Riluzole as a dual targeted radiosensitizer for osteosarcoma: Targeting tumor cells and angiogenic vasculature to enhance single high dose radiotherapy efficacy

Osteosarcoma (OS), a highly aggressive bone cancer prevalent among young adults, poses significant challenges in treatment, particularly due to its intrinsic resistance to conventional radiation therapy. This necessitates the development of efficacious radiosensitizers to enhance treatment outcomes. Single high-dose radiation therapy (SDRT) has emerged as a promising strategy for combatting radioresistant sarcomas, particularly those characterized by extensive vascularity. However, its use in OS is constrained by potential toxicity to surrounding normal tissues. Radiosensitizers facilitate effective tumor eradication at reduced radiation doses, limiting normal tissue toxicity and optimizing the therapeutic window. Tumor microvasculature and intrinsic tumor cell mechanisms combinedly drive OS radioresistance. Anti-angiogenic therapies have largely failed as radiosensitizers due to compensatory signaling and cross-talk between surviving endothelial and tumor cells, which reinforces radioresistance. These observations highlight the urgent need for strategies that concurrently target both tumor cells and angiogenic vasculature to enhance the efficacy of SDRT. Riluzole, an FDA-approved drug for Amyotrophic Lateral Sclerosis, is currently under investigation for repurposing in OS treatment. By inhibiting glutamate release and downregulating xCT/SLC7A11, Riluzole increases reactive oxygen species production, promotes DNA damage and induces apoptosis in tumor cells. In parallel, it has shown to inhibit vascular endothelial growth factor A (VEGFA) induced endothelial cell proliferation and abnormal vessel formation. These combined mechanisms positions Riluzole as a promising dual-target radiosensitizer capable of overcoming key limitations of current therapies. In this study, we hypothesize that Riluzole increases the radiosensitivity of OS tumors to SDRT by targeting radioresistance mechanisms in both tumor cells and angiogenic vasculature. Our preliminary results demonstrate that Riluzole significantly reduced the survival fraction of irradiated OS cells compared to cells only exposed to SDRT, signifying potent radiosensitization. Combination treatment markedly increased apoptosis relative to either treatment alone. Mechanistically, Riluzole significantly inhibited the activity of DNA repair enzyme PARP1, and increased radiation induced ROS levels, resulting in enhanced radiation induced DNA damage. Additionally, pre-treatment with Riluzole reduced VEGFA levels in OS cells, suggesting its potential anti-angiogenic activity. In the long term, our objective is to translate these laboratory discoveries into pre-clinical and clinical studies, potentially offering a novel therapeutic approach of radiation therapy for OS patients.