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Pharmacological research

Pharmacological research

IF: 9.1
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Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression.

Published:1 January 2023 DOI: 10.1016/j.phrs.2022.106565 PMID: 36414124
Junmin Zhang , Pei Liu , Jianwei Chen , Dahong Yao , Qing Liu , Juanhong Zhang , Hua-Wei Zhang , Elaine Lai-Han Leung , Xiao-Jun Yao , Liang Liu

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.

Substances (5)

Materials Related products
Procduct Name CAS Molecular Formula Supplier Price
2′,7′-Dichlorodihydrofluorescein Diacetate 4091-99-0 C24H16Cl2O7 290 suppliers $16.00-$270980.00
2′,7′-Dichlorodihydrofluorescein Diacetate 4091-99-0 C24H16Cl2O7 290 suppliers $16.00-$270980.00
2′,7′-Dichlorodihydrofluorescein Diacetate 4091-99-0 C24H16Cl2O7 290 suppliers $16.00-$270980.00
2′,7′-Dichlorodihydrofluorescein Diacetate 4091-99-0 C24H16Cl2O7 290 suppliers $16.00-$270980.00

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