Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma: A preclinical F98 glioblastoma rat model study


Autoři: Valerie De Meulenaere aff001;  Ellen Bonte aff001;  Jeroen Verhoeven aff002;  Jean-Pierre Kalala Okito aff003;  Leen Pieters aff004;  Anne Vral aff004;  Olivier De Wever aff005;  Luc Leybaert aff006;  Ingeborg Goethals aff007;  Christian Vanhove aff008;  Benedicte Descamps aff008;  Karel Deblaere aff001
Působiště autorů: Department of Radiology, Ghent University Hospital, Ghent, Belgium aff001;  Department of Pharmaceutical analysis, Ghent University, Ghent, Belgium aff002;  Department of Neurosurgery, Ghent University Hospital, Ghent, Belgium aff003;  Department of Human Structure and Repair, Ghent University, Ghent, Belgium aff004;  Department of Experimental Cancer Research, Ghent University, Ghent, Belgium aff005;  Department of Basic Medical Sciences, Ghent University, Ghent, Belgium aff006;  Department of Nuclear Medicine, Ghent University Hospital, Ghent, Belgium aff007;  IBiTech—Medisip—Infinity lab, Ghent University, Ghent, Belgium aff008
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224130

Souhrn

Purpose

Even with an optimal treatment protocol, the median survival of glioblastoma (GB) patients is only 12–15 months. Hence, there is need for novel effective therapies that improve survival outcomes. Recent evidence suggests an important role for connexin (Cx) proteins (especially Cx43) in the microenvironment of malignant glioma. Cx43-mediated gap junctional communication has been observed between tumor cells, between astrocytes and between tumor cells and astrocytes. Therefore, gap junction directed therapy using a pharmacological suppressor or modulator, such as tonabersat, could be a promising target in the treatment of GB. In this preclinical study, we evaluated the possible therapeutic potential of tonabersat in the F98 model.

Procedures

Female Fischer rats were inoculated with ± 25.000 F98 tumor cells in the right frontal lobe. Eight days post-inoculation contrast-enhanced T1-weighted (CE-T1w) magnetic resonance (MR) images were acquired to confirm tumor growth in the brain. After tumor confirmation, rats were randomized into a Control Group, a Connexin Modulation Group (CM), a Standard Medical Treatment Group (ST), and a Standard Medical Treatment with adjuvant Connexin Modulation Group (STCM). To evaluate therapy response, T2-weighted (T2w) and CE-T1w sequences were acquired at several time points. Tumor volume analysis was performed on CE-T1w images and statistical analysis was performed using a linear mixed model.

Results

Significant differences in estimated geometric mean tumor volumes were found between the ST Group and the Control Group and also between the STCM Group and the Control Group. In addition, significant differences in estimated geometric mean tumor volumes between the ST Group and the STCM Group were demonstrated. No significant differences in estimated geometric mean tumor volumes were found between the Control Group and the CM Group.

Conclusion

Our results demonstrate a therapeutic potential of tonabersat for the treatment of GB when used in combination with radiotherapy and temozolomide chemotherapy.

Klíčová slova:

Astrocytes – Cancer treatment – Euthanasia – Glioma – Magnetic resonance imaging – Oncology – Radiation therapy – Gap junctions


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Článek vyšel v časopise

PLOS One


2019 Číslo 10