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

中文翻译：

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Not提取物作为Notch抑制剂的烯醇内酯的分离和评价。

摘要

由于Notch信号传导在细胞增殖和分化中起重要作用，因此该信号传导的异常激活有助于癌症进展。在神经干细胞中，Notch信号通过激活HES1表达来抑制分化。因此，Notch信号抑制剂可能是新的抗癌药物的候选药物，或在神经再生医学中的应用。在这项研究中，使用我们新颖的基于细胞的测定方法，从五味子的甲醇（MeOH）提取物中分离了六种天然的Notch抑制剂。Hongherin（2），强心苷，显示出有效的Notch抑制活性，IC ₅₀为0.62μM ，在HPB-ALL人T细胞急性淋巴细胞性白血病细胞中具有细胞毒性。洪赫林（2）还诱导了C17.2神经干细胞向神经元的分化，与对照相比导致分化增加了65％。从机理上讲，hongherin（2）减少了Notch1（全长）和类似mastermind的蛋白质（MAML）的数量。这表明hongherin（2）通过双重机制抑制Notch信号传导，该双重机制涉及Notch1和MAML蛋白水平的降低。

图形摘要