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Title: ZYH005, a novel DNA intercalator, overcomes all-trans retinoic acid resistance in acute promyelocytic leukemia
Authors: Tong, Q.
You, H.
Chen, X.
Wang, K.
Sun, W.
Pei, Y.
Zhao, X. 
Yuan, M.
Zhu, H.
Luo, Z.
Zhang, Y.
Issue Date: 2018
Publisher: Oxford University Press
Citation: Tong, Q., You, H., Chen, X., Wang, K., Sun, W., Pei, Y., Zhao, X., Yuan, M., Zhu, H., Luo, Z., Zhang, Y. (2018). ZYH005, a novel DNA intercalator, overcomes all-trans retinoic acid resistance in acute promyelocytic leukemia. Nucleic Acids Research 46 (7) : 3284-3297. ScholarBank@NUS Repository.
Rights: Attribution-NonCommercial 4.0 International
Abstract: 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. © The Author(s) 2018.
Source Title: Nucleic Acids Research
ISSN: 0305-1048
DOI: 10.1093/nar/gky202
Rights: Attribution-NonCommercial 4.0 International
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