Targeting Glioblastoma via Selective Alteration of Mitochondrial Redox State

Simple Summary: Glioblastoma is characterized by a pronounced redox imbalance due to elevated glycolytic and mitochondrial oxidative metabolism. New therapeutic strategies have been developed to modulate glioblastoma redox signaling to effectively suppress growth and prolong survival. However, drug selectivity and therapeutic relapse prove to be the major challenges. We describe a pharmacological strategy for the selective targeting and treatment of glioblastoma using the redox active combination drug menadione/ascorbate, which is characterized by tolerance to normal cells and tissues. Menadione/ascorbate treatment of glioblastoma mice suppressed tumor growth and significantly increased survival without adverse side effects. This is accompanied by increased oxidative stress, decreased reducing capacity and decreased cellular density in the tumor alone, as well as increased brain perfusion and decreased regulation of several oncoproteins and oncometabolites, which implies modulation of the immune response and reduced drug resistance. We believe that this therapeutic strategy is feasible and promising and deserves the attention of clinicians.Glioblastoma is one of the most aggressive brain tumors, characterized by a pronounced redox imbalance, expressed in a high oxidative capacity of cancer cells due to their elevated glycolytic and mitochondrial oxidative metabolism. The assessment and modulation of the redox state of glioblastoma are crucial factors that can provide highly specific targeting and treatment. Our study describes a pharmacological strategy for targeting glioblastoma using a redox-active combination drug. The experiments were conducted in vivo on glioblastoma mice (intracranial model) and in vitro on cell lines (cancer and normal) treated with the redox cycling pair menadione/ascorbate (M/A). The following parameters were analyzed in vivo using MRI or ex vivo on tissue and blood specimens: tumor growth, survival, cerebral perfusion, cellular density, tissue redox state, expression of tumor-associated NADH oxidase (tNOX) and transforming growth factor-beta 1 (TGF-beta 1). Dose-dependent effects of M/A on cell viability, mitochondrial functionality, and redox homeostasis were evaluated in vitro. M/A treatment suppressed tumor growth and significantly increased survival without adverse side effects. This was accompanied by increased oxidative stress, decreased reducing capacity, and decreased cellular density in the tumor only, as well as increased cerebral perfusion and down-regulation of tNOX and TGF-beta 1. M/A induced selective cytotoxicity and overproduction of mitochondrial superoxide in isolated glioblastoma cells, but not in normal microglial cells. This was accompanied by a significant decrease in the over-reduced state of cancer cells and impairment of their "pro-oncogenic " functionality, assessed by dose-dependent decreases in: NADH, NAD(+), succinate, glutathione, cellular reducing capacity, mitochondrial potential, steady-state ATP, and tNOX expression. The safety of M/A on normal cells was compromised by treatment with cerivastatin, a non-specific prenyltransferase inhibitor. In conclusion, M/A differentiates glioblastoma cells and tissues from normal cells and tissues by redox targeting, causing severe oxidative stress only in the tumor. The mechanism is complex and most likely involves prenylation of menadione in normal cells, but not in cancer cells, modulation of the immune response, a decrease in drug resistance, and a potential role in sensitizing glioblastoma to conventional chemotherapy.