title: Stabilization of MDA-7/IL-24 for colon cancer therapy.
abstract: 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 G0/G1 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.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, United States.
authors.forename: Shili
authors.initials: S
authors.lastname: Xu
authors.forename: Takashi
authors.initials: T
authors.lastname: Oshima
authors.forename: Toshio
authors.initials: T
authors.lastname: Imada
authors.forename: Munetaka
authors.initials: M
authors.lastname: Masuda
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.forename: Fedora
authors.initials: F
authors.lastname: Grande
authors.forename: Antonio
authors.initials: A
authors.lastname: Garofalo
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D007378:Interleukins / Q000096:biosynthesis* / Q000378:metabolism*; D008297:Male; D062105:Molecular Docking Simulation; D011379:Prognosis; D011810:Quinoxalines / Q000494:pharmacology*; D011994:Recombinant Proteins; D013534:Survival; D016159:Tumor Suppressor Protein p53; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis; D000099180:Interleukin-24
chemical_list: D014408:Biomarkers, Tumor; D019938:Cyclin D1; D006834:Hydrazines; D007378:Interleukins; D011810:Quinoxalines; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D000099180:Interleukin-24; C544427:N'-(7-fluoroH-pyrrolo(1,2-a)quinoxalin-4-yl)pyrazine-2-carbohydrazide