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
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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