000162741 001__ 162741 000162741 005__ 20251017144621.0 000162741 0247_ $$2doi$$a10.3390/cancers17142290 000162741 0248_ $$2sideral$$a145221 000162741 037__ $$aART-2025-145221 000162741 041__ $$aeng 000162741 100__ $$aBenedí, Andrea 000162741 245__ $$aAlisertib 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 000162741 260__ $$c2025 000162741 5060_ $$aAccess copy available to the general public$$fUnrestricted 000162741 5203_ $$aBackground: 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. 000162741 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B31-20R$$9info:eu-repo/grantAgreement/ES/MCIU/FPU17-02586$$9info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PID2022-136799OB-I00$$9info:eu-repo/grantAgreement/ES/UZ/PI-PRD/2021-00 000162741 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es 000162741 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000162741 700__ $$aBeltrán-Visiedo, Manuel$$uUniversidad de Zaragoza 000162741 700__ $$aJiménez-Alduán, Nelia 000162741 700__ $$aSerrano-Del Valle, Alfonso 000162741 700__ $$0(orcid)0000-0002-5175-8394$$aAnel, Alberto$$uUniversidad de Zaragoza 000162741 700__ $$0(orcid)0000-0003-2156-8378$$aNaval, Javier$$uUniversidad de Zaragoza 000162741 700__ $$0(orcid)0000-0002-2315-9079$$aMarzo, Isabel$$uUniversidad de Zaragoza 000162741 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000162741 7102_ $$11002$$2050$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Biología Celular 000162741 773__ $$g17, 14 (2025), 2290 [32 pp.]$$pCancers$$tCancers$$x2072-6694 000162741 8564_ $$s14265264$$uhttps://zaguan.unizar.es/record/162741/files/texto_completo.pdf$$yVersión publicada 000162741 8564_ $$s2676609$$uhttps://zaguan.unizar.es/record/162741/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000162741 909CO $$ooai:zaguan.unizar.es:162741$$particulos$$pdriver 000162741 951__ $$a2025-10-17-14:22:00 000162741 980__ $$aARTICLE