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 As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione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.
- Klíčová slova
- C19-position substituted geldanamycin derivatives, ESCC, HSP90, NQO1, NRF2-NQO1-activated cancer,
- MeSH
- benzochinony * farmakologie chemie MeSH
- faktor 2 související s NF-E2 * metabolismus genetika MeSH
- lidé MeSH
- makrocyklické laktamy * farmakologie chemie terapeutické užití MeSH
- myši nahé MeSH
- myši MeSH
- NAD(P)H dehydrogenasa (chinon) * metabolismus genetika MeSH
- nádorové buněčné linie MeSH
- nádory jícnu * farmakoterapie metabolismus genetika MeSH
- proteiny tepelného šoku HSP90 antagonisté a inhibitory metabolismus MeSH
- protinádorové látky farmakologie chemie MeSH
- skvamózní karcinom jícnu * farmakoterapie genetika metabolismus MeSH
- xenogenní modely - testy protinádorové aktivity * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- benzochinony * MeSH
- faktor 2 související s NF-E2 * MeSH
- geldanamycin MeSH Prohlížeč
- makrocyklické laktamy * MeSH
- NAD(P)H dehydrogenasa (chinon) * MeSH
- NFE2L2 protein, human MeSH Prohlížeč
- NQO1 protein, human MeSH Prohlížeč
- proteiny tepelného šoku HSP90 MeSH
- protinádorové látky MeSH
