The androgen receptor pathway plays a central role in growth and survival of CRPC. The first line of treatment of androgen-dependent prostate cancer is the use of androgen-deprivation therapy. Bicalutamide is used as a second line treatment option for patients who fail androgen-deprivation therapy. Unfortunately, patients will also develop a resistance to bicalutamide treatment. The investigators have previously identified that andrographolide can suppress tumor growth of prostate cancer cells by screening compounds from the Natural Compound Library.
LNCaP and C4-2 cells were treated with either bicalutamide or andrographolide in FBS or charcoal-stripped FBS conditions. Cell growth was determined and the levels of AR expression were measured by qRT-PCR and Western blots. The effects on PSA and NKX3.1 were also examined by ELISA and luciferase reporter assays. AR nuclear translocation was examined by immunofluorescence assays. The effects of andrographolide on the recruitment of AR to the androgen responsive genes were examined by Chromatin Immunoprecipitation (ChIP) Assays.
They identified andrographolide, a diterpenoid lactone isolated from a traditional Chinese and Indian medicinal plant Andrographis paniculata, which exhibit a wide spectrum of biological activities of therapeutic importance, to significantly inhibit prostate cancer cell growth and induce apoptosis. Andrographolide inhibited AR activity, such as inhibition of the expression of androgen-regulated genes (PSA and NKX3.1). It was also able to down regulate AR expression at both mRNA and protein levels and prevent its nuclear translocation. Andrographolide prevented the binding of Hsp90 to AR, resulting in proteasome-mediated AR degradation. Furthermore, andrographolide inhibited bicalutamide resistant C4-2 cell growth by reducing AR expression and activity. Combination of andrographolide with bicalutamide achieved synergistic effect in inhibition of C4-2 cell growth and AR expression.
Presented by Chengfei Liu, et al. at the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA
Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.