Isolation and evaluation of cardenolides from Lansium domesticum as Notch inhibitors

Anna Tsuchiya, Yoshinori Makita, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi, Midori A. Arai

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract: Since Notch signaling plays important roles in cell proliferation and differentiation, aberrant activation of this signaling contributes to cancer progression. In neural stem cells, Notch signaling inhibits differentiation by activating HES1 expression. Therefore, Notch signaling inhibitors may be candidates for new anticancer drugs or have applications in neural regenerative medicine. In this study, six naturally occurring Notch inhibitors were isolated from the methanol (MeOH) extract of Lansium domesticum using our novel cell-based assay. Hongherin (2), a cardiac glycoside, demonstrated potent Notch inhibitory activity with an IC50 of 0.62 μM and was found to be cytotoxic in HPB-ALL human T cell acute lymphoblastic leukemia cells. Hongherin (2) also induced the differentiation of C17.2 neural stem cells to neurons, causing a 65% increase in differentiation compared to the control. Mechanistically, hongherin (2) reduced the amount of Notch1 (full length) and mastermind-like protein (MAML). This indicates that hongherin (2) inhibits Notch signaling through a dual mechanism involving the reduction of both Notch1 and MAML protein levels. Graphic abstract: [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)758-766
Number of pages9
JournalJournal of Natural Medicines
Volume74
Issue number4
DOIs
Publication statusPublished - 2020 Sep 1

Keywords

  • Differentiation
  • Inhibitor
  • Natural products
  • Notch signaling

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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