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.
| Item Type: | Journal article |
|---|---|
| Faculties: | Chemistry and Pharmacy > Department of Pharmacy Chemistry and Pharmacy > Department of Biochemistry |
| Subjects: | 500 Science > 540 Chemistry |
| ISSN: | 0892-6638 |
| Language: | English |
| Item ID: | 89769 |
| Date Deposited: | 25. Jan 2022, 09:32 |
| Last Modified: | 25. Jan 2022, 09:32 |
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