Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression
Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:187 |
|---|---|
| Enthalten in: |
Pharmacological research - 187(2023) vom: 01. Jan., Seite 106565 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhang, Junmin [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 15.02.2023 Date Revised 15.02.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.phrs.2022.106565 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM349272409 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM349272409 | ||
| 003 | DE-627 | ||
| 005 | 20231226042227.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.phrs.2022.106565 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1164.xml |
| 035 | |a (DE-627)NLM349272409 | ||
| 035 | |a (NLM)36414124 | ||
| 035 | |a (PII)S1043-6618(22)00511-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhang, Junmin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 15.02.2023 | ||
| 500 | |a Date Revised 15.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Chrysomycin A | |
| 650 | 4 | |a DNA damage | |
| 650 | 4 | |a Reactive oxygen species | |
| 650 | 4 | |a Topoisomerase II activity | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a chrysomycin A |2 NLM | |
| 650 | 7 | |a 82196-88-1 |2 NLM | |
| 650 | 7 | |a DNA Topoisomerases, Type II |2 NLM | |
| 650 | 7 | |a EC 5.99.1.3 |2 NLM | |
| 650 | 7 | |a KRAS protein, human |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins p21(ras) |2 NLM | |
| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 650 | 7 | |a Topoisomerase II Inhibitors |2 NLM | |
| 700 | 1 | |a Liu, Pei |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jianwei |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Dahong |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Juanhong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hua-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Leung, Elaine Lai-Han |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Xiao-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Liang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Pharmacological research |d 1992 |g 187(2023) vom: 01. Jan., Seite 106565 |w (DE-627)NLM012597384 |x 1096-1186 |7 nnns |
| 773 | 1 | 8 | |g volume:187 |g year:2023 |g day:01 |g month:01 |g pages:106565 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.phrs.2022.106565 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 187 |j 2023 |b 01 |c 01 |h 106565 | ||