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.
Highlights
The NF-kB and p53 signaling pathways function in most cell types and are activated in response to numerous biological stimuli
First identified as a transcription factor involved in the inflammatory response, experimental evidence suggests that NFkB regulates cell growth, survival, and apoptosis [3]
The IC50 of N-2 for cancer cells was independent of the p53 genetic status under the same conditions (Supplementary Table S3 and Fig. S4)
Summary
The NF-kB and p53 signaling pathways function in most cell types and are activated in response to numerous biological stimuli. First identified as a transcription factor involved in the inflammatory response, experimental evidence suggests that NFkB regulates cell growth, survival, and apoptosis [3]. IkB proteins inhibit NF-kB function by preventing NF-kB from binding DNA. Activation of NF-kB involves phosphorylation of specific IkB serine residues by IkB kinases (IKKs) leading to proteasome-mediated degradation of IkB. Upon IkB degradation, the NF-kB complex is free to enter the nucleus where it can regulate the expression of specific genes related to inflammatory or immune responses, cell survival responses, and cellular proliferation [4]. The tumor suppressor protein p53 is a DNA binding transcription factor that plays an important role in guarding the cell in response to various stress signals [5]. MDM2 inhibits p53 accumulation by targeting it for proteasome-mediated degradation [8,9]
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