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

Benedí, Andrea ; Beltrán-Visiedo, Manuel (Universidad de Zaragoza) ; Jiménez-Alduán, Nelia ; Serrano-Del Valle, Alfonso ; Anel, Alberto (Universidad de Zaragoza) ; Naval, Javier (Universidad de Zaragoza) ; Marzo, Isabel (Universidad de Zaragoza)

Resumen: 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.

Idioma: Inglés

DOI: 10.3390/cancers17142290

Año: 2025

Publicado en: Cancers 17, 14 (2025), 2290 [32 pp.]
ISSN: 2072-6694

Financiación: info:eu-repo/grantAgreement/ES/DGA/B31-20R
Financiación: info:eu-repo/grantAgreement/ES/MCIU/FPU17-02586
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2022-136799OB-I00
Financiación: info:eu-repo/grantAgreement/ES/UZ/PI-PRD/2021-00

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
Área (Departamento): Área Biología Celular (Dpto. Bioq.Biolog.Mol. Celular)