Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase

Cancer Cell. 2013 Sep 9;24(3):379-93. doi: 10.1016/j.ccr.2013.08.003.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / metabolism*
  • Drug Resistance, Neoplasm
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Female
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Indoles / pharmacology
  • Indoles / toxicity
  • Lysosomes / metabolism*
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Sphingolipids / metabolism*
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors*
  • Spiro Compounds / pharmacology
  • Spiro Compounds / toxicity
  • Tocopherols / pharmacology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • HSP70 Heat-Shock Proteins
  • Indoles
  • Lu 28-179
  • Sphingolipids
  • Spiro Compounds
  • Sphingomyelin Phosphodiesterase
  • Tocopherols

Associated data

  • GEO/GSE46340