Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells
Autor: | William J. Ray, Chang Bai, Stephen E. Alves, Tara E. Cusick, Brenda L Pennypacker, Evan E. Opas, Michael J. Chisamore, Carlo J. Gambone, Damien Ferraro, David J. Bettoun, Azriel Schmidt, Hilary A. Wilkinson, Angela Scafonas, Michael A. Gentile, Osvaldo A. Flores, Paul Hodor, Meissner Robert S, James J. Perkins |
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Rok vydání: | 2014 |
Předmět: |
Male
Endocrinology Diabetes and Metabolism Clinical Biochemistry Apoptosis urologic and male genital diseases Antiandrogen Biochemistry Rats Sprague-Dawley Mice Prostate cancer Anabolic Agents Endocrinology Tumor Cells Cultured Combinatorial Chemistry Techniques Reverse Transcriptase Polymerase Chain Reaction Chemistry Prostatic Neoplasms Castration-Resistant Receptors Androgen Androgens Molecular Medicine Female medicine.drug medicine.medical_specialty Bicalutamide medicine.drug_class Blotting Western Breast Neoplasms Real-Time Polymerase Chain Reaction DU145 Internal medicine LNCaP Androgen Receptor Antagonists medicine Animals Humans RNA Messenger Molecular Biology Cell Proliferation Prostatic Neoplasms Cell Biology medicine.disease Androgen Rats Mice Inbred C57BL Androgen receptor Selective androgen receptor modulator Azasteroids Cancer research Carbamates |
Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 143:29-39 |
ISSN: | 0960-0760 |
Popis: | Prostate cancer (PCa) initially responds to inhibition of androgen receptor (AR) signaling, but inevitably progresses to hormone ablation-resistant disease. Much effort is focused on optimizing this androgen deprivation strategy by improving hormone depletion and AR antagonism. However we found that bicalutamide, a clinically used antiandrogen, actually resembles a selective AR modulator (SARM), as it partially regulates 24% of endogenously 5α-dihydrotestosterone (DHT)-responsive genes in AR(+) MDA-MB-453 breast cancer cells. These data suggested that passive blocking of all AR functions is not required for PCa therapy. Hence, we adopted an active strategy that calls for the development of novel SARMs, which induce a unique gene expression profile that is intolerable to PCa cells. Therefore, we screened 3000 SARMs for the ability to arrest the androgen-independent growth of AR(+) 22Rv1 and LNCaP PCa cells but not AR(-) PC3 or DU145 cells. We identified only one such compound; the 4-aza-steroid, MK-4541, a potent and selective SARM. MK-4541 induces caspase-3 activity and cell death in both androgen-independent, AR(+) PCa cell lines but spares AR(-) cells or AR(+) non-PCa cells. This activity correlates with its promoter context- and cell-type dependent transcriptional effects. In rats, MK-4541 inhibits the trophic effects of DHT on the prostate, but not the levator ani muscle, and triggers an anabolic response in the periosteal compartment of bone. Therefore, MK-4541 has the potential to effectively manage prostatic hypertrophic diseases owing to its antitumor SARM-like mechanism, while simultaneously maintaining the anabolic benefits of natural androgens. |
Databáze: | OpenAIRE |
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