All-trans retinoic acid (ATRA) is known to be a potent inhibitor of FLT3-ITD acute myeloid leukemia (AML) cells, although the exact mechanism remains unclear. In this work, we report that ATRA causes fatal mitotic catastrophe in FLT3-ITD AML cells by degrading Chk1 kinase, and therefore preventing DNA damage repair. In order to explore a further enhancement in the inhibitory effect of ATRA on FLT3-ITD AML cells, we investigated the suitability of a combination of ATRA and DNA damage drug SN38. In vitro experiments showed that this combinatorial approach effectively inhibited the proliferation of FLT3-ITD cells and induced cell apoptosis in AML. In vivo experiments confirmed that the combination could substantially improve the anti-tumor effect of SN38. Taken together, our results indicate that ATRA down-regulates Chk1 in FLT3-ITD AML cells, and the combination of ATRA and SN38 significantly improves the anti-tumor effect of either ATRA or SN38 when used alone.

中文翻译：

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全反式维甲酸通过下调Chk1激酶发挥选择性抗FLT3-ITD急性髓细胞白血病的功效。

全反式维甲酸（ATRA）是有效的FLT3-ITD急性髓细胞性白血病（AML）细胞抑制剂，尽管其确切机制尚不清楚。在这项工作中，我们报告说ATRA通过降解Chk1激酶在FLT3-ITD AML细胞中引起致命的有丝分裂灾难，从而防止DNA损伤修复。为了探索进一步增强ATRA对FLT3-ITD AML细胞的抑制作用，我们研究了ATRA与DNA损伤药物SN38联合使用的适用性。体外实验表明，这种组合方法可有效抑制FLT3-ITD细胞的增殖并诱导AML细胞凋亡。体内实验证实，该组合可实质上改善SN38的抗肿瘤作用。两者合计，我们的结果表明ATRA下调FLT3-ITD AML细胞中的Chk1，