GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression
Abstract
Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer. Degarelix (Firmagon), a gonadotropin-releasing hormone (GnRH) receptor antagonist differs from luteinizing hormone-releasing hormone (LHRH) agonists by avoiding “testosterone flare” and lower follicle-stimulating hormone (FSH) levels. The direct effect of degarelix and leuprolide on human prostate cancer cells was evaluated. In LNCaP, C4-2BMDVR, and CWR22Rv1 cells, degarelix significantly reduced cell viability compared with the controls (P ≤ 0.01). Leuprolide was stimulatory in the same cell lines. In C4-2B MDVR cells, degarelix alone or combined with abiraterone or enzalutamide reduced the AR-V7 protein expression compared with the control group. SCID mice bearing VCaP xenograft tumors were divided into 4 groups and treated with surgical castration, degarelix, leuprolide, or buffer alone for 4 weeks. Leuprolide slightly suppressed tumor growth compared with the vehicle control group (P > 0.05). Tumors in degarelix-treated mice were 67% of those in the leuprolide-treatment group but 170% larger than in surgically castrated ones. Measurements of intratumoral steroids in serum, tumor samples, or treated cell pellets by LC/MS confirmed that degarelix better decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration, whereas leuprolide had no inhibitory effect. Collectively, our results suggested a selective mechanism of action of degarelix against androgen steroidogenesis and AR-variants. This study provides additional molecular insights regarding the mechanism of degarelix compared with GnRH agonist therapy, which may have clinical implications.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 01, 2019
- Source ID
- 10.1158/1535-7163.mct-18-1337
Entities
People
- Allen C Gao
- Chengfei Liu
- Christopher P Evans
- Emma S. Tomlinson Guns
- Hans H. Adomat
- Joy C. Yang
- Martin E. Gleave
- Vito Cucchiara
Organizations
- Ferring Pharmaceuticals (Switzerland)
- United States Department of Defense
- University of British Columbia
- University of California, Davis