Unknown

Dataset Information

0

ZYH005, a novel DNA intercalator, overcomes all-trans retinoic acid resistance in acute promyelocytic leukemia.


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.

SUBMITTER: Tong Q 

PROVIDER: S-EPMC6283422 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

Similar Datasets

2012-01-01 | S-EPMC3584620 | BioStudies
2020-01-01 | S-EPMC7266268 | BioStudies
2013-01-01 | S-EPMC6812572 | BioStudies
1000-01-01 | S-EPMC4001092 | BioStudies
2017-01-01 | S-EPMC5520717 | BioStudies
2017-01-01 | S-EPMC6063353 | BioStudies
2003-01-01 | S-EPMC275413 | BioStudies
2017-01-01 | S-EPMC5355346 | BioStudies
2015-01-01 | S-EPMC4599186 | BioStudies
2012-01-01 | S-EPMC3294029 | BioStudies