Anti-Cancer Activity of a Novel Small Molecule Compound That Simultaneously Activates p53 and Inhibits NF-κB Signaling

Sun Gwan Hwang, Jinah Park, Joo Young Park, Cheol Hyoung Park, Ki Ho Lee, Jeong Woo Cho, Jong-Ik Hwang, Jae Young Seong

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Article numbere44259
JournalPLoS One
Volume7
Issue number9
DOIs
Publication statusPublished - 2012 Sep 13

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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