Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for castration-resistant prostate cancer (CRPC). Unfortunately, although ADT initially prolongs survival, most patients relapse and develop resistance. Clinical failure of these treatments in CRPC highlights the urgent need to develop novel strategies to more effectively block androgen receptor (AR) signaling and target other oncogenic factors responsible for ADT resistance.
Methods: We developed a small-molecule compound LG1836 and investigated the in vitro and in vivo activity of LG1836 against CRPC in cellular and animal models.
Results: LG1836 exhibits potent in vitro cytotoxicity in CRPC cells. Mechanistic studies demonstrated that LG1836 inhibits the expression of AR and AR variant 7, partially mediated via proteasome-dependent protein degradation. LG1836 also suppresses survivin expression and effectively induces apoptosis in CRPC cells. Significantly, as a single agent, LG1836 is therapeutically efficacious in suppressing the in vivo growth of CRPC in the subcutaneous and intraosseous models and extends the survival of tumor-bearing mice.
Conclusions: These preclinical studies indicate that LG1836 is a promising lead compound for the treatment of CRPC.
Keywords: androgen receptor; bone metastasis; castration-resistant prostate cancer; small-molecule therapy; survivin.
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