LW-213, a newly synthesized flavonoid, induces G2/M phase arrest and apoptosis in chronic myeloid leukemia

• 来源期刊: 中国药理学报（英文版）
• 关键词: chronic myeloid leukemia LW-213 G2/M phase arrest lysosome-dependent apoptosis CDK9 MCL-1
• 年，卷（期）: 2020,（2）
• 页码范围: 249-259
• 页数: 11页
• 语种: 英文

摘要

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.