Novel histamine H3 receptor antagonists with potent antineoplastic properties as targeted drug therapy for breast cancer

MONICA TAQUEZ DELGADO; MELISA NICOUD; IGNACIO OSPITAL; MICHELLE F. CORRÊA; GUSTAVO A. B. FERNANDES; DIEGO MARTINEL LAMAS; JOÃO P. S. FERNANDES; MEDINA VANINA

Congreso; LXVI Reunión Anual de la SAIC, Sociedad Argentina de Investigación Clínica, en el marco de la Reunión conjunta; 2021

We have reported the expression of the histamine H3 receptor (H3R) in human benign and malignant lesions, and cell lines derived from human mammary glands. Its expression is highly correlated with proliferation in breast cancer specimens.In this work, we aimed at investigating the potential antitumoral activity of 4 novel H3R antagonists, 1-(2,3-dihydro-1-benzofuran-2-yl)methylpiperazines (LINS01 compounds), which showed excellent selectivity and high affinity for the human H3R.1,2 Cell viability and proliferation were assessed by cell titer blue assay and colony formation in human MDA-MB-231 and murine 4T1 triple negative breast cancer cells. Cell apoptosis was assessed by Annexin V staining and flow cytometry, while cell migration was evaluated by wound-healing assay and transwell system. The lipid accumulation was assayed by flow cytometry using Nile-red staining.Results indicate that compounds LINS01022, LINS01023, LINS01009, LINS01010 (0.1-100 μM) produced a concentration-dependent inhibition on cell growth. The highest responses were observed for LINS01022 and LINS01023, showing an IC50 in the cell viability assay of 82.7 and 78.2 μM for MDA-MB-231 cells, and 87.0 and 59.2 μM for 4T1 cells. LINS01022 and LINS01023 (25-50 μM) induced cell apoptosis (4 to 7 fold-increase) and differentiation (2 to 3 fold-increase), while suppressed cell migration in both cell lines (P