Down-Regulation of the Androgen Receptor by G‑Quadruplex Ligands Sensitizes Castration-Resistant Prostate Cancer Cells to Enzalutamide

Stabilization of the G-quadruplexes
(G4s) within the androgen receptor
(AR) gene promoter to block transcription may represent an innovative
approach to interfere with aberrant AR signaling in castration resistant
prostate cancer (CRPC). A library of differently functionalized naphthalene
diimides (NDIs) was screened for their ability to stabilize AR G4s:
the core-extended NDI (7) stood out as the most promising
ligand. AR-positive cells were remarkably sensitive to 7 in comparison to AR-negative CRCP or normal prostate epithelial
cells; 7 induced remarkable impairment of AR mRNA and
protein amounts and significant perturbations in the expression levels
of KLK3 and of genes involved in the activation of AR program via
feedback mechanisms. Moreover, 7 synergistically interacted
with Enzalutamide, an inhibitor of AR signaling used in second-line
therapies. Overall, our data show that stabilization of AR G4s may
represent an alternative treatment options for CRPC and other malignancies
relying on aberrant androgen signaling.