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

Abstract

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
Volume61
Issue number19
DOIs
Publication statusPublished - Oct 11 2018

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G-Quadruplexes
Castration
Androgen Receptors
Prostatic Neoplasms
Down-Regulation
Ligands
MDV 3100
Androgens
Genes
Libraries
Prostate
Epithelial Cells

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Down-Regulation of the Androgen Receptor by G-Quadruplex Ligands Sensitizes Castration-Resistant Prostate Cancer Cells to Enzalutamide. / Tassinari, Martina; Cimino-Reale, Graziella; Nadai, Matteo; Doria, Filippo; Butovskaya, Elena; Recagni, Marta; Freccero, Mauro; Zaffaroni, Nadia; Richter, Sara N; Folini, Marco.

In: Journal of Medicinal Chemistry, Vol. 61, No. 19, 11.10.2018, p. 8625-8638.

Research output: Contribution to journalArticle

Tassinari, Martina ; Cimino-Reale, Graziella ; Nadai, Matteo ; Doria, Filippo ; Butovskaya, Elena ; Recagni, Marta ; Freccero, Mauro ; Zaffaroni, Nadia ; Richter, Sara N ; Folini, Marco. / Down-Regulation of the Androgen Receptor by G-Quadruplex Ligands Sensitizes Castration-Resistant Prostate Cancer Cells to Enzalutamide. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 19. pp. 8625-8638.
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abstract = "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.",
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T1 - Down-Regulation of the Androgen Receptor by G-Quadruplex Ligands Sensitizes Castration-Resistant Prostate Cancer Cells to Enzalutamide

AU - Tassinari, Martina

AU - Cimino-Reale, Graziella

AU - Nadai, Matteo

AU - Doria, Filippo

AU - Butovskaya, Elena

AU - Recagni, Marta

AU - Freccero, Mauro

AU - Zaffaroni, Nadia

AU - Richter, Sara N

AU - Folini, Marco

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AB - 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.

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