Novel steroid receptor phyto-modulator compound a inhibits growth and survival of prostate cancer cells.

Abstract

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-kappaB, 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.

• Authors: Alexander Yemelyanov, Jennifer Czwornog, Lajos Gera, Sonali Joshi, Robert T Chatterton Jr, Irina Budunova
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 12 Pg. 4763-73 (Jun 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18559523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine
• AR protein, human
• Acetates
• Androgen Antagonists
• Androgens
• Ethylamines
• RNA, Small Interfering
• Receptors, Androgen
• Receptors, Glucocorticoid
• Transcription Factors
• Luciferases
• Prostate-Specific Antigen
• Tyramine

Topics

• Acetates (chemical synthesis, pharmacology)
• Androgen Antagonists (pharmacology)
• Androgens (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Proliferation (drug effects)
• Colony-Forming Units Assay
• Electrophoretic Mobility Shift Assay
• Ethylamines (chemical synthesis, pharmacology)
• Humans
• Hydrogen Bonding
• Luciferases (metabolism)
• Male
• Prostate-Specific Antigen (metabolism)
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• RNA, Small Interfering (pharmacology)
• Radioligand Assay
• Receptors, Androgen (genetics, metabolism)
• Receptors, Glucocorticoid (agonists, genetics, metabolism)
• Transcription Factors (antagonists & inhibitors, metabolism)
• Transcription, Genetic
• Transcriptional Activation
• Transfection
• Tumor Cells, Cultured
• Tyramine (analogs & derivatives)