NADPH oxidases as therapeutic targets in chronic myelogenous leukemia

[Purpose]: Cancer cells show higher levels of reactive oxygen species (ROS) than normal cells and increasing intracellular ROS levels are becoming a recognized strategy against tumor cells. Thus, diminishing ROS levels could be also detrimental to cancer cells. We surmise that avoiding ROS generation would be a better option than quenching ROS with antioxidants. Chronic myelogenous leukemia (CML) is triggered by the expression of BCR-ABL kinase, whose activity leads to increased ROS production, partly through NADPH oxidases. Here, we assessed NADPH oxidases as therapeutic targets in CML. [Experimental Design]: We have analyzed the effect of different NADPH oxidase inhibitors, either alone or in combination with BCR-ABL inhibitors, in CML cells and in two different animal models for CML. [Results]: NADPH oxidase inhibition dramatically impaired the proliferation and viability of BCR-ABL-expressing cells due to the attenuation of BCR-ABL signaling and a pronounced cell-cycle arrest. Moreover, the combination of NADPH oxidase inhibitors with BCR-ABL inhibitors was highly synergistic. Two different animal models underscore the effectiveness of NADPH oxidase inhibitors and their combination with BCR-ABL inhibitors for CML targeting in vivo. [Conclusion]: Our results offer further therapeutic opportunities for CML, by targeting NADPH oxidases. In the future, it would be worthwhile conducting further experiments to ascertain the feasibility of translating such therapies to clinical practice.This work was supported by the Spanish Government's Ministry of Economy and Competitiveness (BFU2006-10362, BFU2009-10568, CSD2007-00015, BFU2011-28467), the Regional Government of Government of Castile & León (SA010A10-2, SA126A07, BIO/SA59/13) and the SAMUEL SOLORZANO BARRUSO Foundation (FS/7-2012). G.L.P. had a predoctoral fellowship from the Regional Government of Castilla y León, Spain.Peer Reviewe