Summary
Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G1 cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.
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We acknowledge the assistance of Ellen Kroc and animal facility staff and Todd Schuster of Shared Instruments Core facility for help with flow cytometric analyses. We thank Dr. Margret Weis for extensive copy editing of the manuscript during revision.
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National Center for Complementary and Alternative Medicine AT 005383, University of Minnesota Cancer Center Breast Cancer Seed grant CON000000015215, Korea Science and Engineering Foundation (KOSEF) grant No. 2011–0006220.
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Zhang, Y., Shaik, A.A., Xing, C. et al. A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo . Invest New Drugs 30, 1820–1829 (2012). https://doi.org/10.1007/s10637-011-9738-x
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DOI: https://doi.org/10.1007/s10637-011-9738-x