Targeting NOX2 in cancer

Abstract

Reactive oxygen species (ROS) are short-lived, toxic derivatives of oxygen that are produced during mitochondrial respiration and by NADPH oxidases (NOX). By enzymatically generating ROS, the myeloid cell NOX2 plays a critical role in defense against bacteria and other microorganisms. The NOX2-derived ROS have also been ascribed immunosuppressive properties and may damage DNA to induce mutagenesis, but details regarding the role of NOX2 and ROS for the initiation and progression of cancer are partly unexplored. This thesis work utilized genetic and pharmacological tools including transgenic mice, genetically modified cells and pharmacological NOX2 inhibitors to further define the role of NOX2 in cancer. The results presented in paper I implied that a NOX2 inhibitor, histamine dihydrochloride (HDC), promotes the development of monocyte-derived, antigen-presenting dendritic cells to control the in vivo growth of a murine lymphoma (EL-4). Paper II was designed to elucidate the impact of NOX2 on the process of metastasis. The results suggested that extracellularly released NOX2-derived ROS from myeloid cells may dampen natural killer (NK) cell-mediated defense against murine melanoma cells to promote hematogenous metastasis. Paper III aimed at defining the role of NOX2 in a mouse model of chronic myeloid leukemia (CML). It was observed that genetic ablation of NOX2 delayed the in vivo expansion of leukemic cells carrying the BCR-ABL1 mutation. In paper IV, it is shown that genetic and pharmacological inhibition of NOX2 delayed the development of myeloproliferation in a murine model of Kras-induced myeloid leukemia and, also, that inhibition of NOX2 function may confer protection against oxidative stress and DNA damage in cells of the leukemic clone. In summary, these studies identify NOX2 as a conceivable target in cancer therapy.