ZYH005, a Novel DNA Intercalator, Overcomes All-trans Retinoic Acid Resistance in Acute Promyelocytic Leukemia

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2018 Mar 20

PMID 29554366

Citations 5

Authors

Qingyi Tong

Huijuan You

Xintao Chen

Kongchao Wang

Weiguang Sun

Yufeng Pei

Xiaodan Zhao

Ming Yuan

Hucheng Zhu

Zengwei Luo

Yonghui Zhang

Affiliations

Soon will be listed here.

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.

Citing Articles

Synthesis of Thiaphenanthridinones from Sulfinate Esters and 2-Borylanilines.

Nakamura K, Suzuki M, Yoshida S Org Lett. 2024; 26(45):9676-9681.

PMID: 39504126 PMC: 11574856. DOI: 10.1021/acs.orglett.4c03420.

Force-enhanced sensitive and specific detection of DNA-intercalative agents directly from microorganisms at single-molecule level.

Liu T, Cai T, Huo J, Liu H, Li A, Yin M Nucleic Acids Res. 2024; 52(18):e86.

PMID: 39193913 PMC: 11472145. DOI: 10.1093/nar/gkae746.

20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3.

Cheng S, Chen L, Ying J, Wang Y, Jiang W, Zhang Q J Ginseng Res. 2024; 48(3):298-309.

PMID: 38707638 PMC: 11068957. DOI: 10.1016/j.jgr.2023.12.003.

20()-ginsenoside Rh2 induces caspase-dependent promyelocytic leukemia-retinoic acid receptor A degradation in NB4 cells via Akt/Bax/caspase9 and TNF-α/caspase8 signaling cascades.

Zhu S, Liu X, Xue M, Li Y, Cai D, Wang S J Ginseng Res. 2021; 45(2):295-304.

PMID: 33841010 PMC: 8020289. DOI: 10.1016/j.jgr.2020.05.001.

2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia.

Lu Y, Yan J, Xia L, Qin K, Yin Q, Xu H Haematologica. 2018; 104(1):102-112.

PMID: 30076181 PMC: 6312026. DOI: 10.3324/haematol.2018.191916.

References

Li J, Zhu H, Hu J, Mi J, Chen S, Chen Z . Progress in the treatment of acute promyelocytic leukemia: optimization and obstruction. Int J Hematol. 2014; 100(1):38-50. DOI: 10.1007/s12185-014-1603-1. View

Nasr R, de The H . Eradication of acute promyelocytic leukemia-initiating cells by PML/RARA-targeting. Int J Hematol. 2010; 91(5):742-7. DOI: 10.1007/s12185-010-0582-0. View

Luchetti G, Johnston R, Mathieu V, Lefranc F, Hayden K, Andolfi A . Bulbispermine: a crinine-type Amaryllidaceae alkaloid exhibiting cytostatic activity toward apoptosis-resistant glioma cells. ChemMedChem. 2012; 7(5):815-22. PMC: 3519447. DOI: 10.1002/cmdc.201100608. View

Pearl L, Schierz A, Ward S, Al-Lazikani B, Pearl F . Therapeutic opportunities within the DNA damage response. Nat Rev Cancer. 2015; 15(3):166-80. DOI: 10.1038/nrc3891. View

Gu Z, Wu Y, Zhou M, Liu C, Xu H, Yan H . Pharicin B stabilizes retinoic acid receptor-α and presents synergistic differentiation induction with ATRA in myeloid leukemic cells. Blood. 2010; 116(24):5289-97. DOI: 10.1182/blood-2010-02-267963. View

Lipfert J, Klijnhout S, Dekker N . Torsional sensing of small-molecule binding using magnetic tweezers. Nucleic Acids Res. 2010; 38(20):7122-32. PMC: 2978369. DOI: 10.1093/nar/gkq598. View

Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T . Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment. Blood. 2011; 118(6):1600-9. DOI: 10.1182/blood-2011-01-329433. View

Lallemand-Breitenbach V, Zhu J, Chen Z, de The H . Curing APL through PML/RARA degradation by As2O3. Trends Mol Med. 2011; 18(1):36-42. DOI: 10.1016/j.molmed.2011.10.001. View

Zhan G, Zhou J, Liu R, Liu T, Guo G, Wang J . Galanthamine, Plicamine, and Secoplicamine Alkaloids from Zephyranthes candida and Their Anti-acetylcholinesterase and Anti-inflammatory Activities. J Nat Prod. 2016; 79(4):760-6. DOI: 10.1021/acs.jnatprod.5b00681. View

10.

Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiraoka A . Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 1997; 90(3):967-73. View

11.

Zhu H, Chen C, Xue Y, Tong Q, Li X, Chen X . Asperchalasine A, a Cytochalasan Dimer with an Unprecedented Decacyclic Ring System, from Aspergillus flavipes. Angew Chem Int Ed Engl. 2015; 54(45):13374-8. DOI: 10.1002/anie.201506264. View

12.

Vladescu I, McCauley M, Nunez M, Rouzina I, Williams M . Quantifying force-dependent and zero-force DNA intercalation by single-molecule stretching. Nat Methods. 2007; 4(6):517-22. DOI: 10.1038/nmeth1044. View

13.

Yuan M, Chen L, Wang J, Chen S, Wang K, Xue Y . Transition-metal-free synthesis of phenanthridinones from biaryl-2-oxamic acid under radical conditions. Org Lett. 2015; 17(2):346-9. DOI: 10.1021/ol503459s. View

14.

Tatham M, Geoffroy M, Shen L, Plechanovova A, Hattersley N, Jaffray E . RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008; 10(5):538-46. DOI: 10.1038/ncb1716. View

15.

Puigvert J, Sanjiv K, Helleday T . Targeting DNA repair, DNA metabolism and replication stress as anti-cancer strategies. FEBS J. 2015; 283(2):232-45. DOI: 10.1111/febs.13574. View

16.

Voisset E, Moravcsik E, Stratford E, Jaye A, Palgrave C, Hills R . Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice. Blood. 2017; 131(6):636-648. PMC: 5805489. DOI: 10.1182/blood-2017-07-794784. View

17.

Brown D, Kogan S, Lagasse E, Weissman I, Alcalay M, Pelicci P . A PMLRARalpha transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 1997; 94(6):2551-6. PMC: 20126. DOI: 10.1073/pnas.94.6.2551. View

18.

Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L . Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol. 2008; 10(5):547-55. DOI: 10.1038/ncb1717. View

19.

Kogan S, Hong S, Shultz D, Privalsky M, Bishop J . Leukemia initiated by PMLRARalpha: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable. Blood. 2000; 95(5):1541-50. View

20.

Esposito M, Zhao L, Kan Fung T, Rane J, Wilson A, Martin N . Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat Med. 2015; 21(12):1481-90. DOI: 10.1038/nm.3993. View