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Novel Steroid Receptor Phyto-Modulator Compound A Inhibits Growth and Survival of Prostate Cancer Cells

Departments of ¹ Dermatology and ² Obstetrics and Gynecology, Northwestern University, Chicago, Illinois and ³ Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Irina Budunova, Department of Dermatology, Northwestern University, Ward Building 9-332, 303 East Chicago Avenue, Chicago, IL 60611. Phone: 312-503-4679; Fax: 312-503-4325; E-mail: i-budunova{at}northwestern.edu.

Key Words: androgen receptor • glucocorticoid receptor • selective glucocorticoid receptor modulator • prostate cancer • apoptosis • growth

Androgen receptor (AR)– and glucocorticoid receptor (GR)– mediated signaling play opposite roles in prostate tumorigenesis: AR promotes prostate carcinoma (PC) development, whereas GR acts as a tumor suppressor. Compound A (CpdA) is a stable analogue of an aziridine precursor from the African shrub Salsola tuberculatiformis Botschantzev. It was shown recently that, in model cells, CpdA inhibits AR function and strongly enhances anti-inflammatory function of GR. We determined the effects of CpdA in prostate cells with different AR/GR status: (a) RWPE-1 cells (AR^low/GR^low), (b) PC3 and DU145 cells (GR⁺/AR^–), (c) LNCaP cells (GR^–/AR⁺), and (d) LNCaP-GR cells expressing both receptors. Similar to steroid hormones, CpdA induces nuclear translocation of both receptors in prostate cells. Despite this, CpdA inhibits DNA-binding and transactivation potential of AR. In addition, CpdA inhibits GR-mediated transactivation but induces GR transrepression via inhibition of several transcription factors, including nuclear factor-B, AP-1, Ets-1, Elk-1, SRF, CRE/ATF, and NFATc. CpdA strongly decreases growth and induces caspase-dependent apoptosis in highly malignant PC3 and DU145 cells and in other AR/GR-expressing PC cells. The cytostatic effect of CpdA is receptor dependent: down-regulation of GR or AR expression drastically attenuates CpdA-induced PC cell growth inhibition. Finally, virtual docking analysis indicates that CpdA shares binding cavities in AR and GR ligand-binding domains with corresponding hormones and forms hydrogen bonds (H-bond) with the same amino acids that are involved in H-bond formation during steroid binding. Overall, our data suggest that CpdA is a unique dual-target steroid receptor modulator that has a high potential for PC therapy. [Cancer Res 2008;68(12):4763–73]

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