Inhibition of Xanthine Oxidoreductase Enhances the Potential of Tyrosine Kinase Inhibitors against Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is characterized by the expression of the oncogenic kinase BCR-ABL. Although tyrosine kinase inhibitors (TKIs) against BCR-ABL represent the standard therapeutic option for CML, resistances to TKIs can be a serious problem. Thus, the search for novel therapeutic approaches is still needed. CML cells show an increased ROS production, which is required for maintaining the BCR-ABL signaling cascade active. In line with that, reducing ROS levels could be an interesting therapeutic strategy for the clinical management of resistant CML. To analyze the therapeutic potential of xanthine oxidoreductase (XOR) in CML, we tested the effect of XOR inhibitor allopurinol. Here, we show for the first time the therapeutic potential of allopurinol against BCR-ABL-positive CML cells. Allopurinol reduces the proliferation and clonogenic ability of the CML model cell lines K562 and KCL22. More importantly, the combination of allopurinol with imatinib or nilotinib reduced cell proliferation in a synergistic manner. Moreover, the co-treatment arms hampered cell clonogenic capacity and induced cell death more strongly than each single-agent arm. The reduction of intracellular ROS levels and the attenuation of the BCR-ABL signaling cascade may explain these effects. Finally, the self-renewal potential of primary bone marrow cells from CML patients was also severely reduced especially by the combination of allopurinol with TKIs. In summary, here we show that XOR inhibition is an interesting therapeutic option for CML, which can enhance the effectiveness of the TKIs currently used in clinics.

Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison

“…This evidence encourages additional studies in this direction. Although NADPH oxidases seem to be one of the better option for inhibiting ROS production in a specific way, it is important not to overlook other sources of ROS such xanthine oxidoreductase (XOD) ( 159 ) or IDH1 ( 160 ). More information on the various pro-oxidant and antioxidant alternatives for the treatment of leukemia can be found at ( 12 , 47 ).…”

Oxidative Stress and ROS-Mediated Signaling in Leukemia: Novel Promising Perspectives to Eradicate Chemoresistant Cells in Myeloid Leukemia

“…Two enzymes are responsible for O 2 − generation in peroxisomes, respectively xanthine oxidase (XO) and xanthine dehydrogenase (XDH) [ 62 ]. XDH is involved in purine catabolism, by catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid [ 63 , 64 ] and also in the production of reactive nitrogen species (RNS) that are generated when superoxide reacts with nitric oxide produced by NO synthases. The reaction of O 2 − with NO − results in peroxynitrite (ONOO − ), a highly RNS reactive compound [ 14 ].…”

Role of reactive oxygen species in myelodysplastic syndromes

“…In some cancers, low or moderate levels of ROS could promote cell proliferation, differentiation, metastasis, and even chemoresistance, protecting cells from cytotoxic ROS by acting as signaling molecules to activate antioxidant systems in response to stress [5,[10][11][12]. ROS, which are important signaling molecules, are often closely involved in the pathogenesis of numerous diseases and influence tumorigenesis, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML) [13][14][15][16][17].…”