Novel daidzein molecules exhibited anti-prostate cancer activity through nuclear receptor ERβ modulation, in vitro...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Prostate cancer remains a significant health concern with limited effective treatments.
• Daidzein, a soy isoflavone, exhibits anti-cancer properties but lacks specificity.
• Selective estrogen receptor beta (ERβ) modulators are being explored for targeted cancer therapy.

Purpose of the Study:

• To synthesize novel daidzein analogues with enhanced ERβ selectivity.
• To evaluate the anti-cancer efficacy of these analogues against prostate cancer cell lines and in vivo models.
• To elucidate the underlying mechanisms of their anti-cancer activity.

Main Methods:

• Synthesis of eight novel daidzein analogues (NCE1-8).
• In vitro assays: cytotoxicity, receptor binding, luciferase assay, gene expression (cMYC, Cyclin D1), and caspase activity (3, 8, 9).
• In vivo studies: uterotropic, anti-androgenic, and anti-tumour activity in rodent models.

Main Results:

• NCEs demonstrated significant anti-prostate cancer activity in DU145, LNCaP, and PC3 cell lines, exceeding genistein's efficacy by 50%.
• NCEs significantly down-regulated cMYC and Cyclin D1 expression and elevated caspase 3 and 9 levels.
• NCE 1 and 2 exhibited ERβ selectivity; specific methyl substitutions on daidzein enhanced ERβ selectivity and anti-tumour effects without affecting uterotropic or anti-androgenic activities.

Conclusions:

• Novel daidzein analogues (NCEs) possess potent and selective anti-prostate cancer properties.
• The anti-cancer mechanism involves ERβ modulation, downregulation of oncogenes, and induction of apoptosis.
• NCEs with specific methyl substitutions are promising lead compounds for developing novel prostate cancer therapeutics.