ZYH005, a novel DNA intercalator, overcomes all-trans retinoic acid resistance in acute promyelocytic leukemia
| Autor: | Zengwei Luo, Xintao Chen, Hucheng Zhu, Kongchao Wang, Yonghui Zhang, Huijuan You, Xiaodan Zhao, Qingyi Tong, Yufeng Pei, Ming Yuan, Weiguang Sun |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Acute promyelocytic leukemia Oncogene Proteins Fusion DNA damage Retinoic acid Apoptosis Tretinoin Promyelocytic Leukemia Protein Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Arsenic Trioxide Leukemia Promyelocytic Acute Chemical Biology and Nucleic Acid Chemistry immune system diseases Cell Line Tumor Genetics medicine Animals Humans Doxorubicin Arsenic trioxide neoplasms Cell Proliferation Cisplatin Retinoic Acid Receptor alpha medicine.disease Xenograft Model Antitumor Assays Intercalating Agents Phenanthridines Molecular Docking Simulation Leukemia 030104 developmental biology chemistry Drug Resistance Neoplasm Caspases 030220 oncology & carcinogenesis Proteolysis Cancer research DNA Damage medicine.drug |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gky202 |
| Popis: | Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)–one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL. |
| Databáze: | OpenAIRE |
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