Sodium sulfide selectively induces oxidative stress, DNA damage, and mitochondrial dysfunction and radiosensitizes glioblastoma (GBM) cells

• Published in: Redox biology Vol. 26; p. 101220
• Main Authors: Xiao, Adam Y, Maynard, Matthew R, Piett, Cortt G, Nagel, Zachary D, Alexander, J Steven, Kevil, Christopher G, Berridge, Michael V, Pattillo, Christopher B, Rosen, Lane R, Miriyala, Sumitra, Harrison, Lynn
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier 01-09-2019
• Subjects: Apoptosis - drug effects; Apoptosis - radiation effects; Cell Line; Cell Line, Tumor; DNA Damage; DNA Repair - drug effects; DNA Repair - radiation effects; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - radiation effects; Humans; Hydrogen Sulfide - chemistry; Hydrogen Sulfide - pharmacology; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - radiation effects; Neuroglia - drug effects; Neuroglia - pathology; Neuroglia - radiation effects; Organ Specificity; Oxidative Phosphorylation - drug effects; Oxidative Phosphorylation - radiation effects; Oxidative Stress; Photons; Proton Therapy; Radiation-Sensitizing Agents - chemistry; Radiation-Sensitizing Agents - pharmacology; Reactive Oxygen Species - metabolism; Research Paper; Sulfides - chemistry; Sulfides - pharmacology; Hydrogen sulfide; Ionizing radiation; Mitochondria; Reactive oxygen species; DNA damage; Glioblastoma; DNA repair
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2019.101220

Glioblastoma (GBM) has a poor prognosis despite intensive treatment with surgery and chemoradiotherapy. Previous studies using dose-escalated radiotherapy have demonstrated improved survival; however, increased rates of radionecrosis have limited its use. Development of radiosensitizers could improve patient outcome. In the present study, we report the use of sodium sulfide (Na
S), a hydrogen sulfide (H
S) donor, to selectively kill GBM cells (T98G and U87) while sparing normal human cerebral microvascular endothelial cells (hCMEC/D3). Na
S also decreased mitochondrial respiration, increased oxidative stress and induced γH2AX foci and oxidative base damage in GBM cells. Since Na
S did not significantly alter T98G capacity to perform non-homologous end-joining or base excision repair, it is possible that GBM cell killing could be attributed to increased damage induction due to enhanced reactive oxygen species production. Interestingly, Na
S enhanced mitochondrial respiration, produced a more reducing environment and did not induce high levels of DNA damage in hCMEC/D3. Taken together, this data suggests involvement of mitochondrial respiration in Na
S toxicity in GBM cells. The fact that survival of LN-18 GBM cells lacking mitochondrial DNA (ρ
) was not altered by Na
S whereas the survival of LN-18 ρ
cells was compromised supports this conclusion. When cells were treated with Na
S and photon or proton radiation, GBM cell killing was enhanced, which opens the possibility of H
S being a radiosensitizer. Therefore, this study provides the first evidence that H
S donors could be used in GBM therapy to potentiate radiation-induced killing.