162989 20251009133840.0 doi 10.3390/cells14171343 sideral 145547 ART-2025-145547 eng Marco-Brualla, Joaquín The Combination of Ibrutinib with BH3 Mimetics or Dichloroacetate Is Effective in B-CLL 2025 Access copy available to the general public Unrestricted Since its discovery, the BTK inhibitor ibrutinib has redefined the standard treatments for hematological cancers, such as chronic lymphocytic leukemia (CLL). 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. info:eu-repo/grantAgreement/ES/DGA/B31-20R info:eu-repo/grantAgreement/ES/DGA/B23-20R info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00 info:eu-repo/grantAgreement/ES/MICINN/PID2022-136799OB-I00 info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Gonzalo, Oscar (orcid)0000-0002-7444-2341 Azaceta, Gemma Universidad de Zaragoza (orcid)0000-0001-5068-7355 Izquierdo, Isabel Universidad de Zaragoza Palomera, Luis (orcid)0000-0001-8515-3599 Villalba, Martín Marzo, Isabel Universidad de Zaragoza (orcid)0000-0002-2315-9079 Anel, Alberto Universidad de Zaragoza (orcid)0000-0002-5175-8394 1007 610 Universidad de Zaragoza Dpto. Medicina, Psiqu. y Derm. Area Medicina 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 1002 050 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Biología Celular 14, 17 (2025), 1343 [18 pp.] Cells Cells 2073-4409 3050845 http://zaguan.unizar.es/record/162989/files/texto_completo.pdf Versión publicada 2488563 http://zaguan.unizar.es/record/162989/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:162989 articulos driver 2025-10-09-13:25:52 ARTICLE