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Identification of known drugs that act as inhibitors of NF-κB signaling and their mechanism of action
- Source :
- Biochemical Pharmacology. 79:1272-1280
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
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.
- Subjects :
- Antineoplastic Agents
Pharmacology
Biology
Biochemistry
Article
Cell Line
Genes, Reporter
medicine
Humans
Autocrine signalling
Dose-Response Relationship, Drug
L-Lactate Dehydrogenase
Molecular Structure
Lestaurtinib
NF-kappa B
Sunitinib malate
High-Throughput Screening Assays
I-kappa B Kinase
Drug repositioning
IκBα
Mechanism of action
Cancer cell
Drug Screening Assays, Antitumor
medicine.symptom
Signal transduction
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- Biochemical Pharmacology
- Accession number :
- edsair.doi.dedup.....8f4ab6e4853b4afa58c2879a38838db8