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Br J Cancer ; 130(8): 1365-1376, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38396172

RESUMO

BACKGROUND: Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide. Here, we examined whether TTFields enhance the antineoplastic activity of CUSP9v3 against this disease. METHODS: We performed preclinical testing of a multimodal approach of TTFields and CUSP9v3 in different glioblastoma models. RESULTS: TTFields had predominantly synergistic inhibitory effects on the cell viability of glioblastoma cells and non-directed movement was significantly impaired when combined with CUSP9v3. TTFields plus CUSP9v3 significantly enhanced apoptosis, which was associated with a decreased mitochondrial outer membrane potential (MOMP), enhanced cleavage of effector caspase 3 and reduced expression of Bcl-2 and Mcl-1. Moreover, oxidative phosphorylation and expression of respiratory chain complexes I, III and IV was markedly reduced. CONCLUSION: TTFields strongly enhance the CUSP9v3-mediated anti-glioblastoma activity. TTFields are currently widely used for the treatment of glioblastoma patients and CUSP9v3 was shown to have a favorable safety profile in a phase Ib/IIa trial (NCT02770378) which facilitates transition of this multimodal approach to the clinical setting.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Terapia por Estimulação Elétrica , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Reposicionamento de Medicamentos , Reprogramação Metabólica , Temozolomida/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Terapia Combinada
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