VITAMIN D FAVOURS THE THERAPEUTIC ACTION OF HISTAMINE RECEPTOR H4 AGONISTS IN HYPERPLASTIC AND NEOPLASTIC LEYDIG CELLS

LAZZATI JUAN; BELGOROSKY, ALICIA; MONDILLO CAROLINA; VARELA, MARÍA LUISA; ZAIDMAN VERÓNICA; PIGNATARO OMAR P; ABIUSO, ADRIANA MARÍA BELÉN; BESIO MORENO MARCOS; BERENSZTEIN, ESPERANZA

Mar del Plata

Congreso; LXIII Reunión Anual de la SAIC; 2018

Sociedad Argentina de Investigaciones Clínicas (SAIC)

VITAMIN D FAVOURS THE THERAPEUTIC ACTION OF HISTAMINE RECEPTOR H4AGONISTS IN HYPERPLASTIC AND NEOPLASTIC LEYDIG CELLSVarela, María Luisa, Abiuso, Adriana María Belén; Lazzati, Juan Manuel; Zaidman,Verónica Ethel; Besio moreno, Marcos; Belgorosky, Alicia; Pignataro, OmarPedro; Berensztein, Esperanza; Mondillo, CarolinaTesticular Leydig cell (LC) tumors (LCT) are steroid-secreting tumors of unknown etiology. Several clinical features are shared with those of the androgen insensitivity syndrome (AIS), in which 46XY patients show virilization defects and develop LC hyperplasia (LCH). Vitamin D (VD) is believed to play a role in the prevention and treatment of many extra-skeletal diseases, such as cancer. Over one billion people worldwide are VD deficient. VD receptor (VDR) knock-out mice develop 50% more LCH. The histamine receptor H4 (HRH4) is considered a promising target for cancer therapy. Previously, we reported that VUF8430 (HRH4 agonist) inhibits proliferation and steroidogenesis in MA-10 and R2C tumor LC. Likewise, calcitriol (VD?s active form) inhibits R2C proliferation and steroidogenesis, while it promotes HRH4 expression. Accordingly, we detectedVDR and HRH4 in LCT. Objectives:To analyze the concomitant expression of VDR and HRH4 in LCH and xenograft murine models. To evaluate a possible synergism between calcitriol and VUF8430 in vitro, in tumor LC.Methods:R2C were treated with: calcitriol(10-9M), VUF8430(10-5M), or calcitriol(10-9M)+VUF8430(10-5M). Cell proliferation was assessed using sulforhodamine B assay. Aromatase activity was measured using a tritiated water-release assay. Tumor xenograft models were developed in athymic mice (R2C) and C57 mice (MA-10). Plasma steroids were measured by chemiluminescence. Formalinfixed, paraffin-embedded (human and murine) sample sections were evaluated for VDR and HRH4 expression using immunohistochemistry.Results:Calcitriol-, VUF8430- or calcitriol+VUF8430-treated R2C showed diminished proliferation (p