Histamine H4 Receptor Agonism Induces Antitumor Effects in Human T-Cell Lymphoma.

Mariángeles Clauzure,Mónica A Táquez Delgado,Maria V Revuelta,Vanina A Medina,Leandro Cerchietti,Jude M Phillip

doi:10.3390/ijms23031378

Abstract

The discovery of the human histamine H4 receptor (H4R) has contributed to our understanding of the role of histamine in numerous physiological and pathological conditions, including tumor development and progression. The lymph nodes of patients with malignant lymphomas have shown to contain high levels of histamine, however, less is known regarding the expression and function of the H4R in T-cell lymphoma (TCL). In this work we demonstrate the expression of H4R isoforms (mRNA and protein) in three human aggressive TCL (OCI-Ly12, Karpas 299, and HuT78). Histamine and specific H4R agonists (VUF8430 and JNJ28610244) significantly reduced cell viability in a dose-dependent manner (p < 0.05). The combined treatment with the H4R antagonist (JNJ7777120, 10 µM) reversed the effects of the H4R ligands. Importantly, we screened a drug repurposing library of 433 FDA-approved compounds (1 μM) in combination with histamine (10 μM) in Hut78 cells. Histamine produced a favorable antitumor effect with 18 of these compounds, including the histone deacetylase inhibitor panobinostat. Apoptosis, proliferation, and oxidative stress studies confirmed the antitumoral effects of the combination. We conclude that the H4R is expressed in TCL, and it is involved in histamine-mediated responses.

Highlights

IntroductionT-cell lymphomas (TCL) constitute a heterogeneous group of non-Hodgkin lymphomas (NHL) with a complex diagnosis and relatively low incidence, representing around
Published: 26 January 2022T-cell lymphomas (TCL) constitute a heterogeneous group of non-Hodgkin lymphomas (NHL) with a complex diagnosis and relatively low incidence, representing around10–15% of NHL in the Western world
Health Organization (WHO), they are divided into three categories and are classified in subtypes that include peripheral TCL (PTCL)-NOS, anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), and natural killer/T-cell lymphoma (NKTCL) among other rare diseases

Summary

Introduction

T-cell lymphomas (TCL) constitute a heterogeneous group of non-Hodgkin lymphomas (NHL) with a complex diagnosis and relatively low incidence, representing around. 10–15% of NHL in the Western world. Lymphomas that arise from mature T cells can be categorized together under the general term peripheral TCL (PTCL). Health Organization (WHO), they are divided into three categories (nodal, extranodal, and leukemic) and are classified in subtypes that include PTCL-NOS (not otherwise specified), anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), and natural killer/T-cell lymphoma (NKTCL) among other rare diseases. TCL (CTCL) are a subclass of extranodal lymphomas that arise within the skin, including. There are various therapeutics currently available, durable disease control is challenging, especially in advanced-stage TCL that is associated with a poor prognosis. Histone deacetylase inhibitors (HDACi) are an emerging class of antitumor agents with the ability to regulate transcriptional and gene expression patterns and cytotoxicity [4–6]

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