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

Martina Tassinari, Graziella Cimino-Reale, Matteo Nadai, Filippo Doria, Elena Butovskaya, Marta Recagni, Mauro Freccero, Nadia Zaffaroni, Sara N Richter, Marco Folini

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)8625-8638
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number19
Publication statusPublished - Oct 11 2018


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