High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230036, PR China.
High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
Cancer Lett. 2020 Mar 31;473:130-138. doi: 10.1016/j.canlet.2019.12.045. Epub 2020 Jan 2.
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.
全反式维甲酸（ATRA）被认为是一种有效的 FLT3-ITD 急性髓系白血病（AML）细胞抑制剂，尽管确切的机制尚不清楚。在这项工作中，我们报告 ATRA 通过降解 Chk1 激酶导致 FLT3-ITD AML 细胞致命的有丝分裂灾难，从而阻止 DNA 损伤修复。为了进一步增强 ATRA 对 FLT3-ITD AML 细胞的抑制作用，我们研究了 ATRA 和 DNA 损伤药物 SN38 的联合使用是否合适。体外实验表明，这种联合治疗方法能有效抑制 FLT3-ITD 细胞的增殖，并诱导 AML 细胞凋亡。体内实验证实，该联合用药可显著提高 SN38 的抗肿瘤效果。总之，我们的研究结果表明，ATRA 下调 FLT3-ITD AML 细胞中的 Chk1，ATRA 和 SN38 的联合使用显著提高了单独使用 ATRA 或 SN38 的抗肿瘤效果。
