Histamine H2 Receptor in Blood Cells: A Suitable Target for the Treatment of Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) consists in a cancer of early hematopoietic cells arising in the bone marrow, most often of those cells that would turn into white blood cells (except lymphocytes). Chemotherapy is the treatment of choice for AML but one of the major complications is that current drugs are highly toxic and poorly tolerated. In general, treatment for AML consists of induction chemotherapy and post-remission therapy. If no further post-remission is given, almost all patients will eventually relapse. Histamine, acting at histamine type-2 (H) receptors on phagocytes and AML blast cells, helps prevent the production and release of oxygen-free radicals, thereby protecting NK and cytotoxic T cells. This protection allows immune-stimulating agents, such as interleukin-2 (IL-2), to activate cytotoxic cells more effectively, enhancing the killing of tumor cells. Based on this mechanism, post-remission therapy with histamine and IL-2 was found to significantly prevent relapse of AML. Alternatively, another potentially less toxic approach to treat AML employs drugs to induce differentiation of malignant cells. It is based on the assumption that many neoplastic cell types exhibit reversible defects in differentiation, which upon appropriate treatment results in tumor reprogramming and the induction of terminal differentiation. There are promissory results showing that an elevated and sustained signaling through H receptors is able to differentiate leukemia-derived cell lines, opening the door for the use of H agonists for specific differentiation therapies. In both situations, histamine acting through H receptors constitutes an eligible treatment to induce leukemic cell differentiation, improving combined therapies.

The implications of histamine metabolism and signaling in renal function

“…H1R is expressed in the brain, smooth muscle, endothelial cells, DCs, monocytes, and B/T cells (Panula et al, 2015;Thangam et al, 2018). H2R was shown in the brain, smooth muscle, endothelial and epithelial cells, neutrophils, monocytes, and B/T cells (Monczor et al, 2017;Panula et al, 2015). H3R is mostly expressed throughout the mature brain, but also in salivary glands, respiratory epithelium, gastric mucosa, skin, heart, and kidney at the embryonic stage of development (Grange et al, 2020;Panula et al, 2015).…”

Cancer; an induced disease of twentieth century! Induction of tolerance, increased entropy and ‘Dark Energy’: loss of biorhythms (Anabolism v. Catabolism)

“…Stimuli-induced expression of TLRs contributes to the differential recognition of molecular structures or sub-structures of pathogens for specific sensitization and activation of APCs and appropriate response. The important roles that TLRs, decoy (dRs) or pattern recognition receptor molecules (PRRs) play in defense of body for activation of innate or adaptive immune or non-immune pathways for generation of death factors, pro-, and anti-inflammatory responses for human development or initiation or termination of acute or chronic inflammatory processes, immune tolerance and cancer have been extensively studied [ 5 , 7 , 39 , 67 , 72 , 79 , 157 – 162 , 191 , 194 – 207 , 210 – 217 ].…”

“…Other receptor molecules that are able to sequester ligands and participate in termination of inflammation or proliferation of immune or non-immune cells or cancer growth and angiogenesis include receptor molecules for MCSF, iNO, PGE2 and/or low level histamine [ 5 , 7 , 39 ]. Some decoy receptors such as IL-1dRs have been identified for regulation of other cytokines such as IL-8, a member of the IL-1 family, and TNFR superfamily (e.g., osteoprotegerin) [ 5 , 39 , 79 , 191 – 196 , 209 – 217 ].…”

“…Integration of relevant data shows that PI3K/AKT is a common signaling pathway for activation of oncogenes through hypoxia, a major stimulus for expression of VEGF. Several selective inhibitors of PI3Ks (e.g., LY294002, ZSTK474, idelalisib, rituximab, SAR405, VPS34-IN1) with different effects on genetic alterations are being examined for control of inflammation in COPD, other respiratory diseases or autoimmune and neurodegenerative diseases, or for treating several cancers (e.g., CLL, non-hodgkin’s lymphoma, follicular lymphoma, breast cancer, osteoclast survival) [ 5 , 43 , 217 , 218 , 233 , 241 – 245 , 249 ]. The diverse roles of these inhibitors have primarily been shown in HIF-1α and HIF-2α and endogenous VEGF response to hypoxia and suggest that the inhibitors of different classes of PI3Ks inhibit and induce synergistically the common oncogenes, while basal hypoxia-inducible VEGF was partially inhibited.…”

Dynamics of myeloid cell populations during relapse-preventive immunotherapy in acute myeloid leukemia

“…S2A and B). Earlier studies have shown that HDC ligates H 2 Rs to inhibit NOX2-derived ROS formation in vitro [6] in addition to promoting differentiation of myeloid cells [16]. Expression of H 2 R in CD14 ++ and CD16 + monocytes was assessed during immunotherapy and correlated with clinical outcome.…”