期刊
CHEMISTRY & BIODIVERSITY
卷 18, 期 2, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbdv.202000775
关键词
multidrug resistance; P-gp; thiosemicarbazones; collateral sensitivity
资金
- Jiangsu Provincial 333 High-level Talents Cultivation Project [BRA201927]
- Six Talent Peaks Project in Jiangsu Province [2017-YY-039]
- Natural Science Foundation of Jiangsu Province [BK20171179, BK20181151]
- Postgraduate Research and Practice Innovation Program of Jiangsu Province [KYCX20_2506]
- Jiangsu Training Programs of Innovation and Entrepreneurship for Undergraduates [201810313083X]
A compound with potential anti-leukemia effects was found to inhibit proliferation of drug resistant K562/A02 cells overexpressing P-gp, inducing increased ROS levels and apoptosis through regulation of HDAC1, HDAC6, Bax, and Bcl-2 proteins.
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-({(2E)-2-[(3-nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide could significantly inhibit K562/A02 cells proliferation with an IC50 value of 0.96 mu M. Interestingly, N-hydroxy-6-({(2E)-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-({(2E)-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-({(2E)-2-[(3-nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide might be a promising lead to discover novel antileukemia agents against P-gp overexpressing leukemic cells.
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