Over-coming CRPC in highly metastatic PCa with a significant low
administering dose.
Abstract BACKGROUND AND PURPOSETargeting AR-DBD is a potential strategy toward the treatment of CRPC,
however, rational design of a small molecules targeting AR-DBD is still
under development.EXPERIMENTAL APPROCAHMST, ITC and other different assays has been used to confirm the binding
of SBF-1 to AR, also CHIP has been used to confirm the blockade of AR
binding to its target genes. The associated signaling pathway affected
by SBF-1 has been identified by western blotting. Also, mutant AR-LBD
and the AR lacking DBD has led to the identification of the SBF-1
binding location in the AR.KEY RESULTSSBF-1 induced apoptosis and cell cycle arrest in both LNCaP and PC3/AR+
cell lines, also, inhibited the activation of the AR/IGF-1 and
IGF1/AKT/FOXO1/PNCA pathways, which evidenced by decreased expression of
p-AR, IGF-1, p-AKT, PCNA and Bcl-2. By using multiple methods, we found
that SBF-1 could directly bind to AR and block the transcription of its
target genes. Moreover, the interaction between SBF-1 and AR-DBD was
confirmed, which overcame the re-activation of AR signaling by mutations
in the AR-LBD. In the xenograft models of both ARWT and ARmutant
prostate cancer, SBF-1 displayed a strong efficacy at very low doses
including the inhibition of tumor growth, prolongation of survival time
by inhibiting AR signaling.CONCLUSION AND IMPLICATIONSOur study here found a novel identified inhibitor of AR, SBF-1, for the
first time, which is different from the current antiandrogens and may
serve as a leading compound for the treatment of prostate cancer.KEY WORDS: Prostate cancer; SBF-1; androgen receptor; androgen
receptor mutation; DNA binding domain, and ligand binding domain.Abbreviations: AR, androgen receptor; LBD, ligand binding
domain; DBD, DNA binding domain; CRPC, castration resistant prostate
cancer; IGF-1, insulin like growth factor 1.