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

1
Department of Biochemistry and Molecular Biology, Universidad de Salamanca, Plaza Doctores de la Reina, 37007 Salamanca, Spain
2
IBSAL (Institute for Biomedical Research of Salamanca), 37007 Salamanca, Spain
3
Hematology Department, University Hospital of Salamanca, Paseo de San Vicente, 139, 37007 Salamanca, Spain
*
Author to whom correspondence should be addressed.
Antioxidants 2020, 9(1), 74; https://doi.org/10.3390/antiox9010074
Received: 20 December 2019 / Revised: 13 January 2020 / Accepted: 13 January 2020 / Published: 15 January 2020
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.
Keywords: Chronic myeloid leukemia (CML); reactive oxygen species (ROS); BCR-ABL; xanthine oxidoreductase (XOR); allopurinol; tyrosine kinase inhibitors (TKIs); imatinib; nilotinib Chronic myeloid leukemia (CML); reactive oxygen species (ROS); BCR-ABL; xanthine oxidoreductase (XOR); allopurinol; tyrosine kinase inhibitors (TKIs); imatinib; nilotinib
MDPI and ACS Style

Romo-González, M.; Moreno-Paz, S.; García-Hernández, V.; Sánchez-Guijo, F.; Hernández-Hernández, Á. Inhibition of Xanthine Oxidoreductase Enhances the Potential of Tyrosine Kinase Inhibitors against Chronic Myeloid Leukemia. Antioxidants 2020, 9, 74.

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