All-trans retinoic acid exerts selective anti-FLT3-ITD acute myeloid leukemia efficacy through downregulating Chk1 kinase. (31st March 2020)

• Record Type: Journal Article
• Authors: Wang, Wenliang; Jiang, Zongru; Wang, Li; Wang, Aoli; Liu, Juan; Chen, Cheng; Yu, Kailin; Zou, Fengming; Wang, Wenchao; Liu, Jing; Liu, Qingsong
• Is Part Of: Cancer letters. Volume 473(2020)
• Page Start: 130
• Page End: 138
• Publication Date: 2020-03-31
• Subjects: ATRA -- Acute myeloid leukemia -- DNA damage repair -- SN38 -- Combination therapy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.12.045
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: ATRA selectively downregulates Chk1 protein in FLT3-ITD AML cells. ATRA can impede DNA damage repair pathway in FLT3-ITD AML cells. Combining ATRA and genotoxic drugs can synergistically inhibit FLT3-ITD AML.