Discovery of thiosemicarbazone-containing compounds with potent anti-proliferation activity against drug-resistant K562/A02 cells
| Autor: | Nan Sun, Xiaoke Gu, Jingying Qiu, Yueting Zou, Jing Chen, Chunyu Jiang, Xin Li, Qingqing Zhou, Mingyu Guan, Qinghua Song |
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| Rok vydání: | 2020 |
| Předmět: |
Thiosemicarbazones
Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Apoptosis Pharmacology Biochemistry Drug Discovery medicine Humans ATP Binding Cassette Transporter Subfamily B Member 1 Molecular Biology IC50 Cell Proliferation P-glycoprotein chemistry.chemical_classification Reactive oxygen species Leukemia biology Organic Chemistry medicine.disease Drug Resistance Multiple In vitro Multiple drug resistance chemistry Drug Resistance Neoplasm biology.protein Molecular Medicine K562 Cells Reactive Oxygen Species K562 cells |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 30:127638 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2020.127638 |
| Popis: | P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle to successful chemotherapy for leukemia. In this study, a series of thiosemicarbazone-containing compounds (4a-b, 7a-q) were synthesized. Biological evaluation showed that the most active compound 7e displayed potent anti-leukemia activity against P-gp overexpressing drug-resistant K562/A02 cells, with an IC50 value of 0.44 μM. Notably, compound 7e exhibited a selective killing effect on K562/A02 cells by dose-dependently increasing the intracellular levels of reactive oxygen species (ROS), thus exerting a potential collateral sensitivity (CS)-promoting effect in vitro. Moreover, compound 7e could inhibit HDAC1 and HDAC6, and induce the apoptosis of K562/A02 cells by increasing the expression of Bax, decreasing Bcl-2 protein level, and promoting the cleavage of caspase-3 and PARP, respectively. Overall, 7e may be a potential anti-cancer agent against drug-resistant myelogenous leukemia. |
| Databáze: | OpenAIRE |
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