title: Anti-cancer activity of a novel small molecule compound that simultaneously activates p53 and inhibits NF-κB signaling.
abstract: The p53 and NF-κB pathways play important roles in diverse cellular functions, including cell growth, apoptosis, and tumorigenesis. Mutations that inactivate the p53 gene and constitutive NF-κB pathway activation are common occurrences in human cancers. Although many drugs are being developed that selectively activate p53 or inhibit NF-κB, there are few drug candidates that can do both. Simultaneous activation of p53 and inhibition of the NF-κB pathway is therefore a prime target for new cancer drug development. This study is the first report of a high-throughput approach with mass compounds that concurrently target both pathways. Using a cell-based screening assay and a library of 200,000 synthetic compounds, we identified 9 small molecules that simultaneously inhibit NF-κB and activate p53. One of these compounds, N-2, increased the expression of p53 target genes, including p21 and GADD45a. In addition, N-2 inhibited the transcriptional activity of NF-κB, concomitantly repressing interleukin-6 and monocyte chemotactic protein-1 (MCP-1) expression. When cell lines derived from a diverse range of cancers were treated in vitro with N-2, we observed increased cell death. N-2 also significantly inhibited allograft growth in murine models of melanoma and lung carcinoma. Our findings suggest that N-2 may act as a bivalent anti-cancer agent through simultaneous modulation of NF-κB and p53 activities.
authors.affiliation: Drug Development Center, SK Biopharmaceuticals Co, Ltd, Daejeon, Korea.
authors.forename: Sun Gwan
authors.initials: SG
authors.lastname: Hwang
authors.forename: Jinah
authors.initials: J
authors.lastname: Park
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Park
authors.forename: Cheol Hyoung
authors.initials: CH
authors.lastname: Park
authors.forename: Ki-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Cho
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D057166:High-Throughput Screening Assays; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D007928:Lethal Dose 50; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010617:Phenanthridines / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C578956:5-ethyl-3-methyl-6-(1-methyl-1H-pyridin-2-ylidenemethyl)phenanthridinium; D000970:Antineoplastic Agents; D018932:Chemokine CCL2; D015850:Interleukin-6; D016328:NF-kappa B; D010617:Phenanthridines; D011725:Pyridines; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide