NADPH oxidases as therapeutic targets in chronic myelogenous leukemia.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Department of Biochemistry and Molecular Biology, University of Salamanca; Instituto de Investigación Biomédica de Salamanca (IBSAL);
Beatriz
B
Sánchez-Sánchez
Instituto de Investigación Biomédica de Salamanca (IBSAL); CIC, Centro de Investigación del Cáncer, CSIC; and.
Sara
S
Gutiérrez-Herrero
Department of Biochemistry and Molecular Biology, University of Salamanca; Instituto de Investigación Biomédica de Salamanca (IBSAL);
Guillermo
G
López-Ruano
Department of Biochemistry and Molecular Biology, University of Salamanca; Instituto de Investigación Biomédica de Salamanca (IBSAL);
Rodrigo
R
Prieto-Bermejo
Department of Biochemistry and Molecular Biology, University of Salamanca; Instituto de Investigación Biomédica de Salamanca (IBSAL);
Marta
M
Romo-González
Department of Biochemistry and Molecular Biology, University of Salamanca; Instituto de Investigación Biomédica de Salamanca (IBSAL);
Marcial
M
Llanillo
Instituto de Investigación Biomédica de Salamanca (IBSAL); CIC, Centro de Investigación del Cáncer, CSIC; and.
Atanasio
A
Pandiella
Instituto de Investigación Biomédica de Salamanca (IBSAL); CIC, Centro de Investigación del Cáncer, CSIC; and.
Carmen
C
Guerrero
Instituto de Investigación Biomédica de Salamanca (IBSAL); Hospital Universitario de Salamanca, Salamanca, Spain.
Jesús F San
JF
Miguel
Instituto de Investigación Biomédica de Salamanca (IBSAL); Hospital Universitario de Salamanca, Salamanca, Spain.
Fermín
F
Sánchez-Guijo
Instituto de Investigación Biomédica de Salamanca (IBSAL); Hospital Universitario de Salamanca, Salamanca, Spain.
Consuelo
C
Del Cañizo
Department of Biochemistry and Molecular Biology, University of Salamanca; Instituto de Investigación Biomédica de Salamanca (IBSAL); angelhh@usal.es.
Angel
A
Hernández-Hernández
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D016044:Fusion Proteins, bcr-abl