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However, concerns exist regarding its secondary effects in humans and its occasional lack of efficacy in certain malignancies. Therefore, combined therapies with ibrutinib have emerged as promising new approaches. In this study, we aimed to explore its therapeutic potential through different approaches. For this purpose, we combined this drug with the BH3 mimetics ABT-199 and ABT-737, which inhibit anti-apoptotic members of the Bcl-2 family, and with the PDK1 inhibitor dichloroacetate (DCA), respectively. As cell models, we used ex vivo samples from patients and also selected the in vitro CLL cell line Mec-1, generating two sub-lines overexpressing Bcl-XL and Mcl-1, a common feature in this cancer. Results demonstrated a synergistic effect for both approaches, in all tumor cells tested, for both cytostatic and cytotoxic effects. Mechanistically, the expression of Bcl-2-family proteins was explored, exhibiting increases in pro-apoptotic, but also in anti-apoptotic, proteins upon ibrutinib treatment and a relative increase in the amount of the pro-apoptotic protein PUMA after treatment with DCA. Our data provides new insights into combined therapies with ibrutinib for CLL, which further expands our knowledge and the potential of this drug for cancer treatment.<\/jats:p>","DOI":"10.3390\/cells14171343","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T16:18:15Z","timestamp":1756484295000},"page":"1343","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Combination of Ibrutinib with BH3 Mimetics or Dichloroacetate Is Effective in B-CLL"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1710-4821","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Marco-Brualla","sequence":"first","affiliation":[{"name":"Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragon), University of Zaragoza, 50009 Zaragoza, Spain"},{"name":"Faculty of Pharmacy, University San Pablo-CEU, 28660 Boadilla del Monte, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Gonzalo","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragon), University of Zaragoza, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5068-7355","authenticated-orcid":false,"given":"Gemma","family":"Azaceta","sequence":"additional","affiliation":[{"name":"Hematology Department, Lozano Blesa Clinical Hospital, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Izquierdo","sequence":"additional","affiliation":[{"name":"Hematology Department, Lozano Blesa Clinical Hospital, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Palomera","sequence":"additional","affiliation":[{"name":"Hematology Department, Lozano Blesa Clinical Hospital, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4385-4888","authenticated-orcid":false,"given":"Mart\u00edn","family":"Villalba","sequence":"additional","affiliation":[{"name":"IRMB, University of Montpellier, INSERM, CNRS, Montpellier CHU, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2315-9079","authenticated-orcid":false,"given":"Isabel","family":"Marzo","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragon), University of Zaragoza, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5175-8394","authenticated-orcid":false,"given":"Alberto","family":"Anel","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, Aragon Health Research Institute (IIS-Aragon), University of Zaragoza, 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/ajh.27546","article-title":"Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy","volume":"100","author":"Hallek","year":"2025","journal-title":"Am. 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