Icariin-Strontium nanoparticles induce apoptosis accompanied by autophagy in gastric cancer through PI3K/Akt/NF-kB suppression and mitochondrial dysfunction.

Abstract

Gastric cancer (GC) remains a significant worldwide health issue, as current chemotherapeutic options are often limited by severe side effects and inadequate patient outcomes. This study introduces an innovative, sustainable method utilizing icariin-mediated strontium nanoparticles (IR-SrNPs), with the medicinal flavonoid icariin serving as a stabilizing agent. The physicochemical analysis validated the effective synthesis and precise characterization of the IR-SrNPs. In vitro experiments exhibited potent and selective anti-proliferative effects on human gastric adenocarcinoma (AGS) cells, without impacting normal gastric epithelial (GES-1) cells. Mechanistically, IR-SrNPs utilize a dual cell-death strategy: they substantially increase reactive oxygen species (ROS) generation, exceeding cellular antioxidant defences, which leads to the loss of mitochondrial membrane potential (MMP, ΔΨm) and the activation of the intrinsic apoptotic pathway in AGS cells. RT-PCR investigations corroborated this by revealing increased expression of pro-apoptotic genes (Bax, Caspase-3) and diminished expression of the anti-apoptotic gene (Bcl-2). Moreover, IR-SrNPs stimulated autophagic activity, indicated by elevated LC3-II and reduced p62 levels; yet, this is construed as autophagy accompanying apoptosis rather than definitively facilitating apoptosis. The precise suppression of the elevated PI3K/Akt signaling pathway, which is a major regulator of cell survival, markedly improved both the apoptotic and autophagic responses. RT-PCR demonstrated a significant transcriptional downregulation of PI3K, Akt, and NF-κB following IR-SrNP treatment. This protein-level suppression was further validated by Western blot analysis, which showed a marked reduction in the expression of total Akt, p-Akt, and NF-κB. The combined data indicate that IR-SrNPs are a highly promising and efficacious nanotherapeutic treatment for gastric cancer, employing a dual-targeting approach to attenuate the PI3K/Akt pathway.