Glutathione
• proxalutamide

Topics

• Amino Acids (metabolism)
• Androgen Receptor Antagonists (pharmacology)
• Anilides (pharmacology)
• Benzamides (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Glutathione (metabolism)
• Humans
• Male
• Metabolome (drug effects)
• Metabolomics
• Nitriles (pharmacology)
• Nucleosides (metabolism)
• Oxazoles (pharmacology)
• Phenylthiohydantoin (pharmacology)
• Prostatic Neoplasms, Castration-Resistant (metabolism)
• Thiohydantoins (pharmacology)
• Tosyl Compounds (pharmacology)