TY - JOUR AU - Liu Xiao AU - Hu Po AU - Li Hui AU - Yu Xiao-xuan AU - Wang Xiang-yuan AU - Qing Ying-jie AU - Wang Zhan-yu AU - Wang Hong-zheng AU - Zhu Meng-yuan AU - Guo Qing-long AU - Hui Hui PY - 2020 TI - LW-213, a newly synthesized flavonoid, induces G2/M phase arrest and apoptosis in chronic myeloid leukemia JF - Acta Pharmacologica Sinica; Vol 41, No 2 (February 2020): Acta Pharmacologica Sinica Y2 - 2020 KW - N2 - 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 IC 50 values at the low μmol/L levels. LW-213 (5, 10, 15 μM) caused G 2 /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, NH 4 Cl, 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 NH 4 Cl. 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. UR - http://www.chinaphar.com/article/view/10094