Tolerable treatment of glioblastoma with redox-cycling ‘mitocans': a comparative study in vivo

ABSTRACT

Objectives: The present study describes a pharmacological strategy for the treatment of glioblastoma by redoxcycling ‘mitocans’ such as quinone/ascorbate combination drugs, based on their tumor-selective redox-modulating effects and tolerance to normal cells and tissues.

Methods: Experiments were performed on glioblastoma mice (orthotopic model) treated with coenzyme Q0/ascorbate (Q0/A). The drug was injected intracranially in a single dose. The following parameters were analyzed in vivo using MRI orex vivo using conventional assays: tumor growth, survival, cerebral and tumor perfusion, tumor cell density, tissue redox-state, and expression of tumor-associated NADH oxidase (tNOX).

Results: Q0/A markedly suppressed tumor growth and significantly increased survival of glioblastoma mice. This was accompanied by increased oxidative stress in the tumor but not in non-cancerous tissues, increased tumor blood flow, and downregulation of tNOX. The redox-modulating and anticancer effects of Q0/A were more pronounced than those of menadione/ascorbate (M/A) obtained in our previous study. No adverse drug-related side-effects were observed in glioblastoma mice treated with Q0/A.

Discussion: Q0/A differentiated cancer cells and tissues, particularly glioblastoma, from normal ones by redox targeting, causing a severe oxidative stress in the tumor but not in non-cancerous tissues. Q0/A had a pronounced anticancer activity and could be considered safe for the organism within certain concentration limits. The results suggest that the rate of tumor resorption and metabolism of toxic residues must be controlled and maintained within tolerable limits to achieve longer survival, especially at intracranial drug administration.

KEYWORDS:

• Redox-cyclers
• glioblastoma
• oxidative stress
• cerebral perfusion
• tumor cell density
• tNOX
• coenzyme Q0
• menadione
• ascorbate

Acknowledgements

The authors would like to thank Dr. Takayuki Obata (QST, Japan) for his suggestions in the interpretation of the MRI data. The participation of Dr. Raj Parajuli (QST, Japan) in the MRI measurement is gratefully acknowledged. Conception and design: R.B., Z.Z.; Development of methodology: R.B., A.S., Z.Z., Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.S., S.S., R.B.; Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): R.B., Z.Z., A.S., D.L.; Writing, review, and/or revision of the manuscript: R.B., Z.Z., A.S., S.S., D.L.; Administrative, technical, or material support (i.e. reporting or organizing data, constructing databases): I.A.; Study supervision: I.A. Note: The participation of Akira Sumiyoshi and Sayaka Shibata in this study should be considered equal.

Data availability statement

The data presented in this study are available upon request from the corresponding author.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The study was partially supported by the following grants: QST/ICM grant funded by the IC-MedTech Corp., US (granted to R.B.);Kakenhi (#21H04966, #21KK0201, #17KK0102) funded by the Japanese Society for the Promotion of Science; and the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project SUMMIT BG-RRP-2.004-0008-C01. The MRI devices were partially supported by the Project for promoting public utilization of advanced research infrastructure (JPMXS0450400422) funded by the JST/MEXT.