A Novel Antiandrogen, Compound 30, Suppresses Castration-Resistant and MDV3100-Resistant Prostate Cancer Growth In Vitro and In Vivo

Abstract

Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inhibits androgen receptor (AR) activity in LNCaP cells, C4-2 cells, as well as MDV3100-resistant cell lines. Compared with MDV3100, Compound 30 treatment induces greater reduction in AR, prostate-specific antigen (PSA), and AR transcriptional activity, and prevents AR nuclear translocation in AR-sensitive LNCaP cells. Compound 30 has antiproliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100-resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100-resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors. Mol Cancer Ther; 12(5); 567–76. ©2013 AACR.

Selectively Targeting the DNA-binding Domain of the Androgen Receptor as a Prospective Therapy for Prostate Cancer

“…twice daily could be tolerated by the mice with no decrease in body weight over a total duration 4 weeks. The in vivo screening for tumor growth inhibition was initially performed using our previously established castration-resistant tumor xenograft model (37)(38)(39)(40) in castrated hosts (41,42). Post-castration, animals were monitored for regrowth of LNCaP tumors and precastration levels of serum PSA, at which point the mice were treated with compound VPC-14449 (100 mg/kg) or enzalutamide (10 mg/kg) twice daily.…”

Anticancer Activity of a Novel Selective CYP17A1 Inhibitor in Preclinical Models of Castrate-Resistant Prostate Cancer

“…MR49C and MR49F cells were derived from LNCaP cells through serial xenograft passage in ENZ-treated mice as described previously (14). All cell lines were treated in RPMI 1640 in 10% charcoalstripped serum (CSS; Hyclone), with 10 mmol/L ENZ present in the media of MR49C and MR49F cells.…”

“…The objective of this study was to evaluate the anticancer activity of VT-464 compared with abiraterone (ABI) in preclinical models of CRPC, particularly in the enzalutamide (ENZ)-resistant cell lines because preliminary clinical reports indicate that ABI is less effective in patients with a prior ENZ history (12,13). We used both a CRPC cell line model (C4-2) and two previously reported (14) ENZ-resistant cell lines (MR49C, MR49F) to model advanced disease responses to this novel inhibitor and to ABI in vitro and in vivo.…”

Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer

“…1C), VPC-3022 exhibit profound concentration-dependent suppression of cell survival, especially with those that have resistance to the current antiandrogen enzalutamide. Although the particular mechanism(s) of MDV3100-resistance in these cell lines has not yet been clearly elucidated, it involves retention of the androgen receptor and no additional receptor mutations (23). More specifically, at a concentration of 1.5 mmol/L, VPC-3022 inhibited the cell proliferation of MDV3100-resistant cells by almost 100% and LNCaP cells by 50%, but only a small effect was observed on androgen receptor-negative PC3 cells.…”

“…HeLa-AR cells, stably expressing wild-type androgen receptor, were grown in DMEM supplemented with 5% FBS. MDV3100-resistant LNCaP cells were provided by Dr. Zoubeidi (23), and were cultured in RPMI 1640 supplemented with 5% FBS and 10 mmol/L MDV3100. All cells were maintained at 37 C in 5% CO 2 .…”