Abstract
Metabolic reprogramming in cancer cells, vs. non-cancer cells, elevates levels of reactive oxygen species (ROS) leading to higher oxidative stress. The elevated ROS levels suggest a vulnerability to excess prooxidant loads leading to selective cell death, a therapeutically exploitable difference. Co-enzyme Q10 (CoQ10) an endogenous mitochondrial resident molecule, plays an important role in mitochondrial redox homeostasis, membrane integrity, and energy production. BPM31510 is a lipid-drug conjugate nanodispersion specifically formulated for delivery of supraphysiological concentrations of ubidecarenone (oxidized CoQ10) to the cell and mitochondria, in both in vitro and in vivo model systems. In this study, we sought to investigate the therapeutic potential of ubidecarenone in the highly treatment-refractory glioblastoma. Rodent (C6) and human (U251) glioma cell lines, and non-tumor human astrocytes (HA) and rodent NIH3T3 fibroblast cell lines were utilized for experiments. Tumor cell lines exhibited a marked increase in sensitivity to ubidecarenone vs. non-tumor cell lines. Further, elevated mitochondrial superoxide production was noted in tumor cells vs. non-tumor cells hours before any changes in proliferation or the cell cycle could be detected. In vitro co-culture experiments show ubidecarenone differentially affecting tumor cells vs. non-tumor cells, resulting in an equilibrated culture. In vivo activity in a highly aggressive orthotopic C6 glioma model demonstrated a greater than 25% long-term survival rate. Based on these findings we conclude that high levels of ubidecarenone delivered using BPM31510 provide an effective therapeutic modality targeting cancer-specific modulation of redox mechanisms for anti-cancer effects.
Highlights
The Warburg effect was originally described a century ago as an aspect of metabolic rewiring in cancer c ells[1,2], and is considered a distinctive hallmark of cancer, emerging in recent years as an important concept in the field of cancer biology[3]
Metabolic reprogramming in cancer cells results in the generation of higher than normal levels of reactive oxygen species (ROS) from mitochondria and cytoplasmic NADPH o xidases[10,11], which require counterbalancing through antioxidant a ctivity[12]
Using co-cultures of glioma cells and non-tumor cells, we demonstrate that BPM31510 treatment differentially and rapidly raises intramitochondrial O2− anion levels in glioma cells relative to non-tumor cells, an effect that precedes any changes in proliferation or cell cycle status
Summary
The Warburg effect was originally described a century ago as an aspect of metabolic rewiring in cancer c ells[1,2], and is considered a distinctive hallmark of cancer, emerging in recent years as an important concept in the field of cancer biology[3]. NADPH dehydrogenase (quinone) 1 catalyzes the twoelectron reduction of quinones, producing stable q uinols[27,28,29] Enzymes such as NADPH-cytochrome P450 reductase catalyze the reduction to a semiquinone radical in the presence of a suitable electron donor such as NADPH27,30,31, which because of its own lability and high reactivity donates an electron to a neighboring oxygen molecule, resulting in the production of an O2− anion. Multiple such reactions result in an overabundance of O2− anions and cell toxicity. Considering the increased levels of oxidative stress within cancer cells, exposure to the optimum amount of CoQ10 could potentially exclusively affect cancer cells, providing a potentially well-tolerated and effective anti-cancer therapy
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