Targeting ROS overgeneration by N-benzyl-2-nitro-1-imidazole-acetamide as a potential therapeutic reposition approach for cancer therapy.

Autor:	Zeferino, Rodrigo C., Mota, Nádia S. R. S., Grinevicius, Valdelúcia M. A. S., Filipe, Karina B., Sulis, Paola M., Silva, Fátima R. M. B., Filho, Danilo W., Pich, Claus T., Pedrosa, Rozangela C.
Předmět:	ANTINEOPLASTIC agents CANCER chemotherapy ACETIC acid REACTIVE oxygen species ANIMAL experimentation ANTIOXIDANTS APOPTOSIS ASCITES CALCIUM CELL cycle CHALONES COMBINATION drug therapy COMPUTER simulation DNA EHRLICHIOSIS FLOW cytometry IMIDAZOLES MICE MICROSCOPY MOLECULAR biology NEOVASCULARIZATION inhibitors PROTEINS STAINS & staining (Microscopy) SURVIVAL analysis (Biometry) TUMORS OXIDATIVE stress DISEASE progression BENZYL compounds DESCRIPTIVE statistics PHARMACODYNAMICS
Zdroj:	Investigational New Drugs; Jun2020, Vol. 38 Issue 3, p785-799, 15p
Abstrakt:	Summary: BackgroundWe investigated the role of reactive oxygen species (ROS) in the anticancer mechanism of N-benzyl-2-nitro-1-imidazole-acetamide (BZN), a drug used in Chagas' disease treatment. MethodsBALB/c mice, inoculated with Ehrlich ascites carcinoma (EAC), were treated with BZN or BZN + Nacylcysteine (NAC) or NAC for 9 days. Subsequently, the inhibition of tumor growth and angiogenesis as well as animal survival were evaluated. Apoptosis and the cell cycle were evaluated using fluorescence microscopy and flow cytometry, while oxidative stress was evaluated by measuring TBARS content, DNA damage, calcium influx and ROS generation and antioxidant defenses (CAT, SOD, GPx, GST and GR). Immunoblotting was used to evaluate key death and cell cycle proteins. Results BZN treatment inhibited tumor progression (79%), angiogenesis (2.8-fold) and increased animal survival (29%). Moreover, BZN increased ROS levels (42%), calcium influx (55%), TBARS contents (1.9-fold), SOD (4.4-fold), GPx (17.5-fold) and GST (3-fold) activities and GSH depletion (2.5-fold) also caused DNA fragmentation (7.6-fold), increased cleaved PARP and promoted the trapping of cells in the G1 phase, as corroborated by the reduction in cyclin A and increased CDK2 protein levels. In silico DNA and molecular dynamic simulations showed H-bonds and hydrophobic interactions that were confirmed by circular dichroism. Increased apoptosis (232%), induced by treatment with BZN, was demonstrated by apoptotic cell staining and p53 level. Conclusion The current findings indicate that BZN acts as a tumor growth inhibitor and anti-angiogenic agent by ROS overgeneration, which interact with DNA causing damage and triggering apoptosis. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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