구.추천논문
- 조회4,617
Abstract
Sun Gwan Hwang1,2, Jinah Park3, Joo Young Park1, Cheol Hyoung Park1, Ki-Ho Lee1, Jeong Woo Cho1, Jong-Ik Hwang2, Jae Young Seong2*
1 Drug Development Center, SK Biopharmaceuticals Co., Ltd., Daejeon, Korea, 2 Laboratory of G Protein Coupled Receptors, Graduate School of Medicine Korea University, Seoul, Korea, 3 Korean Bioinformation Center, KRIBB, Daejeon, Korea
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.
논문정보
- Research article
- 2012년 09월 (BRIC 등록일 )
- 국내 연구진
- 구・추천논문
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