Assessment of Thiosemicarbazone‐Containing Compounds as Potential Antileukemia Agents against P‐gp Overexpressing Drug Resistant K562/A02 Cells

Abstract P‐Glycoprotein (P‐gp) overexpression is considered to be the leading cause of multidrug resistance (MDR) and failure of chemotherapy for leukemia. In this study, seventeen thiosemicarbazone‐containing compounds were prepared and evaluated as potential antileukemia agents against drug resistant K562/A02 cell overexpressing P‐gp. Among them, N ‐hydroxy‐6‐({(2 E )‐2‐[(3‐nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide could significantly inhibit K562/A02 cells proliferation with an IC 50 value of 0.96 μM. Interestingly, N ‐hydroxy‐6‐({(2 E )‐2‐[(3‐nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide could dose‐dependently increase ROS levels of drug resistant K562/A02 cells, thus displaying a potential collateral sensitivity (CS)‐inducing effect and selectively killing K562/A02 cells. Furthermore, N ‐hydroxy‐6‐({(2 E )‐2‐[(3‐nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide possessed potent inhibitory effect on HDAC1 and HDAC6, and could promote K562/A02 cells apoptosis via dose‐dependently increasing Bax expression, reducing Bcl‐2 protein level, and inducing the cleavage of PARP and caspase3. These present findings suggest that N ‐hydroxy‐6‐({(2 E )‐2‐[(3‐nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide might be a promising lead to discover novel antileukemia agents against P‐gp overexpressing leukemic cells.