Overcoming Docetaxel Resistance in Prostate Cancer by Targeting Cell Cycle Progression with Narciclasine-Based Compounds.

Development of resistance to taxane-based chemotherapy, specifically docetaxel (DTX), in advanced prostate cancer is frequent. Natural compounds, such as narciclasine, an alkaloid derived from plants, offer a potentially advantageous approach. Docetaxel-resistant prostate cancer cell lines (DU145RST and PC3RST) were established and treated with narciclasine (1) and its derivatives, narciclasine-3,4-acetonide (1a) and 7-deoxynarciclasine (1b), and evaluated for cytotoxicity, cell proliferation, cell cycle progression, clonogenicity, and 3D spheroid growth. In silico target prediction was undertaken employing PharmMapper, and the molecular pathways involved in resistance were confirmed by western blot. The resistant cell lines showed an increase in IC50 values above 6 nM in DU145RST and 4 nM in PC3RST of docetaxel; molecular alterations included increased mTOR and S6 signaling pathways. Narciclasine-based compounds decreased cell viability within both sensitive and resistant lines, interestingly displaying increased potency in the resistant sublines alongside minimal toxicity in nontumorigenic cell types. Cell cycle assessments unraveled G2/M arrest, particularly in the resistant model, a decline in clonogenic capacity, 3D spheroid fragmentation, and reduced viability. The in silico analysis identified CDK2, alongside cyclin A2, as targets, which certainly bolsters findings of cell cycle abrogation. Reduced concentrations of both CDK2 and cyclin A2 confirm the observed effects. Overall, the tested compounds 1, 1a, and 1b exhibited potent and selective antitumor activity in docetaxel-resistant prostate cancer models by impairing proliferation and inducing cell cycle arrest. Therefore, these compounds represent promising candidates to overcome taxane resistance through modulation of cell cycle regulators such as CDK2 and cyclin A2.