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http://hdl.handle.net/2445/157937
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DC Field | Value | Language |
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dc.contributor.author | Tutusaus, Anna | - |
dc.contributor.author | Stefanovic, Milica | - |
dc.contributor.author | Boix i Ferrero, Loreto | - |
dc.contributor.author | Cucarull, Blanca | - |
dc.contributor.author | Zamora, Aynara | - |
dc.contributor.author | Blasco, Laura | - |
dc.contributor.author | García de Frutos, Pablo | - |
dc.contributor.author | Reig, María | - |
dc.contributor.author | Fernández-Checa Torres, José Carlos | - |
dc.contributor.author | Marí García, Montserrat | - |
dc.contributor.author | Colell Riera, Anna | - |
dc.contributor.author | Bruix Tudó, Jordi | - |
dc.contributor.author | Morales Muñoz, Albert | - |
dc.date.accessioned | 2020-04-28T22:28:45Z | - |
dc.date.available | 2020-04-28T22:28:45Z | - |
dc.date.issued | 2018-03-30 | - |
dc.identifier.issn | 1949-2553 | - |
dc.identifier.uri | http://hdl.handle.net/2445/157937 | - |
dc.description.abstract | Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy. | - |
dc.format.extent | 17 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Impact Journals | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.24673 | - |
dc.relation.ispartof | Oncotarget, 2018, vol. 9, num. 24, p. 16701-16717 | - |
dc.relation.uri | https://doi.org/10.18632/oncotarget.24673 | - |
dc.rights | cc-by (c) Tutusaus, Anna et al., 2018 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es | - |
dc.source | Articles publicats en revistes (Medicina) | - |
dc.subject.classification | Càncer de fetge | - |
dc.subject.classification | Inhibidors enzimàtics | - |
dc.subject.classification | Tractament adjuvant del càncer | - |
dc.subject.other | Liver cancer | - |
dc.subject.other | Enzyme inhibitors | - |
dc.subject.other | Adjuvant treatment of cancer | - |
dc.title | Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 692345 | - |
dc.date.updated | 2020-04-28T22:28:46Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 29682179 | - |
Appears in Collections: | Articles publicats en revistes (Medicina) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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692345.pdf | 10.45 MB | Adobe PDF | View/Open |
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