Integrating and optimizing tonabersat in standard glioblastoma therapy: A preclinical study.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Glioblastoma*/pathology ; Brain Neoplasms*/pathology ; Benzamides* ; Benzopyrans*; Rats ; Animals ; Connexin 43 ; Standard of Care ; Temozolomide/therapeutic use ; Rats, Inbred F344 ; Antineoplastic Agents, Alkylating/therapeutic use

Glioblastoma (GB), a highly aggressive primary brain tumor, presents a poor prognosis despite the current standard therapy, including radiotherapy and temozolomide (TMZ) chemotherapy. Tumor microtubes involving connexin 43 (Cx43) contribute to glioma progression and therapy resistance, suggesting Cx43 inhibition as a potential treatment strategy. This research aims to explore the adjuvant potential of tonabersat, a Cx43 gap junction modulator and blood-brain barrier-penetrating compound, in combination with the standard of care for GB. In addition, different administration schedules and timings to optimize tonabersat's therapeutic window are investigated. The F98 Fischer rat model will be utilized to investigate tonabersat's impact in a clinically relevant setting, by incorporating fractionated radiotherapy (three fractions of 9 Gy) and TMZ chemotherapy (29 mg/kg). This study will evaluate tonabersat's impact on tumor growth, survival, and treatment response through advanced imaging (CE T1-w MRI) and histological analysis. Results show extended survival in rats receiving tonabersat with standard care, highlighting its adjuvant potential. Daily tonabersat administration, both preceding and following radiotherapy, emerges as a promising approach for maximizing survival outcomes. The study suggests tonabersat's potential to reduce tumor invasiveness, providing a new avenue for GB treatment. In conclusion, this preclinical investigation highlights tonabersat's potential as an effective adjuvant treatment for GB, and its established safety profile from clinical trials in migraine treatment presents a promising foundation for further exploration.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Zoteva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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2XD9773ZMN (tonabersat)
0 (Connexin 43)
YF1K15M17Y (Temozolomide)
0 (Antineoplastic Agents, Alkylating)
0 (Benzamides)
0 (Benzopyrans)

Date Created: 20240315 Date Completed: 20240318 Latest Revision: 20240318

20240318

PMC10942024

10.1371/journal.pone.0300552

38489314