Targeting M2 Macrophages with a Novel NADPH Oxidase Inhibitor
Metadatos
Mostrar el registro completo del ítemEditorial
MDPI
Materia
Macrophage ROS inhibition Vascular tone NADPH oxidase Molecular modelling Macrophage differentiation Tumor microenvironment
Fecha
2023-02-10Referencia bibliográfica
Dilly, S... [et al.]. Targeting M2 Macrophages with a Novel NADPH Oxidase Inhibitor. Antioxidants 2023, 12, 440. [https://doi.org/10.3390/antiox12020440]
Patrocinador
French National Research Agency (ANR) PCVI-08-006 TRIGNOSTUMORResumen
ROS in cancer cells play a key role in pathways regulating cell death, stemness maintenance,
and metabolic reprogramming, all of which have been implicated in resistance to chemo/
immunotherapy. Adjusting ROS levels to reverse the resistance of cancer cells without impairing normal
cell functions is a new therapeutic avenue. In this paper, we describe new inhibitors of NADPH
oxidase (NOX), a key enzyme in many cells of the tumor microenvironment. The first inhibitor, called
Nanoshutter-1, NS1, decreased the level of tumor-promoting “M2” macrophages differentiated from
human blood monocytes. NS1 disrupted the active NADPH oxidase-2 (NOX2) complex at the membrane
and in the mitochondria of the macrophages, as shown by confocal microscopy. As one of the
characteristics of tumor invasion is hypoxia, we tested whether NS1 would affect vascular reactivity
by reducing ROS or NO levels in wire and pressure myograph experiments on isolated blood vessels.
The results show that NS1 vasodilated blood vessels and would likely reduce hypoxia. Finally, as
both NOX2 and NOX4 are key proteins in tumors and their microenvironment, we investigated
whether NS1 would probe these proteins differently. Models of NOX2 and NOX4 were generated by
homology modeling, showing structural differences at their C-terminal NADPH site, in particular in
their last Phe. Thus, the NADPH site presents an unexploited chemical space for addressing ligand
specificity, which we exploited to design a novel NOX2-specific inhibitor targeting variable NOX2
residues. With the proper smart vehicle to target specific cells of the microenvironment as TAMs,
NOX2-specific inhibitors could open the way to new precision therapies.