The Use Of Sodium Sulfide, A Hydrogen Sulfide Donor, To Sensitize Glioblastoma Multiforme To Photon And Proton Radiotherapy

Glioblastoma multiforme (GBM) is the most common glial tumor accounting for 12-15% of all brain tumors worldwide. It is a rapidly progressing, life-threatening disease with a median survival of 3-6 months when left untreated. Minimal advancements in the treatment of GBM have limited its management. Conventional treatment with surgical resection of the primary tumor followed by photon radiation (60 Gy in 2 Gy fractions) in combination with adjuvant chemotherapy can limit recurrence and prolong median survival to 15 months. Proton radiotherapy has received increased attention in recent years due to its more precise energy deposition and 10% higher relative biological effectiveness (RBE) when compared to photon therapy. Several clinical trials have shown that high dose photon/proton therapy reduces central recurrence rate and extends median survival of GBM patients to 21.6 months. Unfortunately, the high rate of radionecrosis has limited its widespread adoption. Radiosensitization agents may overcome this problem by allowing for the use of lower radiation doses to achieve comparable cytotoxic effects; however, no radiosensitizers are currently approved for the treatment of GBM. The current study examines the use of sodium sulfide (Na 2 S), a hydrogen sulfide donor, as a radiosensitizing agent for both photon and proton therapy in two human glioblastoma cell lines, T98G and U87-MG. Survival curves were generated for T98G cells using a colony forming assay. Protons had an increased RBE of 1.18, which is in close agreement to the accepted RBE of 1.1. Na 2 S (0 μM, 10 μM, 100 μM, 500 μM, 1000 μM) was given as a pre-treatment in two 2-hour incubations: 2 hours prior to radiation and again immediately before radiation. Na 2 S alone exhibited a concentration dependent cytotoxic effect with maximal killing of approximately 50% at 500 μM. Further increases in sodium sulfide up to 1000μM had no effect on cell survival. Similar killing was not observed in a non-cancer mouse retinal endothelial cell line even at extremely high doses of 1000 μM suggesting that Na 2 S cytotoxicity is specific and limited to cancer cells. Na 2 S increased killing in both photons and protons at 6 Gy by decreasing the surviving fraction from 27.7% to 20% and 16% to 3% respectively. Initial studies into the mechanism of radiosensitization using bleomycin as a radiomimetic agent have suggested Na 2 S increases the number of DNA double strand breaks (DSB), a highly cytotoxic form of DNA damage, as seen by γH2AX staining in both T98G and U87-MG cells. The benefits of high dose radiation therapy, particularly with proton boost, in the treatment of high-grade central nervous system tumors such as GBM are apparent, but the increased risk of radionecrosis has limited its use. While further studies need to be conducted to elucidate the exact mechanism, preliminary results strongly suggest that sodium sulfide can act as a radiosensitizing agent by increasing DNA DSB formation. Citation Format: Adam Xiao, Rajesh Pidikiti, Matthew Maynard, Nader Sheibani, Lynn Harrison. The use of sodium sulfide, a hydrogen sulfide donor, to sensitize glioblastoma multiforme to photon and proton radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5846. doi:10.1158/1538-7445.AM2017-5846