Genomics

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Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer


ABSTRACT: Anti-androgen therapies including the new androgen receptor (AR) antagonist MDV3100 are the first therapeutic approach in treating prostate cancer (PCa). However, tumors frequently become castration resistant through multiple mechanisms including alternative expression of AR splice variants. To identify new inhibitors which block both full-length AR (AR-FL) and constitutively-active truncated AR splice variants (AR-Vs), a library of natural compounds was screened for molecules that could inhibit AR-driven transcription in PCa cells expressing AR-FL or AR-Vs. We identified the small-molecule Ailanthone (AIL) as a potent inhibitor of both AR-FL and AR-Vs. AIL down-regulates both AR itself and its target genes in PCa cell lines as well as orthotopic animal tumors. Moreover,AIL directly binds to the co-chaperone protein p23 and prevents AR’s interaction with HSP90, which results in the disruption of the AR-chaperone complex followed by Ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4. Meanwhile, overexpression of p23 dose-dependently rescued AIL-mediated cell proliferation inhibition, suggesting that p23 might be a critical target of AIL. Furthermore, treatment of MDV3100-resistant 22RV1 xenografts with AIL reduced tumor volume by 77.5% (2 mg/kg/day AIL, intraperitoneal) and 79.2% (5 mg/kg/day AIL, oral) compared with the control group. Finally, AIL possesses favorable drug-like properties such as good bioavailability (25.7% F), high solubility, lack of CYP inhibition, and low hepatotoxicity, although signs of gastrointestinal toxicity were observed at high doses. In conclusion, AIL overcomes MDV3100 resistance in castration resistant prostate cancer (CRPC) with excellent absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties, thus suggesting that AIL is a potential candidate for the clinical treatment of CRPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85541 | GEO | 2016/11/30

SECONDARY ACCESSION(S): PRJNA338761

REPOSITORIES: GEO

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