Sapogenin based self-assembly structures activating a non-apoptotic cell death via multiple pathways

Induction of distinct cell death pathways is critical to deal with tumor heterogeneity and therapeutic resistance. In our previous study, we reported a promising saponin analog (AG-08) for cancer therapy inducing non-canonical necrotic cell death. Here, we describe that AG-08 forms unique supramolecular structures responsible for its biological activity. After internalization via non-canonical endocytosis pathway, these structures affect several cell signaling pathways including unfolded protein response, immune response, oxidative stress and heat stress. Moreover, we prepared 18 analogs to reveal the role of residues on the formation of supramolecular structures and biological activities. The results have demonstrated that unique structural features are required for particulate structures and unprecedented cell death mechanism. Although small molecule based supramolecular assemblies have widely been accepted as nuisance for drug discovery studies, our results indicate that they may provide a new research field for anti-cancer drug development studies.