Journal
NUCLEIC ACIDS RESEARCH
Volume 46, Issue 7, Pages 3284-3297Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky202
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Funding
- National natural Science Foundation of China [81503305, 21708009]
- China Postdoctoral Science Foundation [2015M582227]
- Program for Changjiang Scholars of Ministry of Education of the People's Republic of China [T2016088]
- National natural Science Foundation [81725021]
- Innovative Research Groups of the National Natural Science Foundation of China [81721005]
- Academic Frontier Youth Team of HUST
- Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST
- Fundamental Research Fund for the Central Universities [2017KFYXJJ153, 2017KFYXJJ152]
- Singapore Ministry of Education Academic Research Fund Tier 3 [MOE 2012-T3-1-001]
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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.
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