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

AbstractNotch 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 aSpilanthes acmella extract led to the identification of five sesquiterpene lactones: tagitinin A (1), 1 β,2α-epoxytagitinin C (2), tagitinin C (3), orizabin (4), and 2 α-hydroxytirotundin (5). 1 β,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. Compound2 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 compound2 transcriptionally suppressesNotch1 mRNA. In addition, we found that oxidative stress induction is critical for Notch signaling inhibition and the cytotoxicity of compound2. This is the first mechanism of small molecule Notch inhibition. Our results demonstrate that 1 β,2α-epoxytagitinin C (2) is a potential anti-leukemia agent and further investigation of this compound is warranted.Graphical abstract
Source: Journal of Natural Medicines - Category: Drugs & Pharmacology Source Type: research