162741 20251017144621.0 doi 10.3390/cancers17142290 sideral 145221 ART-2025-145221 eng Benedí, Andrea Alisertib and Barasertib Induce Cell Cycle Arrest and Mitochondria-Related Cell Death in Multiple Myeloma with Enhanced Efficacy Through Sequential Combination with BH3-Mimetics and Panobinostat 2025 Access copy available to the general public Unrestricted Background: The treatment landscape for multiple myeloma (MM) has significantly evolved in recent decades with novel therapies like proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. However, MM remains incurable, necessitating new pharmacological strategies. Mitotic kinases, such as Aurora proteins, have emerged as potential targets. Selective inhibitors of Aurora A and B,- alisertib (MLN8237) and barasertib (AZD1152), respectively, have shown anti-myeloma activity in preclinical studies, with alisertib demonstrating modest efficacy in early clinical trials. Methods and Results: This study investigated the mechanisms of action of alisertib and barasertib and their combination with antitumor agents in a panel of five MM cells lines. Both drugs induced cell cycle arrest phase and abnormal nuclear morphologies. Alisertib caused prolonged mitotic arrest, whereas barasertib induced transient arrest, both resulting in the activation of mitotic catastrophe. These findings revealed three potential outcomes: cell death, senescence, or polyploidy. High mitochondrial reactive oxygen species (mROS) were identified as possible drivers of cell death. Caspase inhibition reduced caspase-3 activation but did not prevent cell death. Interestingly, alisertib at low doses remained toxic to Bax/BakDKO cells, although mitochondrial potential disruption and cytochrome c release were observed. Sequential combinations of high-dose Aurora kinase inhibitors with BH3-mimetics, and in specific cases with panobinostat, showed a synergistic effect. Conversely, the simultaneous combination of alisertib and barasertib showed mostly antagonistic effects. Conclusions: Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules. info:eu-repo/grantAgreement/ES/DGA/B31-20R info:eu-repo/grantAgreement/ES/MCIU/FPU17-02586 info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00 info:eu-repo/grantAgreement/ES/MICINN/PID2022-136799OB-I00 info:eu-repo/grantAgreement/ES/UZ/PI-PRD/2021-00 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 Beltrán-Visiedo, Manuel Universidad de Zaragoza Jiménez-Alduán, Nelia Serrano-Del Valle, Alfonso Anel, Alberto Universidad de Zaragoza (orcid)0000-0002-5175-8394 Naval, Javier Universidad de Zaragoza (orcid)0000-0003-2156-8378 Marzo, Isabel Universidad de Zaragoza (orcid)0000-0002-2315-9079 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 17, 14 (2025), 2290 [32 pp.] Cancers Cancers 2072-6694 14265264 http://zaguan.unizar.es/record/162741/files/texto_completo.pdf Versión publicada 2676609 http://zaguan.unizar.es/record/162741/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:162741 articulos driver 2025-10-17-14:22:00 ARTICLE