Anti-Leukemic Properties of Histamine in Monocytic Leukemia: The Role of NOX2

Abstract

In patients with acute myeloid leukemia (AML), treatment with histamine dihydrochloride (HDC) and low-dose IL-2 (HDC/IL-2) in the post-chemotherapy phase has been shown to reduce the incidence of leukemic relapse. The clinical benefit of HDC/IL-2 is pronounced in monocytic forms of AML, where the leukemic cells express histamine type 2 receptors (H2R) and the NAPDH oxidase-2 (NOX2). HDC ligates to H2Rs to inhibit NOX2-derived formation of reactive oxygen species, but details regarding the anti-leukemic actions of HDC remain to be elucidated. Here, we report that human NOX2+ myelomonocytic/monocytic AML cell lines showed increased expression of maturation markers along with reduced leukemic cell proliferation after exposure to HDC in vitro. These effects of HDC were absent in corresponding leukemic cells genetically depleted of NOX2 (NOX2−/−). We also observed that exposure to HDC altered the expression of genes involved in differentiation and cell cycle progression in AML cells and that these effects required the presence of NOX2. HDC promoted the differentiation also of primary monocytic, but not non-monocytic, AML cells in vitro. In a xenograft model, immunodeficient NOG mice were inoculated with wild-type or NOX2−/− human monocytic AML cells and treated with HDC in vivo. The administration of HDC reduced the in vivo expansion of NOX2+/+, but not of NOX2−/− human monocytic AML cells. We propose that NOX2 may be a conceivable target in the treatment of monocytic AML.

Histamine targets myeloid-derived suppressor cells and improves the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade

“…Based on results showing that HDC was devoid of anti-tumor efficacy in mice genetically deficient in NOX2 and in mice where MDSCs were depleted by GR1-neutralizing antibodies, we conclude that the anti-tumor properties of HDC rely on the presence of NOX2 + GR1 + cells. Although alternative or supplementary mechanisms are conceivable, these findings confirm and extend results suggesting that HDC targets NOX2 to exert anti-tumor efficacy in murine cancer models [16, 24, 25]. We also report that treatment of mice with HDC reduced the accumulation of intratumoral MDSCs and the number of splenocytes in two experimental tumor models and that the use of a HDC-based regimen reduced MDSC counts in blood of AML patients in complete remission.…”

NOX2 in autoimmunity, tumor growth and metastasis

“…The proposed mechanism involved ROS‐induced transfer of mitochondria from stromal cells to AML blasts through AML‐derived tunneling nanotubes; these events did not occur in leukemic cells that were genetically deprived of NOX2 . In addition, pharmacological inhibition of NOX2 using histamine dihydrochloride, which is used in conjunction with low‐dose interleukin‐2 for relapse prevention in the postchemotherapy phase of AML , reduced the expansion of xenografted human AML cells in vivo in a NOX2‐dependent manner .…”

Histamine receptors and cancer pharmacology: an update

“…Histamine additionally modulates gene expression involved in differentiation and cell cycle progression, inducing differentiation of AML cells and also of primary monocytic, but not non‐monocytic AML cells in vitro . Importantly, histamine treatment reduced the in vivo expansion of NOX2 +/+ , but not of NOX2 −/− human monocytic AML cells (Kiffin et al ., 2018). Histamine/IL‐2 immunotherapy involves the induction of immunosuppressive Tregs cells that may be targeted for improving the therapeutic efficiency of the combined therapy (Sander et al ., 2017).…”