Meßner 2020 FASEB J

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Meßner M, Schmitt S, Ardelt MA, Fröhlich T, Müller M, Pein H, Huber-Cantonati P, Ortler C, Koenig LM, Zobel L, Koeberle A, Arnold GJ, Rothenfußer S, Kiemer AK, Gerbes AL, Zischka H, Vollmar AM, Pachmayr J (2020) Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma. FASEB J [Epub ahead of print].

» PMID: 32652772

Meßner Martina, Schmitt Sabine, Ardelt Maximilian A, Froehlich Thomas, Mueller Martin, Pein Helmut, Huber-Cantonati Petra, Ortler Carina, Koenig Lars M, Zobel Lena, Koeberle Andreas, Arnold Georg J, Rothenfußer Simon, Kiemer Alexandra K, Gerbes Alexander L, Zischka Hans, Vollmar Angelika M, Pachmayr Johanna (2020) FASEB J

Abstract: 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.

Keywords: Antibiotics, Electron acceptor auxotrophy, Mitochondrial biogenesis, Sorafenib resistance, Tumor relapse Bioblast editor: Plangger M O2k-Network Lab: DE Munich Zischka H


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2020-07