학술논문
Tumor Treating Fields (TTFields) combined with the drug repurposing approach CUSP9v3 induce metabolic reprogramming and synergistic anti-glioblastoma activity in vitro.
Document Type
Academic Journal
Author
Cao Q; Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany.; Hajosch A; Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany.; Kast RE; IIAIGC Study Center, Burlington, VT, USA.; Loehmann C; Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany.; Hlavac M; Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany.; Fischer-Posovszky P; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.; Strobel H; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.; Westhoff MA; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.; Siegelin MD; Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA.; Wirtz CR; Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany.; Halatsch ME; Department of Neurosurgery, Cantonal Hospital of Winterthur, Winterthur, Switzerland.; Karpel-Massler G; Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany. georg.karpel@gmail.com.
Source
Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
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.
(© 2024. The Author(s).)
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.
(© 2024. The Author(s).)