title: Arsenic trioxide treatment decreases the oxygen consumption rate of tumor cells and radiosensitizes solid tumors.
abstract: Arsenic trioxide (As(2)O(3)) is an effective therapeutic against acute promyelocytic leukemia and certain solid tumors. Because As(2)O(3) inhibits mitochondrial respiration in leukemia cells, we hypothesized that As(2)O(3) might enhance the radiosensitivity of solid tumors by increasing tumor oxygenation [partial pressure of oxygen (pO(2))] via a decrease in oxygen consumption. Two murine models of radioresistant hypoxic cancer were used to study the effects of As(2)O(3). We measured pO(2) and the oxygen consumption rate in vivo by electron paramagnetic resonance oximetry and (19)fluorine-MRI relaxometry. Tumor perfusion was assessed by Patent blue staining. In both models, As(2)O(3) inhibited mitochondrial respiration, leading to a rapid increase in pO(2). The decrease in oxygen consumption could be explained by an observed decrease in glutathione in As(2)O(3)-treated cells, as this could increase intracellular reactive oxygen species that can disrupt mitochondrial membrane potential. When tumors were irradiated during periods of As(2)O(3)-induced augmented oxygenation, radiosensitivity increased by 2.2-fold compared with control mice. Notably, this effect was abolished when temporarily clamped tumors were irradiated. Together, our findings show that As(2)O(3) acutely increases oxygen consumption and radiosensitizes tumors, providing a new rationale for clinical investigations of As(2)O(3) in irradiation protocols to treat solid tumors.
authors.affiliation: Biomedical Magnetic Resonance Group, Louvain Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Diepart
authors.forename: Oussama
authors.initials: O
authors.lastname: Karroum
authors.forename: Julie
authors.initials: J
authors.lastname: Magat
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.forename: Julien
authors.initials: J
authors.lastname: Verrax
authors.forename: Pedro Buc
authors.initials: PB
authors.lastname: Calderon
authors.forename: Vincent
authors.initials: V
authors.lastname: Grégoire
authors.forename: Philippe
authors.initials: P
authors.lastname: Leveque
authors.forename: Julie
authors.initials: J
authors.lastname: Stockis
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dauguet
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Jordan
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010087:Oxides / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D011838:Radiation-Sensitizing Agents; D000077237:Arsenic Trioxide