Targeting M2 Macrophages with a Novel NADPH Oxidase Inhibitor

Abstract

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.

Unlocking the power of NOX2: A comprehensive review on its role in immune regulation

“…Supporting this concept in other cancer types, the microenvironment of human mesothelial tumors is enriched in infiltrating granulocytes, which inhibit T-cell proliferation and activation in a NOX2-dependent mechanism [ 199 ]. Moreover, several lines of evidence suggest that NOX2-derived sROS promote an anti-inflammatory phenotype in tumor-associated macrophages [ 200 , 201 ]. Altogether, cell type-specific inhibition of NOX2 ( e.g.…”

Design, Synthesis of Hydrogen Peroxide Response AIE Fluorescence Probes Based on Imidazo [1,2-a] Pyridine

“…Hydrogen peroxide (H 2 O 2 ) is produced when NADPH oxidase complexes are activated by cytokines, neurotransmitters, and peptides that promote cell growth. It acts as a second messenger in signal transduction during host defense, immune response, and pathogen invasion [ 2 ]. However, abnormal production or accumulation of H 2 O 2 can disrupt protein structure and function, resulting in oxidative cell damage and causing diseases such as cancer, cardiovascular disease, and neurological disorders.…”