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Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression
Zhang JunMin1,2; Liu Pei1; Chen JianWei1,3; Yao DaHong1; Liu Qing1; Zhang JuanHong1,2,4; Zhang Hua Wei3; Leung Elaine Lai Han5; Yao XiaoJun1; Liu Liang1
2023-01
Source PublicationPharmacological Research
ISSN1043-6618
Volume187
Abstract

A primary strategy employed in cancer therapy is the inhibition of topoisomerase II (Topo II), implicated in cell survival. However, side effects and adverse reactions restrict the utilization of Topo II inhibitors. Thus, investigations focus on the discovery of novel compounds that are capable of inhibiting the Topo II enzyme and feature safer toxicological profiles. Herein, we upgrade an old antibiotic chrysomycin A from Streptomyces sp. 891 as a compelling Topo II enzyme inhibitor. Our results show that chrysomycin A is a new chemical entity. Notably, chrysomycin A targets the DNA-unwinding enzyme Topo II with an efficient binding potency and a significant inhibition of intracellular enzyme levels. Intriguingly, chrysomycin A kills KRAS-mutant lung adenocarcinoma cells and is negligible cytotoxic to normal cells at the cellular level, thus indicating a capability of potential treatment. Furthermore, mechanism studies demonstrate that chrysomycin A inhibits the Topo II enzyme and stimulates the accumulation of reactive oxygen species, thereby inducing DNA damage-mediated cancer cell apoptosis. Importantly, chrysomycin A exhibits excellent control of cancer progression and excellent safety in tumor-bearing models. Our results provide a chemical scaffold for the synthesis of new types of Topo II inhibitors and reveal a novel target for chrysomycin A to meet its further application.

KeywordApoptosis Chrysomycin a Dna Damage Reactive Oxygen Species Topoisomerase Ii Activity
DOI10.1016/j.phrs.2022.106565
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000895773500006
PublisherAcademic Press
Scopus ID2-s2.0-85142362596
Fulltext Access
Citation statistics
Document TypeJournal article
CollectionDEPARTMENT OF BIOMEDICAL SCIENCES
INSTITUTE OF COLLABORATIVE INNOVATION
Corresponding AuthorLeung Elaine Lai Han; Yao XiaoJun; Liu Liang
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao
2.School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China
3.School of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310000, China
4.College of Life Science, Northwest Normal University, Lanzhou, 730070, China
5.Cancer Center, Faculty of Health Science, and MOE Frontiers Science Center for Precision Oncology, University of Macau, Macao
First Author AffilicationUniversity of Macau
Corresponding Author AffilicationCancer Centre;  University of Macau
Recommended Citation
GB/T 7714
Zhang JunMin,Liu Pei,Chen JianWei,et al. Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression[J]. Pharmacological Research, 2023, 187.
APA Zhang JunMin., Liu Pei., Chen JianWei., Yao DaHong., Liu Qing., Zhang JuanHong., Zhang Hua Wei., Leung Elaine Lai Han., Yao XiaoJun., & Liu Liang (2023). Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression. Pharmacological Research, 187.
MLA Zhang JunMin,et al."Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression".Pharmacological Research 187(2023).
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