1 Department of Clinical Medicine - Molekylær Medicinsk afdeling (MOMA), Department of Clinical Medicine, Health, Aarhus University2 Department of Political Science, Aarhus BSS, Aarhus University3 Fakultetssekretariat - administration, Faculty of Agricultural Sciences, Aarhus University, Aarhus University4 unknown5 Department of Political Science, Aarhus BSS, Aarhus University6 Department of Clinical Medicine - Molekylær Medicinsk afdeling (MOMA), Department of Clinical Medicine, Health, Aarhus University
Lysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome-destabilizing experimental anticancer agent siramesine inhibits ASM by interfering with the binding of ASM to its essential lysosomal cofactor, bis(monoacylglycero)phosphate. Like siramesine, several clinically relevant ASM inhibitors trigger cancer-specific lysosomal cell death, reduce tumor growth in vivo, and revert multidrug resistance. Their cancer selectivity is associated with transformation-associated reduction in ASM expression and subsequent failure to maintain sphingomyelin hydrolysis during drug exposure. Taken together, these data identify ASM as an attractive target for cancer therapy.