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Anti-cancer activity of a novel small molecule compound that simultaneously activates p53 and inhibits NF-?B signaling.

ABSTRACT: The p53 and NF-?B pathways play important roles in diverse cellular functions, including cell growth, apoptosis, and tumorigenesis. Mutations that inactivate the p53 gene and constitutive NF-?B pathway activation are common occurrences in human cancers. Although many drugs are being developed that selectively activate p53 or inhibit NF-?B, there are few drug candidates that can do both. Simultaneous activation of p53 and inhibition of the NF-?B 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-?B 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-?B, 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-?B and p53 activities.

SUBMITTER: Hwang SG

PROVIDER: S-EPMC3441512 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Anti-cancer activity of a novel small molecule compound that simultaneously activates p53 and inhibits NF-κB signaling.

Hwang Sun Gwan SG Park Jinah J Park Joo Young JY Park Cheol Hyoung CH Lee Ki-Ho KH Cho Jeong Woo JW Hwang Jong-Ik JI Seong Jae Young JY

PloS one 20120913 9

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 ...[more]

PMID: 23028510

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Anti-cancer activity of a novel small molecule compound that simultaneously activates p53 and inhibits NF-?B signaling.

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Anti-cancer activity of a novel small molecule compound that simultaneously activates p53 and inhibits NF-κB signaling.

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