SAT-320 Candidate Compounds from a Plant Extract Library Exhibit Anti-Androgen Receptor Activity and Induce Cell Cycle Arrest in Prostate Cancer Cells

Abstract L.A. Dimaapi: None. R.G. Azur: None. P.D. Bagamasbad: None. Androgen deprivation therapy (ADT) remains to be the standard of care for prostate cancer (PCa). However, a fraction of patients undergoing ADT eventually become resistant to treatment. Resistance to ADT is attributed to several mechanisms such as androgen receptor (AR) point mutations, splice variants, or overexpression allowing PCa to further progress into a more aggressive state known as castration-resistant PCa (CRPC). In an effort to find novel AR antagonists that may circumvent CRPC, we previously screened plant extracts using a promoter-based luciferase reporter assay where we identified extract A32 to exhibit significant anti-AR activity without potent cytotoxicity. Using liquid chromatography-mass spectrometry analysis, we identified candidate compounds A32-40, A32-42, and A42-46 which contribute to the ability of A32 to suppress AR activity similar to the known AR antagonists. To elucidate the molecular basis for the anti-AR activity of the candidate compounds, we conducted RNA-sequencing analysis in LNCaP cells treated with DHT, DHT with AR antagonist enzalutamide as a positive control, and DHT plus the candidate compounds. The sequencing reads were processed and mapped to the human genome to quantitate gene expression. Differentially expressed genes (DEGs) with respect to the DHT only treatment were identified for each treatment group. Gene ontology (GO) analysis of the DEGs revealed that enzalutamide and all the candidate compounds similarly downregulate genes related to cell cycle control, cell division, DNA replication, and chromatin organization. Additionally, compound A32-46 appears to downregulate genes that function in neddylation, a process that is upregulated in PCa tumors. To support findings of our GO analysis, gene set enrichment analysis (GSEA) was also performed where we found enzalutamide and all the candidate compounds had lower enrichment for genes involved in cell cycle progression and cell proliferation with respect to the DHT-treated cells. Overall, this study highlights the potential of these compounds to be further developed as therapeutics for PCa. Saturday, June 1, 2024