Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models
| Autor: | Cucarull B, Tania Hernáez-Alsina, Montserrat Marí, Milica Stefanovic, Maria Reig, Jordi Bruix, Subías M, Anna Colell, Albert Morales, García de Frutos P, Anna Tutusaus, Loreto Boix |
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| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Generalitat de Catalunya |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Sorafenib Cancer Research A-1331852 Bcl-xL Apoptosis lcsh:RC254-282 Article combination therapy Càncer de fetge liver cancer 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Bcl-2 family In vivo Regorafenib Medicine Combination therapy biology business.industry apoptosis Apoptosi medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens digestive system diseases Mitochondria mitochondria 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Hepatocellular carcinoma Cancer research biology.protein business Liver cancer medicine.drug |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Cancers Volume 12 Issue 2 Cancers, Vol 12, Iss 2, p 332 (2020) Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | © 2020 by the authors. Background: The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. Methods: In in vitro and in vivo HCC models, we tested regorafenib’s effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment. Results: In hepatoma cell lines and Hep3B liver spheroids, regorafenib cytotoxicity was potentiated by BCL-xL siRNA transfection or pharmacological inhibition (A-1331852), while BCL-2 antagonism had no effect. Mitochondrial outer membrane permeabilization, cytochrome c release, and caspase-3 activation mediated A-1331852/regorafenib-induced cell death. In a patient-derived xenograft (PDX) HCC model, BCL-xL inhibition stimulated regorafenib activity, drastically decreasing tumor growth. Moreover, regorafenib-resistant HepG2 cells displayed increased BCL-xL and reduced MCL-1 expression, while A-1331852 reinstated regorafenib efficacy in vitro and in a xenograft mouse model. Interestingly, BCL-xL levels, associated with poor prognosis in liver and colorectal cancer, and the BCL-xL/MCL-1 ratio were detected as being increased in HCC patients. Conclusion: Regorafenib primes tumor cells to BH3-mimetic-induced cell death, allowing BCL-xL inhibition with A-1331852 or other strategies based on BCL-xL degradation to enhance regorafenib efficacy, offering a novel approach for HCC treatment, particularly for tumors with an elevated BCL-xL/MCL-1 ratio. This research was funded by Study funded by grants from Instituto de Salud Carlos III (PI16/00930 and PI19/01410), CIBEREHD and CIBERNED; Ministerio de Ciencia e Innovación (RTI2018-095672-B-I00 and RTI2018-095572-B-100) and co-funded by FEDER (MCI/AEI/FEDER, UE); AGAUR (2017_SGR_177 to A.M.) and CERCA Programme/Generalitat de Catalunya. |
| Databáze: | OpenAIRE |
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