Integrating and Optimizing Tonabersat in Standard Glioblastoma Therapy: A Preclinical Study

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2024 Mar 15

PMID 38489314

Authors

Velislava Zoteva

Valerie De Meulenaere

Christian Vanhove

Luc Leybaert

Robrecht Raedt

Leen Pieters

Anne Vral

Tom Boterberg

Karel Deblaere

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Connexin-43 in Cancer: Above and Beyond Gap Junctions!.

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Tonabersat enhances temozolomide-mediated cytotoxicity in glioblastoma by disrupting intercellular connectivity through connexin 43 inhibition.

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