Molecular mechanism of anticancer activity of selected coastal marsh plants from Saudi Arabia

However, the cytotoxic and antioxidant properties of halophyteshave been previously reported, the underlying molecular mechanisms remain poorly understood. In the present study, we not only evaluate the cytotoxic and antioxidant potential of extracts from halophytic species but also, for the first time, elucidate their mechanistic mode of action using an integrated high-content screening and RT-PCR approach to verify apoptosis induction and the modulation of apoptosis-related signaling pathways. Phytochemical screening revealed a diverse array of secondary metabolites, with S. fruticosa and A. marina showing the richest compositions. Notably, these two species also exhibited exceptional antioxidant capacity, with IC₅₀ values (6.04 and 10.05 µg/mL, respectively) significantly outperforming ascorbic acid. More importantly, this study advances our understanding of the molecular mechanisms underlying the anticancer properties of these extracts. A. marina demonstrated remarkable cytotoxicity against MCF-7, HepG2, and HCT116 cancer cell lines (IC₅₀ < 0.17 µg/mL), accompanied by high selectivity indices (up to 1723.1), indicating a strong therapeutic window. Mechanistic investigations using high-content screen and RT-PCR revealed that the most active extracts induce apoptosis via mitochondrial dysfunction, evidenced by loss of mitochondrial membrane potential, increased plasma membrane permeability (up to 465%) y, and cytochrome c release (> 740%). Furthermore, gene expression profiling demonstrated significant upregulation of pro-apoptotic markers (BAX, Caspase-3), downregulation of anti-apoptotic BCL-2, and modulation of oncogenic and cell cycle regulatory pathways, including CDK1, Cyclin B1, p21, c-MYC, and PI3K/AKT/mTOR signaling. Hierarchical clustering grouped S. fruticosa, A. marina, and Atriplex halimus as the most potent extracts.

The online version contains supplementary material available at 10.1007/s13205-025-04686-8.