Drug developers are taking a close look at inhibitors of the enzyme sphingosine kinase in the ongoing search for treatments that specifically attack cancer cells without harming normal ones.

In this regard, investigators at Tulane University School of Medicine (New Orleans, LA, USA) reported in the August 2, 2012, online edition issue of the journal Experimental Biology and Medicine that they had evaluated two novel SK inhibitors, SKI-II and ABC294640.

Sphingosine (2-amino-4-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid. Sphingosine can be phosphorylated in vivo via two kinases, sphingosine kinase type 1 and sphingosine kinase type 2. Phosphorylation leads to the formation of sphingosine-1-phosphate, a potent signaling lipid. Sphingolipid metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate, are lipid-signaling molecules involved in diverse cellular processes.

Sphingosine kinase catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (S1P), a lipid mediator with both intra- and extracellular functions. Intracellularly, S1P regulates proliferation and survival, and extracellularly, it is a ligand for cell surface G protein-coupled receptors. This protein, and its product S1P, play a key role in TNF-alpha signaling and the NF-kappa-B activation pathway important in inflammatory, antiapoptotic, and immune processes.

In the current study, the investigators characterized the inhibitors SKI-II and ABC294640 in luminal, endocrine-resistant (MDA-MB-361) and basal-A, triple-negative (MDA-MB-468) breast cancer cells and compared them with previously published data in other breast cancer cell models.

They reported that both SKI-II and ABC294640 demonstrated greater efficacy in basal-A compared with luminal breast cancer. ABC294640, in particular, induced apoptosis and blocked proliferation both in vitro and in vivo in this triple-negative breast cancer system. Furthermore, SK expression promoted survival and endocrine therapy resistance in previously sensitive breast cancer cells.

"Sphingosine kinase is a relatively new molecular target," said senior author Dr. Barbara Beckman, professor of pharmacology at Tulane University School of Medicine. "In this study, we show that overexpression of SK promotes resistance to first-line breast cancer therapies, such as tamoxifen. We further found that treatment with the sphingosine kinase inhibitors SKI-II and ABC294640 induced cell death and blocked drug-resistant tumor growth without similar effects in a model system representing relatively normal breast cells."

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