A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R–3327G and anabolic activity on skeletal muscle mass & function in castrated mice

Autor: Azriel Schmidt, Michael Chisamore, Carlo J. Gambone, Gregory Michael Dillon, Stephen E. Alves, Matthew Baran, Sean Riley, Michael A. Gentile, Osvaldo A. Flores, Hilary A. Wilkinson
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
medicine.medical_specialty
medicine.drug_class
Endocrinology
Diabetes and Metabolism
Clinical Biochemistry
Antineoplastic Agents
Biochemistry
Androgen deprivation therapy
Mice
03 medical and health sciences
Prostate cancer
Anabolic Agents
0302 clinical medicine
Endocrinology
Prostate
Internal medicine
medicine
Animals
Humans
Testosterone
Orchiectomy
Muscle
Skeletal
Molecular Biology
business.industry
Carcinoma
Prostatic Neoplasms
Androgen Antagonists
Cell Biology
Androgen
medicine.disease
Xenograft Model Antitumor Assays
Androgen receptor
Ki-67 Antigen
030104 developmental biology
medicine.anatomical_structure
Selective androgen receptor modulator
Chemotherapy
Adjuvant
Receptors
Androgen
Azasteroids
030220 oncology & carcinogenesis
Molecular Medicine
Carbamates
business
Zdroj: The Journal of Steroid Biochemistry and Molecular Biology. 163:88-97
ISSN: 0960-0760
Popis: The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT which may provide potent anti-androgenic activity at the prostate yet protective activity on skeletal muscle and behavior in patients.
Databáze: OpenAIRE
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