Isolation and evaluation of cardenolides from Lansium domesticum as Notch inhibitors
| Autor: | Masami Ishibashi, Midori A. Arai, Yoshinori Makita, Takashi Koyano, Thaworn Kowithayakorn, Anna Tsuchiya |
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| Rok vydání: | 2020 |
| Předmět: |
Receptors
Notch 010405 organic chemistry Chemistry T cell Cell Notch signaling pathway Plants 01 natural sciences Regenerative medicine Neural stem cell 0104 chemical sciences Cell biology Cardenolides 010404 medicinal & biomolecular chemistry medicine.anatomical_structure medicine Humans Molecular Medicine Cytotoxic T cell HES1 Signal Transduction Cardiac glycoside medicine.drug |
| Zdroj: | Journal of Natural Medicines. 74:758-766 |
| ISSN: | 1861-0293 1340-3443 |
| DOI: | 10.1007/s11418-020-01432-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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