論文 - 詳細
| RRC ID | 54861 |
|---|---|
| 著者 | Hori R, Yamaguchi K, Sato H, Watanabe M, Tsutsumi K, Iwamoto S, Abe M, Onodera H, Nakamura S, Nakai R. |
| タイトル | The discovery and characterization of K-563, a novel inhibitor of the Keap1/Nrf2 pathway produced by Streptomyces sp. |
| ジャーナル | Cancer Med |
| Abstract |
Keap1/Nrf2 pathway regulates the antioxidant stress response, detoxification response, and energy metabolism. Previous reports found that aberrant Keap1/Nrf2 pathway activation due to Kelch-like ECH-associated protein 1 (Keap1) mutations or Nuclear factor E2-related factor 2 (Nrf2) mutations induced resistance of cancer cells to chemotherapy and accelerated cell growth via the supply of nutrients. Therefore, Keap1/Nrf2 pathway activation is associated with a poor prognosis in many cancers. These previous findings suggested that inhibition of Keap1/Nrf2 pathway could be a target for anti-cancer therapies. To discover a small-molecule Keap1/Nrf2 pathway inhibitor, we conducted high-throughput screening in Keap1 mutant human lung cancer A549 cells using a transcriptional reporter assay. Through this screening, we identified the novel Keap1/Nrf2 pathway inhibitor K-563, which was isolated from actinomycete Streptomyces sp. K-563 suppressed the expression of Keap1/Nrf2 pathway downstream target genes or the downstream target protein, which induced suppression of GSH production, and activated reactive oxygen species production in A549 cells. K-563 also inhibited the expression of downstream target genes in other Keap1- or Nrf2-mutated cancer cells. Furthermore, K-563 exerted anti-proliferative activities in these mutated cancer cells. These in vitro analyses showed that K-563 was able to inhibit cell growth in Keap1- or Nrf2-mutated cancer cells by Keap1/Nrf2 pathway inhibition. K-563 also exerted synergistic combinational effects with lung cancer chemotherapeutic agents. An in vivo study in mice xenotransplanted with A549 cells to further explore the therapeutic potential of K-563 revealed that it also inhibited Keap1/Nrf2 pathway in lung cancer tumors. K-563, a novel Keap1/Nrf2 pathway inhibitor, may be a lead compound for development as an anti-cancer agent. |
| 巻・号 | 8(3) |
| ページ | 1157-1168 |
| 公開日 | 2019-3-1 |
| DOI | 10.1002/cam4.1949 |
| PMID | 30735010 |
| PMC | PMC6434342 |
| MeSH | Animals Antineoplastic Agents / chemistry Antineoplastic Agents / isolation & purification Antineoplastic Agents / metabolism* Antineoplastic Agents / pharmacology* Cell Line, Tumor Cell Proliferation / drug effects Disease Models, Animal Drug Resistance, Neoplasm / drug effects Genes, Reporter Humans Kelch-Like ECH-Associated Protein 1 / genetics Kelch-Like ECH-Associated Protein 1 / metabolism* Magnetic Resonance Spectroscopy Mice Molecular Structure Mutation NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism* RNA Interference Reactive Oxygen Species / metabolism Signal Transduction / drug effects* Streptomyces / metabolism* Xenograft Model Antitumor Assays |
| IF | 3.357 |
| 引用数 | 5 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | LK-2(RCB1970) TGBC24TKB(RCB1196) |