Ponatinib对人慢性髓系白血病细胞株K562自噬的影响OACSTPCD

Tyrosine kinase inhibitors(TKIs)are targeted drugs for the treatment of leukemia.At present,there are three generations of them,among which the third-generation Ponatinib has the strongest effect and the fastest response,but the difference in the mechanism between other TKIs is not clear.To investigate the differences,chronic myeloid leukemia K562 cells were treated with first-generation Imatinib and third-generation Ponatinib.The changes in the number of viable cells,mitochondrial activity,reactive oxygen species(ROS)and autophagy related molecules were observed.Ponatinib inhibited the proliferation and survival rate of K562 cells more significantly than Imatinib,and reduced mitochondrial activity,but there was no significant difference in ROS.Compared with Imatinib,Ponatinib significantly promoted the autophagy marker LC3 B protein and reduced the autophagy receptor protein p62,while the phosphorylation of AMPKα,ULK1 and Beclin1 proteins was not detected.In addition,Bafilomycin A1,but not Brefeldin A and N-acetyl-L-cysteine,blocked the inhibitory effect of Ponatinib on p62 protein.These results suggest that Ponatinib caused mitochondrial damage in K562 cells more significantly than Imatinib,which in turn induced more pronounced autophagy,a finding that may provide important clues to explain the stronger therapeutic effect of Ponatinib.