Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
Institute of Pharmacy, Center for Public Health, Paracelsus Medical University, Salzburg, Austria.
FASEB J. 2020 Sep;34(9):11860-11882. doi: 10.1096/fj.202001128R. Epub 2020 Jul 11.
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.
索拉非尼是晚期肝细胞癌（HCC）患者的当前标准治疗方法。然而，在治疗过程中经常会发生获得性药物耐药，并且在索拉非尼治疗终止后肿瘤迅速复发。为了确定这种限制治疗的生长恢复的机制，我们建立了稳健的索拉非尼耐药 HCC 细胞模型，这些模型表现出线粒体功能障碍和化疗交叉耐药性。我们发现，索拉非尼停药后肿瘤细胞增殖迅速复发，这是由于线粒体结构的更新以及代谢向高电子传递系统（ETS）活性的转变所致。翻译抑制抗生素替加环素损害了线粒体 DNA 编码的 ETS 亚基的生物发生，并限制了谷氨酰胺氧化所需的电子受体周转率。因此，替加环素可防止体外和体内小鼠异种移植中的肿瘤复发。这些结果为正在接受索拉非尼治疗或因严重不良反应而中断治疗的进展期 HCC 患者提供了一种有前途的二线治疗方法。
