Identification of 1β,2α-epoxytagitinin C as a Notch inhibitor, oxidative stress mechanism and its anti-leukemia activity

Yoshinori Makita, Shun Saito, Anna Tsuchiya, Masami Ishibashi, Midori A. Arai

Research output: Contribution to journalArticlepeer-review


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), 1β,2α-epoxytagitinin C (2), tagitinin C (3), orizabin (4), and 2α-hydroxytirotundin (5). 1β,2α-Epoxytagitinin C (2) exhibited Notch signaling inhibition, with an IC50 of 25.6 μM, 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 μM) 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 1β,2α-epoxytagitinin C (2) is a potential anti-leukemia agent and further investigation of this compound is warranted. Graphical abstract: [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)234-243
Number of pages10
JournalJournal of Natural Medicines
Issue number1
Publication statusPublished - 2022 Jan


  • Notch signaling
  • Oxidative stress
  • Sesquiterpene lactones
  • Tagitinin

ASJC Scopus subject areas

  • Molecular Medicine


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