Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2).
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 hepatocyte...
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doaj-5946c7d11dd94528b0e01039b1c142de2021-03-03T20:01:59ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01106e013004610.1371/journal.pone.0130046Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2).Gustavo Jabor GozziAmanda do Rocio Andrade PiresGlaucio ValdameriMaria Eliane Merlin RochaGlaucia Regina MartinezGuilhermina Rodrigues NoletoAlexandra AccoCarlos Eduardo Alves de SouzaAurea EchevarriaCamilla Moretto Dos ReisAttilio Di PietroSílvia Maria Suter Correia CadenaIn 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.https://doi.org/10.1371/journal.pone.0130046 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gustavo Jabor Gozzi Amanda do Rocio Andrade Pires Glaucio Valdameri Maria Eliane Merlin Rocha Glaucia Regina Martinez Guilhermina Rodrigues Noleto Alexandra Acco Carlos Eduardo Alves de Souza Aurea Echevarria Camilla Moretto Dos Reis Attilio Di Pietro Sílvia Maria Suter Correia Cadena |
spellingShingle |
Gustavo Jabor Gozzi Amanda do Rocio Andrade Pires Glaucio Valdameri Maria Eliane Merlin Rocha Glaucia Regina Martinez Guilhermina Rodrigues Noleto Alexandra Acco Carlos Eduardo Alves de Souza Aurea Echevarria Camilla Moretto Dos Reis Attilio Di Pietro Sílvia Maria Suter Correia Cadena Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2). PLoS ONE |
author_facet |
Gustavo Jabor Gozzi Amanda do Rocio Andrade Pires Glaucio Valdameri Maria Eliane Merlin Rocha Glaucia Regina Martinez Guilhermina Rodrigues Noleto Alexandra Acco Carlos Eduardo Alves de Souza Aurea Echevarria Camilla Moretto Dos Reis Attilio Di Pietro Sílvia Maria Suter Correia Cadena |
author_sort |
Gustavo Jabor Gozzi |
title |
Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2). |
title_short |
Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2). |
title_full |
Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2). |
title_fullStr |
Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2). |
title_full_unstemmed |
Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2). |
title_sort |
selective cytotoxicity of 1,3,4-thiadiazolium mesoionic derivatives on hepatocarcinoma cells (hepg2). |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pone.0130046 |
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