Curative Role of Dithiophenolato Titanium (IV)-Chitosan Nanocomposite Complex Against Carbon Tetrachloride-Induced Liver Injuries

Abstract

Background Titanium-based compounds have been incorporated as promising antineoplastic metals. In our previous studies, dithiophenolato titanium (IV) Complex "DBT" and its chitosan nanocomposite "DBT-CSNPs" were prepared and we showed that these compounds have antibacterial activities, cytotoxic, and have abilities to bind with DNA helixes. Therefore, in this study, we evaluated the LD50 values of dithiophenolato titanium (IV)-complex (DBT) and its high thermal stable chitosan nanoparticles (DBT-CSNPs). Then their therapeutic effects against liver injuries induced by carbon tetrachloride (CCl4) were assessed and compared with cisplatin treatment. Additionally, the anti-proliferative activity of DBT and DBT-CSNPs against human liver cancer (HepG2) cell lines through the analysis of the cell cycle was evaluated. Methods Nine groups of rats were prepared: normal, DBT, DBT-CSNPs, CSNPs, CCl4, CCl4-DBT, CCl4-DBT-CSNPs, CCl4-CSNPs and CCl4-cisplatin. Liver histopathology and the biochemical markers involving oxidative stress, apoptosis, liver and kidney functions, and lipid profile were determined. Results The results revealed that the treatment with DBT-CSNPs and DBT after CCl4 administration abolished liver damage since it reduced the apoptosis induced by CCl4 via the reduction of DNA fragmentation, Bax and caspase- 8 with an elevation of Bcl2 and Bcl2/Bax ratio. Also, these treatments caused nonsignificant changes in the markers of oxidative stress. Therefore, liver histopathology and functions, lipid profile, and kidney functions were improved. Cisplatin treatment reduced liver injury with a degree less than DBT-CSNPs and DBT, but it induced nephrotoxicity. Administration of DBT-CSNPs and DBT to healthy rats for 14 days has no adverse effect. Also, the results showed that DBT-CSNPs and DBT inhibited the proliferation of HepG2 cells by arresting cells in the G2/M phase and inducing cell death. Conclusion DBT-CSNPs and DBT have a therapeutic effect against CCl4-induced liver injuries via the reduction of apoptosis induced by CCl4. Moreover, both compounds have antineoplastic activities against the HepG2 cell line. In all cases, DBT-CSNPs have a greater effect due to their nanostructure. Therefore, both compounds can be used in the pharmacological fields, particularly DBT-CSNPs.