Abstract
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell neoplasm characterized by an uncontrolled proliferation of moderately and well differentiated cells of the granulocytic lineage. LW-213, a newly synthesized flavonoid compound, was found to exert antitumor effects against breast cancer through inducing G2/M phase arrest. We investigated whether LW-213 exerted anti-CML effects and the underlying mechanisms. We showed that LW-213 inhibited the growth of human CML cell lines K562 and imatinid-resistant K562 (K562r) in dose- and time-dependent manners with IC50 values at the low μmol/L levels. LW-213 (5, 10, 15 μM) caused G2/M phase arrest of K562 and K562r cells via reducing the activity of G2/M phase transition-related proteins Cyclin B1/CDC2 complex. LW-213 treatment induced apoptosis of K562 and K562r cells via inhibiting the expression of CDK9 through lysosome degradation, thus leading to the suppression of RNAPII phosphorylation, down-regulation of a short-lived anti-apoptic protein MCL-1. The lysosome inhibitor, NH4Cl, could reverse the anti-CML effects of LW-213 including CDK9 degradation and apoptosis. LW-213 treatment also degraded the downstream proteins of BCR-ABL1, such as oncoproteins AKT, STAT3/5 in CML cells, which was blocked by NH4Cl. In primary CML cells and CD34+ stem cells, LW-213 maintained its pro-apoptotic activity. In a K562 cells-bearing mice model, administration of LW-213 (2.5, 5.0 mg/kg, ip, every other day for 4 weeks) dose-dependently prolonged the survival duration, and significantly suppressed huCD45+ cell infiltration and expression of MCL-1 in spleens. Taken together, our results demonstrate that LW-213 may be an efficient agent for CML treatment.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China [No. 81673461, 81873046 and 81830105], the Drug Innovation Major Project [2017ZX09301014, 2018ZX09711001-003-007], the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [No. SKLNMZZCX201823], the Social Development Project of Jiangsu Provincial Science and Technology Department [NO. BE2018711], and the “Double First-Class” University project [CPU 2018GF11, CPU2018GF05].
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XL designed and performed the research; PH analyzed the data and wrote the paper; HL and XXY performed the research and analyzed the data; XYW and YJQ performed the research; ZYW collected data and performed the statistical analysis; HZW and MYZ collected and analyzed data; and QLG and HH conceptualized the project and directed the experimental design and data analysis.
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Liu, X., Hu, P., Li, H. et al. LW-213, a newly synthesized flavonoid, induces G2/M phase arrest and apoptosis in chronic myeloid leukemia. Acta Pharmacol Sin 41, 249–259 (2020). https://doi.org/10.1038/s41401-019-0270-4
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DOI: https://doi.org/10.1038/s41401-019-0270-4
