TY - JOUR
T1 - Isolation and evaluation of cardenolides from Lansium domesticum as Notch inhibitors
AU - Tsuchiya, Anna
AU - Makita, Yoshinori
AU - Koyano, Takashi
AU - Kowithayakorn, Thaworn
AU - Ishibashi, Masami
AU - Arai, Midori A.
N1 - Funding Information:
This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), Strategic Priority Research Promotion Program, Chiba University, “Phytochemical Plant Molecular Sciences,” Terumo life science foundation, Takahashi industrial and economic research foundation, and a Workshop on Chirality at Chiba University (WCCU). This work was inspired and supported by the international and interdisciplinary environments of the JSPS Core-to-Core Program, “Asian Chemical Biology Initiative,” and JSPS A3 Foresight Program.
Publisher Copyright:
© 2020, The Japanese Society of Pharmacognosy.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.].
AB - 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.].
KW - Differentiation
KW - Inhibitor
KW - Natural products
KW - Notch signaling
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U2 - 10.1007/s11418-020-01432-7
DO - 10.1007/s11418-020-01432-7
M3 - Article
C2 - 32648094
AN - SCOPUS:85087671462
SN - 1340-3443
VL - 74
SP - 758
EP - 766
JO - Journal of Natural Medicines
JF - Journal of Natural Medicines
IS - 4
ER -
