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Experimental Drug Blocks Growth of Virus-Induced Cancer

By BiotechDaily International staff writers
Posted on 29 Jan 2014
Image: Micrograph of KSHV-induced tumor showing abundant small branching blood vessels and spindle cells (Photo courtesy of Wikimedia Commons).
Image: Micrograph of KSHV-induced tumor showing abundant small branching blood vessels and spindle cells (Photo courtesy of Wikimedia Commons).
An experimental drug that selectively targets the enzyme sphingosine kinase (SK) blocked the growth of primary effusion lymphoma (PEL), a deadly tumor linked to the Kaposi's sarcoma-associated herpesvirus (KSHV) that frequently occurs in those infected with HIV.

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 extra-cellular 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.

Investigators at the Louisiana State University Health Sciences Center (New Orleans, USA) and the Tulane University School of Medicine (New Orleans, LA, USA) had previously shown that the experimental SK inhibitor ABC294640, an orally available small molecule developed by Apogee Biotechnology Corporation (Hummelstown, PA, USA), induced apoptosis and blocked proliferation in a triple-negative breast cancer system. Furthermore, SK expression promoted survival and endocrine therapy resistance in previously sensitive breast cancer cells.

In the current study, which was published in the January 2014 issue of the journal Molecular Cancer Therapeutics, the investigators reported that ABC294640 induced dose-dependent caspase cleavage and apoptosis for cultured PEL cells from KSHV+ patients, in part through inhibition of constitutive signal transduction associated with PEL cell proliferation and survival. Furthermore, they demonstrated that systemic administration of ABC294640 induced tumor regression in an established human PEL xenograft model.

"It is still early in our understanding of how these special lipids contribute to viral cancers, but this is a major potential advance. There are no therapies available to fight viral tumors by selectively blocking these pathways, all while not harming normal, uninfected cells," said senior author Dr. Christopher Parsons, associate professor of medicine, microbiology, immunology, and parasitology at Louisiana State University Health Sciences Center. "Our research thus far indicates that this molecule is safe, with the potential to stand alone as a single, orally administered drug with no need to combine it with other toxic drugs now routinely used but which fail to work for many patients."

Related Links:

Louisiana State University Health Sciences Center
Tulane University School of Medicine
Apogee Biotechnology Corporation



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