Ailanthone: a new potential drug for castration-resistant prostate cancer
Author(s): Shihong Peng1 , Zhengfang Yi1 and Mingyao Liu1,2
Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castration-resistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens . Mechanisms of CRPC progression include AR amplification and overexpression , AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (AR-Vs) , and induction of intracrine androgen metabolic enzymes . Current anti-androgen therapies including MDV3100 (Enzalutamide) and abiraterone have focused on the androgen-dependent activation of AR through its ligand-binding domain (LBD), but do not provide a continuing clinical benefit for patients with CRPC and presumably fail due to multiple mechanisms including the expression of AR-Vs lacking the LBD . These AR-Vs signal in the absence of ligand and are therefore resistant to LBD-targeting AR antagonists or agents that repress androgen biosynthesis .
To identify compounds that block the transcriptional activities of both ligand-dependent full-length AR (AR-FL) and AR-Vs, we used the MMTV-luciferase (MMTV-luc) reporter system that contains AR-binding elements  to screen approximately 100 compounds from a library of natural compounds from Traditional Chinese Medicine and identified a small-molecule compound termed ailanthone, which is extracted from the whole seedlings of Ailanthus altissima (Simaroubaceae) that has antimalarial and antitumor activities . In our work recently reported in the paper entitled "Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer" in Nature Communications , ailanthone not only blocked the ligand-induced activities of full-length AR but also inhibited AR-V which lacks the LBD at low concentrations (AR-FL half maximal inhibitory concentration [IC50 ] = 69 nmol/L, 95% confidence interval [CI] = 53-89 nmol/L; AR1-651 [a constructed AR splice variant] IC50 = 309 nmol/L, 95% CI = 236-687 nmol/L in 22RV1 cells). Ailanthone decreased the androgen-dependent induction of endogenous AR downstream genes PSA , TMPRSS2 , FKBP5 , SLC45A3 , and NDRG1 mRNA expression in LNCaP cells. To investigate whether ailanthone suppressed the functioning of AR-V...
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