Salinomycin as a death switch: how gastric cancer cells choose their demise

Gastric cancer (GC) remains a significant global health challenge due to the prevalence of multidrug resistance (MDR) that leads to therapy failure. MDR is driven by tumor heterogeneity and the presence of cancer stem cells (CSCs). Drug repurposing represents an innovative therapeutic strategy to overcome MDR. In this view, Salinomycin (Sal) has shown promising anticancer activity and selectivity against CSCs. Since its mechanisms in GC are not fully understood, we investigated its activity in a panel of four GC cell lines: SNU1, NCI-N87, AGS, and KATO-III. Our results demonstrate that Sal induces distinct forms of regulated cell death (RCD) in a cell line-specific manner. Sal treatment led to apoptosis in SNU1 and NCI-N87 cells, while it triggered ferroptosis in AGS and KATO-III cells. Autophagy was a common early event in all cell lines. Western blot analysis confirmed the activation of distinct signaling axes: mTOR/survivin/CASP-3/BAX in apoptotic cells and mTOR/survivin/SLC7A11/GPX4 in ferroptotic cells. Bioinformatics analysis revealed a unique 20-differentially expressed gene signature for ferroptosis-prone GC cells. Notably, Sal significantly reduced the proportion of CD44⁺ and CD133⁺ CSCs in the drug-resistant KATO-III and NCI-N87 cell lines. By selectively inducing either apoptosis or ferroptosis, Sal effectively overcomes MDR and targets the CSC population by reducing the capability to form spheroids and colonies. Moreover, our ferroptosis-related gene signature resulted useful to stratify GC patients and was found associated with better outcomes, highlighting the translational potential of Sal treatment. Indeed, it was effective to promote both apoptotic and ferroptotic RCD on patient-derived gastric cancer organoids. Notably, autophagy was a common RCD mechanism also in this preclinical model. Our findings suggest that Sal is a promising candidate for GC treatment, and understanding a tumor's specific molecular susceptibilities could enable the development of personalized therapeutic strategies.