Cytotoxic and antiproliferative effects of thymoquinone on rat C6 glioma cells depend on oxidative stress

• Published in: Molecular and cellular biochemistry Vol. 462; no. 1-2; pp. 195 - 206
• Main Authors: Krylova, N. G., Drobysh, M. S., Semenkova, G. N., Kulahava, T. A., Pinchuk, S. V., Shadyro, O. I.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2019; Springer; Springer Nature B.V
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Astrocytes; Benzoquinones - chemistry; Benzoquinones - pharmacology; Biochemistry; Biomedical and Life Sciences; Brain tumors; Cancer; Cardiology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Comparative analysis; Cytotoxicity; Glioblastoma; Glioblastoma cells; Glioma; Glioma - enzymology; Glioma - pathology; Glioma cells; Gliomas; Hydrogen peroxide; Life Sciences; Low concentrations; MAP kinase; MAP Kinase Signaling System - drug effects; Medical Biochemistry; Membrane permeability; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial permeability transition pore; NADH; NADH-quinone oxidoreductase; Nicotinamide adenine dinucleotide; Oncology; Oxidation-Reduction; Oxidative stress; Oxidative Stress - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Quinone; Quinone oxidoreductase; Quinones; Rats; Reactive oxygen species; Redox properties; Reduction; Sensitivity enhancement; Toxicity; Reactive oxygen species; Mitochondrial dysfunction; Glioma; Thymoquinone; Apoptosis
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-019-03622-8

Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its ability to cross the blood–brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes. Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20–50 μM) promoted cell-cycle arrest and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduction of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70–100 μM) induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells to standard chemotherapeutic drugs.