Stabilization of MDA-7/IL-24 for colon cancer therapy

Colon cancer is one of the most commonly diagnosed cancers in the United States. Recombinant MDA-7/IL-24 has showed its selective cytotoxicity against cancer cells, and Ad-mda7 (INGN-241) is currently under clinical investigation for solid tumors. Here, we investigated the expression of MDA-7/IL-24 in colorectal cancer (CRC) tissues from 202 patients. Compared with the adjacent mucosa, CRC tissues displayed significantly lower MDA-7/IL-24 levels. The MDA-7/IL-24 levels in CRC were significantly associated with patients' survival rate in a 6-year period. These results indicate MDA-7/IL-24 level is both a diagnostic and prognostic biomarker for CRC, and support the role of MDA-7/IL-24 in the treatment of CRC. To elevate MDA-7/IL-24 level for colon cancer treatment, we successfully developed a small-molecule compound SC144 with the ability to up-regulate MDA-7/IL-24 expression via direct binding and stabilizing MDA-7/IL-24 in human colon cancer cells. Among the analogs tested, SC144 exhibited the highest cytotoxicity in a panel of colon cancer cell lines in a p53-independent manner, accompanied by cell cycle arrest in G(0)/G(1) with downregulation of Cyclin D1 levels, and apoptosis induction with upregulation of cell surface-bound Fas/CD95. These results combined with our previous studies support the anticancer role of MDA-7/IL-24 as well as the clinical development of SC144 for colon cancer treatment. (C) 2013 Elsevier Ireland Ltd. All rights reserved.