Nitric Oxide Prevents Glioblastoma Stem Cells’ Expansion and Induces Temozolomide Sensitization

Abstract

Glioblastoma multiforme (GBM) has high mortality and recurrence rates. Malignancy resilience is ascribed to Glioblastoma Stem Cells (GSCs), which are resistant to Temozolomide (TMZ), the gold standard for GBM post-surgical treatment. However, Nitric Oxide (NO) has demonstrated anti-cancer efficacy in GBM cells, but its potential impact on GSCs remains unexplored. Accordingly, we investigated the effects of NO, both alone and in combination with TMZ, on patient-derived GSCs. Experimentally selected concentrations of diethylenetriamine/NO adduct and TMZ were used through a time course up to 21 days of treatment, to evaluate GSC proliferation and death, functional recovery, and apoptosis. Immunofluorescence and Western blot analyses revealed treatment-induced effects in cell cycle and DNA damage occurrence and repair. Our results showed that NO impairs self-renewal, disrupts cell-cycle progression, and expands the quiescent cells’ population. Consistently, NO triggered a significant but tolerated level of DNA damage, but not apoptosis. Interestingly, NO/TMZ cotreatment further inhibited cell cycle progression, augmented G0 cells, induced cell death, but also enhanced DNA damage repair activity. These findings suggest that, although NO administration does not eliminate GSCs, it stunts their proliferation, and makes cells susceptible to TMZ. The resulting cytostatic effect may potentially allow long-term control over the GSCs’ subpopulation.

The Role of Bacteria in Central Nervous System Tumors: Opportunities and Challenges

“…Polyamines, which are highly basic compounds, promote the survival of myeloid cells and myeloid-driven immunosuppression in the acidic and hypoxic microenvironments of gliomas [ 117 , 118 ]. NO in the immune microenvironment can induce immunogenic cell death, normalize tumor vessels, and promote sensitivity to chemotherapeutic agents [ 119 , 120 , 121 , 122 , 123 ]. Therefore, the strategic modulation of arginine metabolism by gut bacteria emerges as a promising avenue for the suppression of tumor growth.…”