期刊
JOURNAL OF NATURAL MEDICINES
卷 76, 期 1, 页码 234-243出版社
SPRINGER JAPAN KK
DOI: 10.1007/s11418-021-01584-0
关键词
Notch signaling; Sesquiterpene lactones; Tagitinin; Oxidative stress
资金
- Japan Society for the Promotion of Science (JSPS)
- Takahashi Industrial and Economic Research Foundation
- NAGASE Science Technology Foundation
- Sumitomo Foundation
- Pharmaceutical Society of Japan
- JSPS
- JSPS A3 Foresight Program
- Asian Chemical Biology Initiative
Notch signaling pathway is crucial in cell differentiation and proliferation, but abnormal activation can lead to tumorigenesis. Compound 1 beta,2 alpha-epoxytagitinin C (2) was discovered to inhibit Notch signaling and exhibit strong cytotoxicity against the Notch-activated leukemia cell line HPB-ALL.
Notch signaling plays crucial roles in cell differentiation and proliferation, but aberrant activation of this signaling results in tumorigenesis and cancer progression. Notch signaling is thus a promising drug target for oncotherapy, and the development of Notch signaling inhibitors is eagerly awaited. Notch inhibitory activity-guided fractionation of a Spilanthes acmella extract led to the identification of five sesquiterpene lactones: tagitinin A (1), 1 beta,2 alpha-epoxytagitinin C (2), tagitinin C (3), orizabin (4), and 2 alpha-hydroxytirotundin (5). 1 beta,2 alpha-Epoxytagitinin C (2) exhibited Notch signaling inhibition, with an IC50 of 25.6 mu M, and was further evaluated for its activity against HPB-ALL, a Notch-activated leukemia cell line. Compound 2 showed potent cytotoxicity against HPB-ALL (IC50 1.7 mu M) and arrested the cell cycle at the G2/M phase, but did not induce apoptotic cell death. Notch inhibitory mechanism analysis suggested that compound 2 transcriptionally suppresses Notch1 mRNA. In addition, we found that oxidative stress induction is critical for Notch signaling inhibition and the cytotoxicity of compound 2. This is the first mechanism of small molecule Notch inhibition. Our results demonstrate that 1 beta,2 alpha-epoxytagitinin C (2) is a potential anti-leukemia agent and further investigation of this compound is warranted. [GRAPHICS] .
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据