biostudies-literatureTakchi RU.S. Department of DefenseNCI NIH HHSU.S. Department of Health & Human Services | National Institutes of Health309https://www.ebi.ac.uk/biostudies/studies/S-EPMC11066049biostudies-literatureUnknown15(5)Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L were developed as imaging probes (ISO1) or as cancer therapeutics, alone (SV119 [C6], SW43 [C10]) and as delivery vehicles for cytotoxic drug cargoes (C6-Erastin, C10-SMAC). However, the exact mechanism of S2L-induced cytotoxicity remains to be fully elucidated. A series of high-affinity S2L were evaluated regarding their cytotoxicity profiles across cancer cell lines. While C6 and C10 displayed distinct cytotoxicities, C0 and ISO1 were essentially non-toxic. Confocal microscopy and lipidomics analysis in cellular and mouse models revealed that C10 induced increases in intralysosomal free cholesterol and in cholesterol estersCell death & diseaseCytotoxic sigma-2 ligands trigger cancer cell death via cholesterol-induced-ER-stress.PMC11066049R01 CA276378R01 CA163764W81XWH-17-1-0102Takchi RHawkins WGGong QPrudner BCSpitzer DHagi TVan Tine BAJin LXNewcomer KFVangveravong SfalseCytotoxic sigma-2 ligands trigger cancer cell death via cholesterol-induced-ER-stress.Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L were developed as imaging probes (ISO1) or as cancer therapeutics, alone (SV119 [C6], SW43 [C10]) and as delivery vehicles for cytotoxic drug cargoes (C6-Erastin, C10-SMAC). However, the exact mechanism of S2L-induced cytotoxicity remains to be fully elucidated. A series of high-affinity S2L were evaluated regarding their cytotoxicity profiles across cancer cell lines. While C6 and C10 displayed distinct cytotoxicities, C0 and ISO1 were essentially non-toxic. Confocal microscopy and lipidomics analysis in cellular and mouse models revealed that C10 induced increases in intralysosomal free cholesterol and in cholesterol esters2024-01-01T00:00:00Z2024 May2026-06-03T03:53:10.968Z2026-04-24T03:09:08.928ZS-EPMC110660493869797810.1038/s41419-024-06693-8