Blocking nitric oxide production for glioblastoma: A targeted therapeutic approach

Glioblastoma (GBM) represents the foremost prevalent and aggressive form of primary brain tumor, characterized by high morbidity and mortality rates. Nitric oxide (NO) has been shown to have diverse effects on various cancers, including GBM. Our previous study has shown NO synthase (NOS) hyperactivation in GBM cell lines. GBM cell survival was reversed by the NOS-targeting pharmacological inhibition in vitro. The current work explores the impact of inducible and neuronal NOS (iNOS and nNOS) inhibitors, BA-103 and BA-101, respectively, on a glioblastoma xenograft model. Both agents mitigate nitrosative stress through distinct mechanisms. NOD-SCID mice were used to establish a subcutaneous xenograft tumor model with U-87 MG cells. BA-103 and BA-101 were administered to mice via intraperitoneal injections. Tumor metrics, including weight and volume, were assessed. Immunofluorescence and Western blots were conducted to assess nitrosative stress, tumor proliferation, and cell death. Treatment with the NOS inhibitors, particularly with BA-101, significantly reduced tumor volume in the xenograft model. A dose-dependent study with BA-101 identified 80 mg/kg as the most efficacious dose for GBM treatment. Combining BA-101 with the antitumor drug temozolomide (TMZ) synergistically reduced tumor size and significantly increased survivability in mice bearing TMZ-sensitive cells. Our findings suggest that targeting nNOS holds promise as a therapeutic strategy for GBM treatment.