UBC Theses and Dissertations
Inhibition of castration resistant prostate cancer by sintokamide A : an antagonist of the amino-terminus of the androgen receptor Tavakoli, Iran
The majority of lethal castration resistant prostate cancer(CRPC)is considered to involve a transcriptionally active androgen receptor (AR). All current therapies target AR ligand-binding domain (LBD) to inhibit receptor activity. Unfortunately these therapies fail perhaps b mechanisms involving expression of constitutively active AR splice variants that lack LBD and/or de nove androgen synthesis. Recent studies have provided evidence that R N-terminus domain (NTD is druggable with the development of EPI-OO1, antagonist that has specificity and efficacy on CRPC xenografts. Here we reveal an unrelated class of compounds, SINT1 as potent therapeutic agent fr CRPC that targets NTD. To examine the effects of SINT1 on AR transcriptional activity, endogenous gene expression and reporter constructs regulated by AR were examined. The ability of SINT1 to directly inhibit transactivation of the NTD was tested using a chimera of NTD fused to the GA14DBD. Reporter assays for glucocorticoid (GR) and progesterone receptor (PR) were measured to ensure specificity. Combination study of SINT1 and EPI-002 was performed by measuring AR transcriptional activity. BrdU incorporation was analyzed to indicate changes in proliferation. Effect of SINT1 on AR N/C interaction was assessed using a 2-hybrid assay. Animals bearing LNCaP xenografts were castrated and randomized into two groups. One week after castration, the animals were treated every 3 days with an intratumoral dose of aSINT1 (30 MG/KG) or vehicle. SINT1: blocked AR activity as measured by reduction in PSA mRNA and reporter activity induced by androgen; reduced transactivation of AR NTD to baseline levels; had no effects on transcriptional activities of related steroid receptors; was effective in blocking androgen-induced proliferation in LNCaP cells but not PC3 cells; caused an increase in caspase-3/7 activity; showed an additive inhibitory effect to EPI-002; reduced AR N/C interactive; regressed some CRPC xenografts with no change in animal body weight compared to DMSO-treated tumors. Together these data support that SINT1 is a specific inhibitor of the AR NTD without effects on highly related steroid hormone receptors and no apparent toxicity in animals. SINT1 is an antagonist to AR NTD that causes regression of CRPC xenografts.
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