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Article

Combined Activity of the Redox-Modulating Compound Setanaxib (GKT137831) with Cytotoxic Agents in the Killing of Acute Myeloid Leukemia Cells

1
Institute of Molecular Cell Biology, CMB, Jena University Hospital, 07745 Jena, Germany
2
Innere Medizin II, Hämatologie und Onkologie, Jena University Hospital, 07747 Jena, Germany
3
Leibniz Institute on Aging—Fritz Lipman Institute, 07745 Jena, Germany
4
Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany
5
Innere Medizin C, Universitätsmedizin Greifswald, 17475 Greifswald, Germany
6
Institute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Academic Editors: Wei Han, Peter K.N. Yu and Sander Bekeschus
Antioxidants 2022, 11(3), 513; https://doi.org/10.3390/antiox11030513
Received: 2 January 2022 / Revised: 27 February 2022 / Accepted: 4 March 2022 / Published: 8 March 2022
(This article belongs to the Special Issue Redox in Cancer Occurence and Therapy)
Acute myeloid leukemia (AML) cells harbor elevated levels of reactive oxygen species (ROS), which promote cell proliferation and cause oxidative stress. Therefore, the inhibition of ROS formation or elevation beyond a toxic level have been considered as therapeutic strategies. ROS elevation has recently been linked to enhanced NADPH oxidase 4 (NOX4) activity. Therefore, the compound Setanaxib (GKT137831), a clinically advanced ROS-modulating substance, which has initially been identified as a NOX1/4 inhibitor, was tested for its inhibitory activity on AML cells. Setanaxib showed antiproliferative activity as single compound, and strongly enhanced the cytotoxic action of anthracyclines such as daunorubicin in vitro. Setanaxib attenuated disease in a mouse model of FLT3-ITD driven myeloproliferation in vivo. Setanaxib did not significantly inhibit FLT3-ITD signaling, including FLT3 autophosphorylation, activation of STAT5, AKT, or extracellular signal regulated kinase 1 and 2 (ERK1/2). Surprisingly, the effects of Setanaxib on cell proliferation appeared to be independent of the presence of NOX4 and were not associated with ROS quenching. Instead, Setanaxib caused elevation of ROS levels in the AML cells and importantly, enhanced anthracycline-induced ROS formation, which may contribute to the combined effects. Further assessment of Setanaxib as potential enhancer of cytotoxic AML therapy appears warranted. View Full-Text
Keywords: acute myeloid leukemia (AML); reactive oxygen species (ROS); NADPH oxidase 4 (NOX4); CRISPR/Cas9-mediated deletion; inhibitor; Setanaxib; GKT137831 acute myeloid leukemia (AML); reactive oxygen species (ROS); NADPH oxidase 4 (NOX4); CRISPR/Cas9-mediated deletion; inhibitor; Setanaxib; GKT137831
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MDPI and ACS Style

Demircan, M.B.; Mgbecheta, P.C.; Kresinsky, A.; Schnoeder, T.M.; Schröder, K.; Heidel, F.H.; Böhmer, F.D. Combined Activity of the Redox-Modulating Compound Setanaxib (GKT137831) with Cytotoxic Agents in the Killing of Acute Myeloid Leukemia Cells. Antioxidants 2022, 11, 513. https://doi.org/10.3390/antiox11030513

AMA Style

Demircan MB, Mgbecheta PC, Kresinsky A, Schnoeder TM, Schröder K, Heidel FH, Böhmer FD. Combined Activity of the Redox-Modulating Compound Setanaxib (GKT137831) with Cytotoxic Agents in the Killing of Acute Myeloid Leukemia Cells. Antioxidants. 2022; 11(3):513. https://doi.org/10.3390/antiox11030513

Chicago/Turabian Style

Demircan, Muhammed Burak, Peter C. Mgbecheta, Anne Kresinsky, Tina M. Schnoeder, Katrin Schröder, Florian H. Heidel, and Frank D. Böhmer. 2022. "Combined Activity of the Redox-Modulating Compound Setanaxib (GKT137831) with Cytotoxic Agents in the Killing of Acute Myeloid Leukemia Cells" Antioxidants 11, no. 3: 513. https://doi.org/10.3390/antiox11030513

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