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

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.

Development of a novel FRET probe for the real-time determination of ceramidase activity.

Fretful novelty: We developed two novel doubly labelled fluorescent ceramide analogues that exhibit significant FRET and undergo hydrolysis by ceramidases. We present a fluorescent sphingolipid FRET probe that allows homogeneous ratiometric determination of enzyme activity in real-time.

Novel fluorescent ceramide derivatives for probing ceramidase substrate specificity.

Ceramidases are key regulators of cell fate. The biochemistry of different ceramidases and of their substrate ceramide appears to be complex, mainly due to specific biophysical characteristics at the water-membrane interface. In the present study, we describe the design and synthesis of a set of fluorescently labeled ceramides as substrates for acid and neutral ceramidases.

Potent inhibition of acid sphingomyelinase by phosphoinositide analogues.

The different mammalian sphingomyelinases are involved in cell regulation, apoptosis and inflammatory events. Recent reports suggest pharmacological potential especially for inhibitors of the acid sphingomyelinase. Phosphatidyl inositol-3,5bisphosphate (PtdIns3,5P(2)) is the most potent selective acid sphingomyelinase inhibitor known to date.