Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7

Balaji Chandrasekaran, Ashish Tyagi, Uttara Saran, Venkatesh Kolluru, Becca V. Baby, Venkat R. Chirasani, Nikolay V. Dokholyan, Jyh M. Lin, Amandeep Singh, Arun K. Sharma, Murali K. Ankem, Chendil Damodaran

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3 Scopus citations

Abstract

We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.

Original languageEnglish (US)
Article number1137783
JournalFrontiers in Pharmacology
Volume14
DOIs
StatePublished - 2023

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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