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

Abstract

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 2 S), a hydrogen sulfide (H 2 S) donor, to selectively kill GBM cells (T98G and U87) while sparing normal human cerebral microvascular endothelial cells (hCMEC/D3). Na 2 S also decreased mitochondrial respiration, increased oxidative stress and induced γH2AX foci and oxidative base damage in GBM cells. Since Na 2 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 2 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 2 S toxicity in GBM cells. The fact that survival of LN-18 GBM cells lacking mitochondrial DNA (ρ 0 ) was not altered by Na 2 S whereas the survival of LN-18 ρ + cells was compromised supports this conclusion. When cells were treated with Na 2 S and photon or proton radiation, GBM cell killing was enhanced, which opens the possibility of H 2 S being a radiosensitizer. Therefore, this study provides the first evidence that H 2 S donors could be used in GBM therapy to potentiate radiation-induced killing.

Effects of Hydrogen Sulfide Donor NaHS on Porcine Vascular Wall-Mesenchymal Stem Cells

“…The NaHS ability to interfere with cell cycle was already demonstrated in other cell types, such as intestinal epithelial cells [32] and in human lung fibroblasts [10]. Oxidative stress was suggested as a potential mechanism of H 2 S-induced damage; however the ROS level in NaHS-treated pVW-MSCs, investigated in the present work, demonstrated that NaHS did not induce any increase in free radicals in pVW-MSCs, differently from reports in other cell types such HT-29-CI [11]. On the other hand, we previously demonstrated that pVW-MSCs are particularly resistant to oxidative stress since lipopolysaccharide (LPS), a common ROS inducer in many cellular types, did not cause oxidative stress in pVW-MSCs [33].…”

“…Recent interest has been addressed to the role of H 2 S in the field of mesenchymal stem cells (MSCs), so the use of H 2 S donors has been proposed to treat various pathological situations such as osteoporosis, immune disorders, inflammation and cardiovascular disease [17][18][19][20][21]. However, some H 2 S donors' adverse effects were evidenced in different cell types [10][11][12], therefore, for the safe therapeutic use of these molecules, it is necessary to consider first that very different effects could depend on the context. In the present research, we investigated the effects of a well known H 2 S donor, NaHS, on vascular stem cells isolated from the porcine thoracic aorta (pVW-MSCs).…”

“…Accordingly, cytoprotective effects were demonstrated in human, mouse and rat cardiomyocytes [8], and on the contrary, cell death was detected in rat intestinal epithelial cells [9] and in human lung fibroblasts [10]. The toxicity of H 2 S donors seems to be due to a DNA-damaging mutagen property [11], as demonstrated in glioblastoma (GBM) cells, where NaHS interferes with cell cycle phases. The genotoxic effects could involve autoxidation mechanisms that generate reactive oxygen species (ROS) radicals [11,12] or mechanisms that impair DNA repairing via post-translational sulfhydration [13].…”

“…The toxicity of H 2 S donors seems to be due to a DNA-damaging mutagen property [11], as demonstrated in glioblastoma (GBM) cells, where NaHS interferes with cell cycle phases. The genotoxic effects could involve autoxidation mechanisms that generate reactive oxygen species (ROS) radicals [11,12] or mechanisms that impair DNA repairing via post-translational sulfhydration [13].…”

Diallyl trisulfide, a H2S donor, inhibits cell growth of human papillary thyroid carcinoma KTC‐1 cells through a positive feedback loop between H2S and cystathionine‐gamma‐lyase

“…Besides, H 2 S has also been reported to regulate cell cycle, proliferation, autophagy, apoptosis, and oxidative stress in malignant tumors (Hellmich & Szabo, ). For instance, H 2 S has been reported to selectively induce oxidative stress, DNA damage, and mitochondrial dysfunction in glioblastoma cells (Xiao et al, ). However, the function of H 2 S in carcinogenesis is controversial, as another study found that administration of H 2 S accelerated gastric cancer metastasis (Wang, Shi, et al, 2019; Wang, Tao, et al, ).…”