Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells.
Invest New Drugs
; 39(2): 442-457, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33411211
ABSTRACT
Prostate cancers are reliant on androgens for growth and survival. Clinicians and researchers are looking for potent treatments for the resistant forms of prostate cancer; however, a handful of small molecules used in the treatment of castration-resistant prostate cancer have not shown potent effects owing to the mutations in the AR (Androgen Receptor). We used SBF-1, a well-characterized antitumor agent with potent cytotoxic effects against different kinds of cancers and investigated its effect on human prostate cancer. SBF-1 substantially inhibited the proliferation, induced apoptosis, and caused cell cycle arrest in LNCaP and PC3/AR+ prostate cancer cell lines. SBF-1 inhibited the activation of the IGF-1-PNCA pathway, as demonstrated by decreased expression of IGF-1 (insulin-like growth factor 1), proliferating cell nuclear antigen (PCNA), and its downstream Bcl-2 protein. Using microscale thermophoresis (MST) and isothermal titration calorimetry (ITC) assays, we observed a direct binding of SBF-1 to the AR. SBF-1 binds to the AR-DBD (DNA-binding domain) and blocks the transcription of its target gene. SBF-1 demonstrated a potent antitumor effect in vivo; it inhibited AR signaling and suppressed tumor growth in animals. Our study suggests that SBF-1 is an inhibitor of the AR and might be used in the treatment of prostate cancer.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Saponinas
/
Receptores Androgênicos
/
Colestenonas
/
Proteínas de Ligação a DNA
/
Antagonistas de Androgênios
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article