Arsenic trioxide treatment decreases the oxygen consumption rate of tumor cells and radiosensitizes solid tumors
Menée sur deux modèles murins de cancer résistant à la radiothérapie, cette étude montre que le trioxyde d'arsenic (As2O3) diminue le taux de consommation d'oxygène des cellules tumorales et sensibilise les tumeurs solides aux rayonnements ionisants
Arsenic trioxide (As2O3) is an effective therapeutic against acute promyelocytic leukemia (APL) and certain solid tumors. Because As2O3 inhibits mitochondrial respiration in leukemia cells, we hypothesized that As2O3 might enhance the radiosensitivity of solid tumors by increasing tumor oxygenation (pO2) via a decrease in oxygen consumption. Two murine models of radioresistant hypoxic cancer were used to study the effects of As2O3. We measured pO2 and the oxygen consumption rate in vivo by electron paramagnetic resonance oximetry and 19F-MRI relaxometry. Tumor perfusion was assessed by Patent blue staining. In both models, As2O3 inhibited mitochondrial respiration, leading to a rapid increase in pO2. The decrease in oxygen consumption could be explained by an observed decrease in glutathione in As2O3-treated cells, as this could increase intracellular reactive oxygen species (ROS) that can disrupt mitochondrial membrane potential. When tumors were irradiated during periods of As2O3-induced augmented oxygenation, radiosensitivity increased 2.2-fold compared to control mice. Notably, this effect was abolished when temporarily clamped tumors were irradiated. Together, our findings demonstrate that As2O3 acutely increases oxygen consumption and radiosensitizes tumors, providing a new rationale for clinical investigations of As2O3 in irradiation protocols to treat solid tumors.