All-trans retinoic acid exerts selective anti-FLT3-ITD acute myeloid leukemia efficacy through downregulating Chk1 kinase

Wenliang Wang; Zongru Jiang; Li Wang; Aoli Wang; Juan Liu; Cheng Chen; Kailin Yu; Fengming Zou; Wenchao Wang; Jing Liu; Qingsong Liu

doi:10.1016/j.canlet.2019.12.045

All-trans retinoic acid exerts selective anti-FLT3-ITD acute myeloid leukemia efficacy through downregulating Chk1 kinase

Cancer Lett. 2020 Mar 31:473:130-138. doi: 10.1016/j.canlet.2019.12.045. Epub 2020 Jan 2.

Authors

Wenliang Wang¹, Zongru Jiang¹, Li Wang¹, Aoli Wang², Juan Liu¹, Cheng Chen¹, Kailin Yu², Fengming Zou², Wenchao Wang³, Jing Liu⁴, Qingsong Liu⁵

Affiliations

¹ 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.
² 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.
³ 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; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China. Electronic address: [email protected].
⁴ 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; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China. Electronic address: [email protected].
⁵ 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; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Institutes of Physical Science and Information Technology, Key Laboratory of Structure and Functional Regulation of Hybrid Materials, Ministry of Education, Anhui University, Hefei, Anhui, 230601, PR China. Electronic address: [email protected].

PMID: 31904486
DOI: 10.1016/j.canlet.2019.12.045

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.

Keywords: ATRA; Acute myeloid leukemia; Combination therapy; DNA damage repair; SN38.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
Cell Line, Tumor
Checkpoint Kinase 1 / antagonists & inhibitors*
Checkpoint Kinase 1 / metabolism
Child, Preschool
DNA Damage / drug effects
DNA Repair / drug effects
Down-Regulation / drug effects
Drug Synergism
Gene Expression Regulation, Leukemic / drug effects*
Humans
Irinotecan / pharmacology
Irinotecan / therapeutic use
Leukemia, Myeloid, Acute / blood
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / pathology
Male
Mice
Middle Aged
Mitosis / drug effects
Primary Cell Culture
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Tandem Repeat Sequences / genetics
Topoisomerase I Inhibitors / pharmacology
Topoisomerase I Inhibitors / therapeutic use
Tretinoin / pharmacology*
Tretinoin / therapeutic use
Xenograft Model Antitumor Assays
fms-Like Tyrosine Kinase 3 / genetics

Substances

Protein Kinase Inhibitors
Topoisomerase I Inhibitors
Tretinoin
Irinotecan
FLT3 protein, human
fms-Like Tyrosine Kinase 3
CHEK1 protein, human
Checkpoint Kinase 1