title: Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2).
abstract: In this work, we evaluated the cytotoxicity of mesoionic 4-phenyl-5-(2-Y, 4-X or 4-X-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride derivatives (MI-J: X=OH, Y=H; MI-D: X=NO2, Y=H; MI-4F: X=F, Y=H; MI-2,4diF: X=Y=F) on human hepatocellular carcinoma (HepG2), and non-tumor cells (rat hepatocytes) for comparison. MI-J, M-4F and MI-2,4diF reduced HepG2 viability by ~ 50% at 25 μM after 24-h treatment, whereas MI-D required a 50 μM concentration, as shown by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The cytotoxicity was confirmed with lactate dehydrogenase assay, of which activity was increased by 55, 24 and 16% for MI-J, MI-4F and MI-2,4diF respectively (at 25 μM after 24 h). To identify the death pathway related to cytotoxicity, the HepG2 cells treated by mesoionic compounds were labeled with both annexin V and PI, and analyzed by flow cytometry. All compounds increased the number of doubly-stained cells at 25 μM after 24 h: by 76% for MI-J, 25% for MI-4F and MI-2,4diF, and 11% for MI-D. It was also verified that increased DNA fragmentation occurred upon MI-J, MI-4F and MI-2,4diF treatments (by 12%, 9% and 8%, respectively, at 25 μM after 24 h). These compounds were only weakly, or not at all, transported by the main multidrug transporters, P-glycoprotein, ABCG2 and MRP1, and were able to slightly inhibit their drug-transport activity. It may be concluded that 1,3,4-thiadiazolium compounds, especially the hydroxy derivative MI-J, constitute promising candidates for future investigations on in-vivo treatment of hepatocellular carcinoma.
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Gustavo Jabor
authors.initials: GJ
authors.lastname: Gozzi
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Amanda do Rocio Andrade
authors.initials: Ado R
authors.lastname: Pires
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Glaucio
authors.initials: G
authors.lastname: Valdameri
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Maria Eliane Merlin
authors.initials: ME
authors.lastname: Rocha
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Glaucia Regina
authors.initials: GR
authors.lastname: Martinez
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Guilhermina Rodrigues
authors.initials: GR
authors.lastname: Noleto
authors.affiliation: Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Acco
authors.affiliation: Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Alves de Souza
authors.affiliation: Departamento de Química, Universidade Federal Rural do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Aurea
authors.initials: A
authors.lastname: Echevarria
authors.affiliation: Departamento de Química, Universidade Federal Rural do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Camilla
authors.initials: C
authors.lastname: Moretto Dos Reis
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR 5086 CNRS/Université Lyon 1, IBCP, Lyon, France.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Sílvia Maria
authors.initials: SM
authors.lastname: Suter Correia Cadena
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013830:Thiadiazoles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013830:Thiadiazoles