Histidine decarboxilase inhibitors in combination with carboplatin as a new therapeutic option for the treatment of Leydig cell tumors

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

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2019

SAIC-SAFE-SAB-SAP

Testicular Leydig cell tumors (LCT) are endocrine tumors which lead to various clinical complications in boys and adults. To date, carboplatin (CP) and orchiectomy are considered the gold standard for LCT management. However, treatment-related infertility highlights the need for new therapeutic options. We have previously shown that histamine (HA), a biogenic amine synthetized by Histidine Decarboxylase (HDC), plays a role as autocrine growth factor in R2C and MA-10 Leydig tumor cells, the former characterized by aromatase (CYP19) overexpression. Given that both cell lines express high HDC levels as human pediatric LCT, herein we evaluated the efficacy of HDC inhibitors (α-MHD and EGCG, synthetic and natural, respectively) alone or in combination with CP, as anti-LCT agents. Methods: In vitro: R2C and MA-10 cells were treated with HDC inhibitors for 48 h and then subjected to [3H]-Thymidine incorporation to assess cell proliferation. In vivo: C57 x BALB/c offspring (F1) and SwissNu/Nu mice were injected with MA-10 cells and R2C cells to generate allograft and xenograft LCT models, respectively. When LCT volume reached 40 mm3, mice were treated every other day with α-MHD or EGCG, alone or combined with CP. Results: α-MHD and EGCG decreased R2C and MA-10 cell proliferation in vitro (p < 0.01). In F1 mice, α-MHD + CP was more effective than CP alone at reducing tumor growth (56% vs. 38%, p < 0.05), whereas EGCG had no effect. In SwissNu/Nu mice, EGCG was even more effective than α-MHD at enhancing CP anti-tumor potential (p< 0.0001), possibly because R2C tumors rely on CYP19 overexpression for sustained tumor growth and EGCG can inhibit CYP19 expression as well as HDC activity. Conclusion: HDC inhibitors increase the anti-tumor effect of CP in murine LCT models and could be a promising therapeutic option in patients. EGCG is known to protect spermatogenesis against irradiation in vivo, underscoring the importance of our results in terms of fertility preservation.