Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.
نویسندگان
چکیده
Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. EPI-001 interacted with the AF-1 region, inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity.
منابع مشابه
P-84: Characterization of Androgen Receptor Structure and Nucleocytoplasmic Shuttling of the Rice Field Eel
Background: Androgen receptor (AR) plays a critical role in prostate cancer and male sexual differentiation.Mechanisms by which AR acts and regulations of AR nucleocytoplasmic shuttling are not understood well. Materials and Methods: Degenerate PCR and RACE Cloning of AR Gene; Phylogenetic Analysis and Molecular Modeling;Real-time Fluorescent Quantitative RT-PCR; Northern Blot Hybridization;In ...
متن کاملInhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer
Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown tha...
متن کاملQSAR Study of 17β-HSD3 Inhibitors by Genetic Algorithm-Support Vector Machine as a Target Receptor for the Treatment of Prostate Cancer
The 17β-HSD3 enzyme plays a key role in treatment of prostate cancer and small inhibitorscan be used to efficiently target it. In the present study, the multiple linear regression (MLR),and support vector machine (SVM) methods were used to interpret the chemical structuralfunctionality against the inhibition activity of some 17β-HSD3inhibitors. Chemical structuralinformation were described thro...
متن کاملPI3K and mTOR inhibitor, NVP-BEZ235, is more toxic than X-rays in prostate cancer cells
Background: Radiotherapy and adjuvant androgen deprivation therapy have historically been the first treatment choices for prostate cancer but treatment resistance often limits the capacity to effectively manage the disease. Therefore, alternative therapeutic approaches are needed. Here, the efficacies of radiotherapy and targeting the pro-survival cell signaling components epidermal growth fact...
متن کاملWOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer.
Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This is effective in the majority of patients, but inevitably resistance develops and patients progress to life-threatening metastatic disease - hence the quest for new effective therapies for 'castrate-resistant' prostate cancer (CRPC). Studies into what pathways can drive tumour recurrence under these conditions...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Cancer cell
دوره 17 6 شماره
صفحات -
تاریخ انتشار 2010