Anti-Cancer Activity of a Novel Small Molecule Compound That Simultaneously Activates p53 and Inhibits NF-kappa B Signaling
- Authors
- Hwang, Sun Gwan; Park, Jinah; Park, Joo Young; Park, Cheol Hyoung; Lee, Ki-Ho; Cho, Jeong Woo; Hwang, Jong-Ik; Seong, Jae Young
- Issue Date
- 13-9월-2012
- Publisher
- PUBLIC LIBRARY SCIENCE
- Keywords
- ANCHORAGE-INDEPENDENT GROWTH; DNA-DAMAGE; TRANSCRIPTION FACTOR; CELL-GROWTH; INDUCED PHOSPHORYLATION; SESQUITERPENE LACTONE; CANCER-THERAPY; LUNG-CANCER; APOPTOSIS; MDM2
- Citation
- PLOS ONE, v.7, no.9
- Indexed
- SCIE
SCOPUS
- Journal Title
- PLOS ONE
- Volume
- 7
- Number
- 9
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/107463
- DOI
- 10.1371/journal.pone.0044259
- ISSN
- 1932-6203
- Abstract
- The p53 and NF-kappa B pathways play important roles in diverse cellular functions, including cell growth, apoptosis, and tumorigenesis. Mutations that inactivate the p53 gene and constitutive NF-kappa B pathway activation are common occurrences in human cancers. Although many drugs are being developed that selectively activate p53 or inhibit NF-kappa B, there are few drug candidates that can do both. Simultaneous activation of p53 and inhibition of the NF-kappa 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-kappa 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-kappa 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-kappa B and p53 activities.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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