Eduardo Carrillo1, Sebastián Ramírez-Rivera2, Giuliano Bernal2, Gisela Aquea3, Catherine Tessini4, Franz A Thomet5. 1. Laboratory of Organometallics, Department of Chemistry, Universidad Técnica Federico Santa María, Avenida España N° 1680, Valparaíso, Chile. 2. Laboratory of Molecular and Cellular Biology of Cancer, Department of Biomedical Sciences, Faculty of Medicine, Universidad Católica del Norte, Larrondo N° 1281, Coquimbo, Chile. 3. Laboratory of Biological Chemistry, Institute of Chemistry, Faculty of Sciences, Pontificia Universidad Católica de Valparaíso, Brasil N° 2950, Valparaíso, Chile. 4. LabQI, Department of Chemistry, Universidad Técnica Federico Santa María, Avenida España N° 1680, Valparaíso, Chile. 5. Laboratory of Organometallics, Department of Chemistry, Universidad Técnica Federico Santa María, Avenida España N° 1680, Valparaíso, Chile. Electronic address: franz.thomet@usm.cl.
Abstract
AIMS: Ruthenium-based compounds exhibit critical biochemical properties making them suitable for diverse pharmacological applications. The aim of this work was to study the anticancer effects of three ruthenium complexes on a human gastric cancer cell line. MAIN METHODS: We synthetized three [Ru(η6-anethole)(en)X]PF6 complexes, where (en) is ethylenediamine and X is Cl (1), Br (2) or I (3), which were then evaluated by MTT assay, RT-qPCR and flow cytometry on the human gastric cancer cell line AGS. KEY FINDINGS: Compound 3 exhibited the highest cytotoxicity (IC50 = 11.27 ± 1.08 μM) of the series, with an activity almost three-fold more potent than the commercial drug cisplatin, and also revealed a 4.5-fold less potent cytotoxicity in the human normal gastric cell line GES-1. The exchange of the halogen (Cl, Br or I) on the organometallic compound slightly alters its solubility in PBS and lipophilicity (expressed as Log P). Studies of gene expression revealed that compound 3 induces a significant overexpression of the pro-apoptotic genes Caspase-3, PUMA and DIABLO in the gastric cancer cell line AGS after 6 h. In contrast, only PUMA was significantly overexpressed in the normal gastric cell line GES-1. Compound 3 induced the activation of multiple caspases in AGS cells: a sign of apoptosis. Characterization via single-crystal X-ray diffraction for compound 3 confirmed the key structural features for this type of organometallic complexes. SIGNIFICANCE: Our data suggests that compound 3 may be an interesting anticancer molecule for the treatment of gastric cancer.
AIMS: Ruthenium-based compounds exhibit critical biochemical properties making them suitable for diverse pharmacological applications. The aim of this work was to study the anticancer effects of three ruthenium complexes on a humangastric cancer cell line. MAIN METHODS: We synthetized three [Ru(η6-anethole)(en)X]PF6 complexes, where (en) is ethylenediamine and X is Cl (1), Br (2) or I (3), which were then evaluated by MTT assay, RT-qPCR and flow cytometry on the humangastric cancer cell line AGS. KEY FINDINGS: Compound 3 exhibited the highest cytotoxicity (IC50 = 11.27 ± 1.08 μM) of the series, with an activity almost three-fold more potent than the commercial drug cisplatin, and also revealed a 4.5-fold less potent cytotoxicity in the human normal gastric cell line GES-1. The exchange of the halogen (Cl, Br or I) on the organometallic compound slightly alters its solubility in PBS and lipophilicity (expressed as Log P). Studies of gene expression revealed that compound 3 induces a significant overexpression of the pro-apoptotic genes Caspase-3, PUMA and DIABLO in the gastric cancer cell line AGS after 6 h. In contrast, only PUMA was significantly overexpressed in the normal gastric cell line GES-1. Compound 3 induced the activation of multiple caspases in AGS cells: a sign of apoptosis. Characterization via single-crystal X-ray diffraction for compound 3 confirmed the key structural features for this type of organometallic complexes. SIGNIFICANCE: Our data suggests that compound 3 may be an interesting anticancer molecule for the treatment of gastric cancer.