Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F25%3A10491819" target="_blank" >RIV/00216208:11160/25:10491819 - isvavai.cz</a>
Výsledek na webu
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=kQ9ICO_E4u" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=kQ9ICO_E4u</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1080/10985549.2024.2438817" target="_blank" >10.1080/10985549.2024.2438817</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma
Popis výsledku v původním jazyce
In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
Název v anglickém jazyce
Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma
Popis výsledku anglicky
In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10608 - Biochemistry and molecular biology
Návaznosti výsledku
Projekt
<a href="/cs/project/EH22_008%2F0004607" target="_blank" >EH22_008/0004607: Nové technologie pro translační výzkum ve farmaceutických vědách /NETPHARM</a><br>
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Ostatní
Rok uplatnění
2025
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Molecular and Cellular Biology
ISSN
0270-7306
e-ISSN
1098-5549
Svazek periodika
45
Číslo periodika v rámci svazku
2
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
19
Strana od-do
79-97
Kód UT WoS článku
001382430300001
EID výsledku v databázi Scopus
2-s2.0-85212957590