| 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
|
| リソース情報 |
| ヒト・動物細胞 |
LK-2(RCB1970)
TGBC24TKB(RCB1196) |
