Dicentrine and its N-oxide derivatives induces apoptotic and necrotic cell death in prostate cancer cell lines

Abstract

As part of our continuous research for the discovery of anticancer natural products, the effects of alkaloid (6aS)-dicentrine (1) and its respective (6aS,6S)- (1a) and (6aS,6R)-(1b) N-oxides against two prostate cancer cell lines (PC3 and DU145) were evaluated for the first time. Alkaloid 1 exhibited IC₅₀ values of 18.43 and 23.53 μM for both tested cells. On the other hand, 1a demonstrated higher IC₅₀ values (46.36 and 33.85 μM) whereas 1b displayed reduced activity (IC₅₀ > 50 μM) for both cells. These results suggest that the stereochemistry of the N-oxide moiety plays an important role in the antitumor activity. Molecular docking indicated differential residue interactions between compounds 1, 1a, and 1b with EGFR and TP53 which could result in their differential modulation. Alkaloid 1 induced strong necrotic and apoptotic cell death in all tested cell lines, while 1a caused reduced necrotic and apoptotic cell death in PC3, a TP53-null cell line, moderate necrotic cell death in DU145, a mutant TP53 cell line, and strong necrotic death in HEK293, an embryonic kidney cell line with wild-type TP53. Alkaloid 1b did not induce the death of PC3, but induced necrotic cell death in both DU145 and HEK293. The alkaloids were shown to efficiently modulate gene and protein expression and activate TP53 and EGFR pathways with potential implications for targeting tumors with specific TP53 mutations. Altogether, the obtained results showed that (6aS)-dicentrine (1) and its N-oxide derivatives, especially 1a, displayed potential as antitumor agents and justify its continued investigation as a therapeutic candidate.