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Messner, Martina; Schmitt, Sabine; Ardelt, Maximilian A.; Fröhlich, Thomas; Müller, Martin; Pein, Helmut; Huber-Cantonati, Petra; Ortler, Carina; König, 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): Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma. In: FASEB Journal, Vol. 34, No. 9: pp. 11860-11882
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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.