Identification of known drugs that act as inhibitors of NF-kappaB signaling and their mechanism of action

Biochem Pharmacol. 2010 May 1;79(9):1272-80. doi: 10.1016/j.bcp.2009.12.021. Epub 2010 Jan 11.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor*
  • Genes, Reporter
  • High-Throughput Screening Assays
  • Humans
  • I-kappa B Kinase / metabolism
  • L-Lactate Dehydrogenase / metabolism
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / physiology
  • Signal Transduction


  • Antineoplastic Agents
  • NF-kappa B
  • L-Lactate Dehydrogenase
  • I-kappa B Kinase