Figure 8.

EPI-045 has antitumor activity in LNCaP-RAL^R xenografts. (A) LNCaP and LNCaP-RAL^R tumor growth in castrated mice treated every other day with ralaniten (50 mg/kg), EPI-045 (50 mg/kg), or vehicle. To reduce first pass metabolism and hepatic mediated glucuronidation, drugs were administered by tail vein injection. Tumors were harvested 2 days after last treatment. Data presented as mean ± SEM and analyzed by two-way ANOVA with Tukey’s test applied post hoc. (B) Representative photographs of LNCaP-RAL^R tumors. Scale bars: 10 mm. (C) Body weight change over the course of the experiment. n = 10 (VEH), n = 11 (EPI-045), n = 4 (RAL). (D) IHC from LNCaP-RAL^R tumors showing AR, UGT2B15, Ki67, and TUNEL counterstained with DAPI. (E) Quantification of proliferative and apoptotic indices from tumors. Data presented as mean ± SEM and represents three sections from three different tumors per treatment group. Ki67:2732 (vehicle); 2514 (ralaniten); and 2619 (EPI-045) cells in total were counted. For TUNEL staining, 3123 (vehicle), 3538 (ralaniten), and 3400 (EPI-045) cells were counted. (F) Real-time PCR of AR, PSA, FKBP5, and RHOU transcript normalized to SDHA harvested from LNCaP-RAL^R tumors. Data presented as mean ± SEM and analyzed by two-way ANOVA with Dunnett’s test applied post hoc (n = 8 tumors/sample except RAL, n = 7). *p < 0.05; **p < 0.01; ^#p < 0.0001; n.s., not significant. RAL, ralaniten; VEH, vehicle.