bims-noxint 2022-03-27 papers

Issue of 2022–03–27
two papers selected by
Laia Caja Puigsubira, Uppsala University

Antioxidants (Basel). 2022 Mar 08. pii: 513. [Epub ahead of print]11(3):

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

Muhammed Burak Demircan, Peter C Mgbecheta, Anne Kresinsky, Tina M Schnoeder, Katrin Schröder, Florian H Heidel, Frank D Böhmer.

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.

Keywords: CRISPR/Cas9-mediated deletion; GKT137831; NADPH oxidase 4 (NOX4); Setanaxib; acute myeloid leukemia (AML); inhibitor; reactive oxygen species (ROS)

DOI: https://doi.org/10.3390/antiox11030513

Redox Biol. 2022 Mar 18. pii: S2213-2317(22)00070-2. [Epub ahead of print]52 102298

Architecture of the NADPH oxidase family of enzymes.

Blessing C Ogboo, Uriy V Grabovyy, Aniket Maini, Scott Scouten, Albert van der Vliet, Andrea Mattevi, David E Heppner.

The NADPH Oxidases (NOX) catalyze the deliberate production of reactive oxygen species (ROS) and are established regulators of redox-dependent processes across diverse biological settings. Proper management of their activity is controlled through a conserved electron transfer (ET) cascade from cytosolic NADPH substrate through the plasma membrane to extracellular O2. After decades-long investigations of their biological functions, including potential as drug targets, only very recently has atomic-resolution information of NOX enzymes been made available. In this graphical review, we summarize the present structural biology understanding of the NOX enzymes afforded by X-ray crystallography and cryo-electron microscopy. Combined molecular-level insights predominantly informed by DUOX1 full-length Cryo-EM structures suggest a general structural basis for the control of their catalytic activity by intracellular domain-domain stabilization.

DOI: https://doi.org/10.1016/j.redox.2022.102298