Tinostamustine (EDO-S101) and Its Combination with Celecoxib or Temozolomide as a Therapeutic Option for Adult-Type Diffuse Gliomas.

Adult-type diffuse gliomas are characterized by inevitable recurrence and very poor prognosis. Novel treatment options, including multimodal drugs or effective drug combinations, are therefore eagerly awaited. Tinostamustine is an alkylating and histone deacetylase inhibiting molecule with great potential in cancer treatment. Thus, the aim of this study was to investigate its effects on glioma cells. In this context, tinostamustine was evaluated in monotherapy and as a combination therapy, with either celecoxib or temozolomide; additionally, the results were compared to the golden glioma chemotherapy standard-temozolomide. Our experiments, conducted on both temozolomide-sensitive U-87 MG astrocytoma and temozolomide-resistant U-138 MG glioblastoma cells revealed that tinostamustine and its combination with either celecoxib or temozolomide exert dose-dependent cytotoxicity, cause cell cycle arrest, induce oxidative stress-mediated apoptosis of malignant glioma cells, and mitigate their migratory potential. Astrocytoma cells were more susceptible to the tested treatments than glioblastoma cells, and, generally, those dual therapies were superior in anti-glioma efficacy compared to temozolomide. Overall, our study provides evidence that tinostamustine and the combination therapies consisting of tinostamustine and celecoxib or tinostamustine and temozolomide may represent a new approach for the effective treatment of malignant gliomas.