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GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression.
Mol Cancer Ther 2019; 18(10):1811-1821MC

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.

Authors+Show Affiliations

Department of Urologic Surgery, University of California at Davis, Sacramento, California.Department of Urologic Surgery, University of California at Davis, Sacramento, California.Department of Urologic Surgery, University of California at Davis, Sacramento, California.Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.Department of Urologic Surgery, University of California at Davis, Sacramento, California. UC Davis Comprehensive Cancer Center, University of California at Davis, Sacramento, California.Department of Urologic Surgery, University of California at Davis, Sacramento, California. cpevans@ucdavis.edu. UC Davis Comprehensive Cancer Center, University of California at Davis, Sacramento, California.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31341032

Citation

Cucchiara, Vito, et al. "GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression." Molecular Cancer Therapeutics, vol. 18, no. 10, 2019, pp. 1811-1821.
Cucchiara V, Yang JC, Liu C, et al. GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression. Mol Cancer Ther. 2019;18(10):1811-1821.
Cucchiara, V., Yang, J. C., Liu, C., Adomat, H. H., Tomlinson Guns, E. S., Gleave, M. E., ... Evans, C. P. (2019). GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression. Molecular Cancer Therapeutics, 18(10), pp. 1811-1821. doi:10.1158/1535-7163.MCT-18-1337.
Cucchiara V, et al. GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression. Mol Cancer Ther. 2019;18(10):1811-1821. PubMed PMID: 31341032.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression. AU - Cucchiara,Vito, AU - Yang,Joy C, AU - Liu,Chengfei, AU - Adomat,Hans H, AU - Tomlinson Guns,Emma S, AU - Gleave,Martin E, AU - Gao,Allen C, AU - Evans,Christopher P, Y1 - 2019/07/24/ PY - 2018/12/12/received PY - 2019/03/28/revised PY - 2019/07/23/accepted PY - 2019/7/26/pubmed PY - 2019/7/26/medline PY - 2019/7/26/entrez SP - 1811 EP - 1821 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 18 IS - 10 N2 - 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. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/31341032/GnRH_Antagonists_Have_Direct_Inhibitory_Effects_On_Castration-Resistant_Prostate_Cancer_Via_Intracrine_Androgen_and_AR-V7_Expression L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=31341032 DB - PRIME DP - Unbound Medicine ER -