imd-0354 and Colorectal-Neoplasms

Elevated expression of transmembrane serine protease 4 (TMPRSS4) correlates with poor prognosis in non-small cell lung cancer, gastric cancer, colorectal cancer, prostate cancer, and other cancer patients. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, proliferation, and metastasis. In addition, we reported novel 2-hydroxydiarylamide derivatives, IMD-0354 and KRT1853, as TMPRSS4 serine protease inhibitors. Here, we further evaluated the effects of the representative derivatives on TMPRSS4-mediated cellular function and signaling. IMD-0354 and KRT1853 inhibited cancer cell invasion, migration, and proliferation in TMPRSS4-expressing prostate, colon, and lung cancer cells. Both compounds suppressed TMPRSS4-mediated induction of Sp1/3, AP-1, and NF-κB transcription factors. Furthermore, TMPRSS4 promoted cancer cell survival and drug resistance, and both compounds enhanced anoikis sensitivity as well as reduced bcl-2 and survivin levels. Importantly, KRT1853 efficiently reduced tumor growth in prostate and colon cancer xenograft models. These results strongly recommend KRT1853 for further development as a novel anti-cancer agent.

Topics: Animals; Benzamides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Female; HCT116 Cells; HeLa Cells; Humans; Lung Neoplasms; Male; Membrane Proteins; Prostatic Neoplasms; Serine Endopeptidases; Serine Proteinase Inhibitors; Signal Transduction; Xenograft Model Antitumor Assays

Nuclear factor kappaB (NF-kappaB) activation is involved in various inflammatory illnesses, for example inflammatory bowel disease, and is thought to be a key factor in the tumor-promoting mechanism of inflammation-associated tumorigenesis. This study investigated whether inhibitors of IKKbeta, which is a critical kinase for NF-kappaB activation, reduce colitis-associated tumorigenesis in mice.. We used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. Effects of IKKbeta inhibitors, NBD peptide, and IMD-0354 were examined.. In a colitis-associated cancer model, treatment with the IKKbeta inhibitors NBD peptide and IMD-0354 significantly reduced the number of tumors compared with the untreated group. The tumors were also significantly smaller in the inhibitor-treated mice than in the untreated mice. Macrophage and neutrophil infiltration decreased with the inhibitor treatment. NF-kappaB activation and the expression of Cox-2 and iNOS were observed in tumor tissues, and the inhibitors ameliorated their expression. These inhibitors blocked NF-kappaB activation and the expression of proinflammatory cytokines mediated by the culture supernatant of inflamed colon in murine primary macrophages. In-vitro and in-vivo experiments showed that these drugs, especially NBD peptide, could also inhibit the proliferation of colonic epithelial cells.. These results imply that IKKbeta-targeted NF-kappaB blockade is an attractive therapeutic approach for the prevention of colitis-associated tumors.

Topics: Animals; Antineoplastic Agents; Azoxymethane; Benzamides; Cell Proliferation; Colitis; Colorectal Neoplasms; Dextran Sulfate; Drug Delivery Systems; Drug Screening Assays, Antitumor; I-kappa B Kinase; Macrophages; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; NF-kappa B; Peptides