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Meßner, M.* ; Schmitt, S.* ; Ardelt, M.A.* ; Fröhlich, T.* ; Müller, M.* ; Pein, H.* ; Huber-Cantonati, P.* ; Ortler, C.* ; Koenig, L.M.* ; Zobel, L.* ; Koeberle, A.* ; Arnold, G.J.* ; Rothenfußer, S.* ; Kiemer, A.K.* ; Gerbes, A.L.* ; Zischka, H. ; Vollmar, A.M.* ; Pachmayr, J.*

Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma.

FASEB J. 34, 11860-11882 (2020)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Antibiotics ; Electron Acceptor Auxotrophy ; Mitochondrial Biogenesis ; Sorafenib Resistance ; Tumor Relapse; Cancer-cells; Oxidative-phosphorylation; Mitochondrial Biogenesis; Antitumor-activity; Therapy; Proliferation; Translation; Inhibition; Mitophagy; Receptor
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Zeitschrift FASEB Journal
Quellenangaben Band: 34, Heft: 9, Seiten: 11860-11882 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Bethesda, Md.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOXI)