Transformation-Associated Changes in Sphingolipid Metabolism Sensitize Cells to Lysosomal Cell Death Induced by Inhibitors of Acid Sphingomyelinase

Abstract

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.

Secretory sphingomyelinase in health and disease

“…Although unexpected with respect to reduced SM levels in cancerous compared to normal tissue (Hendrich and Michalak, 2003;Barceló-Coblijn et al, 2011), ASM activity is down-regulated in cancer (Petersen et al, 2013) and may consequently sensitize these cells to further decreases in enzyme activity levels. Lysosomal stability and integrity requires L-ASM activity (Kirkegaard et al, 2010), while the cytoprotective properties of ASM down-regulation in cancer cells are assumed to relate to the secreted form required for vesicle and membrane turnover (Magenau et al, 2011).…”

“…While the ASM/ceramide pathway has been well established as a bona fide system in the chemotherapeutic treatment of cancers and many commonly used chemotherapeutic agents mediate cell death via ASMinduced ceramide formation [reviewed in Henry et al, (2013)], recent evidence (Don et al, 2014) suggests that reducing ASM activity with functional inhibitors such as desipramine may induce lysosomal rupture in cancer cells (Petersen et al, 2013). Although unexpected with respect to reduced SM levels in cancerous compared to normal tissue (Hendrich and Michalak, 2003;Barceló-Coblijn et al, 2011), ASM activity is down-regulated in cancer (Petersen et al, 2013) and may consequently sensitize these cells to further decreases in enzyme activity levels.…”

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

“…102,103 Another form of lysosomal cell death where inhibition of acid sphingomyelinase (ASM) enhances membrane permeabilization and destabilization of cell lysosomes has also been reported. 104 Pyroptosis is a caspasedependent form of programmed cell death that differs in many respects from apoptosis. It is an inflammatory type of cell death and unlike apoptosis, depends on the activation of caspase-1 or caspase-11 (caspase-5 in humans).…”

“…34,41 Structure-activity studies have revealed the important role of the C-2 amino group in GAELs as it affects cytotoxicity. 39,43 Some cationic amphiphilic drugs (CADs) have also been shown to induce non-apoptotic lysosomal cell death, 104 perhaps, due to their amphipathic nature. In addition, several cationic amphiphiles have been proposed to have membranolytic mode of action, which may possibly explain their selectivity towards cancer cells.…”

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

“…A clearly protective role of inhibition of macrodomain formation was recently shown in irradiation-induced mortality (54). Otherwise, non-lysosomal sphingomyelinase can protect against cytotoxic agents (55).…”