title: Identification of known drugs that act as inhibitors of NF-kappaB signaling and their mechanism of action.
abstract: Nuclear factor-kappa B (NF-kappaB) is a transcription factor that plays a critical role across many cellular processes including embryonic and neuronal development, cell proliferation, apoptosis, and immune responses to infection and inflammation. Dysregulation of NF-kappaB signaling is associated with inflammatory diseases and certain cancers. Constitutive activation of NF-kappaB signaling has been found in some types of tumors including breast, colon, prostate, skin and lymphoid, hence therapeutic blockade of NF-kappaB signaling in cancer cells provides an attractive strategy for the development of anticancer drugs. To identify small molecule inhibitors of NF-kappaB signaling, we screened approximately 2800 clinically approved drugs and bioactive compounds from the NIH Chemical Genomics Center Pharmaceutical Collection (NPC) in a NF-kappaB mediated beta-lactamase reporter gene assay. Each compound was tested at fifteen different concentrations in a quantitative high throughput screening format. We identified nineteen drugs that inhibited NF-kappaB signaling, with potencies as low as 20 nM. Many of these drugs, including emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, and lestaurtinib, inhibited NF-kappaB signaling via inhibition of IkappaBalpha phosphorylation. Others, such as ectinascidin 743, chromomycin A3 and bortezomib utilized other mechanisms. Furthermore, many of these drugs induced caspase 3/7 activity and had an inhibitory effect on cervical cancer cell growth. Our results indicate that many currently approved pharmaceuticals have previously unappreciated effects on NF-kappaB signaling, which may contribute to anticancer therapeutic effects. Comprehensive profiling of approved drugs provides insight into their molecular mechanisms, thus providing a basis for drug repurposing.
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Miller
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Srilatha
authors.initials: S
authors.lastname: Sakamuru
authors.forename: Sunita J
authors.initials: SJ
authors.lastname: Shukla
authors.forename: Matias S
authors.initials: MS
authors.lastname: Attene-Ramos
authors.forename: Paul
authors.initials: P
authors.lastname: Shinn
authors.forename: Danielle
authors.initials: D
authors.lastname: Van Leer
authors.forename: William
authors.initials: W
authors.lastname: Leister
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D007770:L-Lactate Dehydrogenase; D051550:I-kappa B Kinase