Identification of the Brucea javanica Constituent Brusatol as a EGFR-Tyrosine Kinase Inhibitor in a Cell-Free Assay

Autor(en)

Chonticha Suwattanasophon, Agnes Mistlberger-Reiner, Jon Alberdi-Cedeño, Marc Pignitter, Veronika Somoza, Jürgen König, Thomanai Lamtha, Panatda Wanaragthai, Duangnapa Kiriwan, Kiattawee Choowongkomon

Abstrakt

Inhibitors of the tyrosine kinase (TK) activity of the epidermal growth factor receptor (EGFR) are routinely used in cancer therapy. However, there is a need to discover a new TK inhibitor. This study evaluated extracts from Brucea javanica and its components for their potential as novel EGFR-TK inhibitors. The cytotoxic effect of a g aqueous extract and its fractions was assessed by MTT assays with A549 lung cancer cells. The two fractions with the highest cytotoxicity were analyzed by LC/MS and ¹H NMR. Brusatol was identified as the main constituent of these fractions, and its cytotoxic and pro-apoptotic activities were confirmed in A549 cells. To elucidate the inhibitory activity of brusatol against EGFR-TK, a specific ADP-GloTM kinase assay was used. In this assay, the IC₅₀ value for EGFR-TK inhibition was 333.1 nM. Molecular dynamic simulations and docking experiments were performed to identify the binding pocket of brusatol to be located in the intracellular TK-domain of EGFR. This study demonstrates that brusatol inhibits EGFR-TK and therefore harbors a potential as a new therapeutic drug for the therapy of EGFR-depending cancers.

Organisation(en)

Institut für Physiologische Chemie, Department für Ernährungswissenschaften

Externe Organisation(en)

Kasetsart University, University of the Basque Country, Deutsche Forschungsanstalt für Lebensmittelchemie, Technische Universität München

Journal

ACS Omega

Band

8

Seiten

28543-28552

Anzahl der Seiten

10

ISSN

2470-1343

DOI

https://doi.org/10.1021/acsomega.3c02931

Publikationsdatum

07-2023

Peer-reviewed

Ja

ÖFOS 2012

301303 Medizinische Biochemie, 301206 Pharmakologie

ASJC Scopus Sachgebiete

Chemistry(all), Chemical Engineering(all)

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/identification-of-the-brucea-javanica-constituent-brusatol-as-a-egfrtyrosine-kinase-inhibitor-in-a-cellfree-assay(32bb4779-c757-4a5c-9f35-f8c049044467).html