Drug Modulating the Sphingosine Molecular Pathway Prevents Chronic Intestinal Inflammation from Progressing to Colitis-Associated Cancer

A recently published study found that fingolimod, a drug currently approved for the treatment of multiple sclerosis, could potentially eliminate or reduce the progression of colitis-associated cancer (CAC).

Fingolimod is a sphingosine 1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction. Sphingosine-1-phosphate (S1P) is phosphorylated from sphingosine by the action of the enzyme sphingosine kinase 1 (SphK1). 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-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation pathway important in inflammatory, antiapoptotic, and immune processes.

Investigators at Virginia Commonwealth University (Richmond, USA) reported in the December 27, 2012, online edition of the journal Cancer Cell that S1P produced by upregulation of SphK1 linked chronic intestinal inflammation to CAC and that both conditions were worsened by deletion of Sphk2. S1P was essential for production of inflammatory molecules including NF-kappaB-regulated cytokine IL-6, persistent activation of the transcription factor STAT3 (signal transducer and activator of transcription-3), and consequent upregulation of the S1P receptor, S1PR1.

Treatment of mice with fingolimod decreased SphK1 and S1PR1 expression and eliminated the NF-kappaB/IL-6/STAT3 amplification cascade and development of CAC, even in mice lacking the Sphk2 gene, and may be useful in treating colon cancer in individuals with ulcerative colitis.

"Perhaps the most significant aspect of this study is the therapeutic potential of fingolimod in the treatment of colitis-associated cancer," said senior author Dr. Sarah Spiegel, professor of biochemistry and molecular biology at the Virginia Commonwealth University. "Since this drug is already approved for clinical use, we are hoping to initiate a clinical trial to study its efficacy in patients with CAC in combination with approved therapies."

"Because one of the consequences of inflammatory bowel diseases is an increased risk of developing colorectal cancer, the next step in our research is to examine blood samples from patients with irritable bowel syndrome and colitis-associated cancer to measure levels of S1P," said Dr. Spiegel. "Colorectal cancer is one of the leading causes of cancer-related deaths, and we are hopeful that this research will lead to more effective treatments."

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