ABSTRACT
The effect of a new pyridoxine derivative B6NO on doxorubicin cytotoxicity and Nrf2-dependent cellular processes in vitro was studied. Antioxidant B6NO enhances the cytotoxic effect of doxorubicin on tumor cells, which is associated with G2/M cell division arrest and an increase in activity of proapoptotic enzyme caspase-3. The antioxidant promotes intracellular accumulation and nuclear translocation of Nrf2 transcription factor in non-tumor and tumor cells. In non-tumor cells, B6NO increases the expression of antioxidant system proteins and reduces ROS generation in the presence of doxorubicin. In tumor cells, no activation of Nrf2-dependent processes occurs under the action of the antioxidant. Our findings demonstrate the prospect of further studies of pyridoxine derivatives as antioxidants to reduce adverse reactions during chemotherapy.
Subject(s)
Antioxidants , Apoptosis , Caspase 3 , Doxorubicin , NF-E2-Related Factor 2 , Pyridoxine , Reactive Oxygen Species , Doxorubicin/pharmacology , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Humans , Pyridoxine/pharmacology , Pyridoxine/analogs & derivatives , Caspase 3/metabolism , Caspase 3/genetics , Antioxidants/pharmacology , Apoptosis/drug effects , Reactive Oxygen Species/metabolism , Cell Line, Tumor , G2 Phase Cell Cycle Checkpoints/drug effectsABSTRACT
The effect of synthetic analogues of dinitrosyl mononuclear iron complexes (DNICs) with functional sulfur-containing ligands (NO donors) on the activity of myeloperoxidase (MPO) was studied, and their efficiency was evaluated. It was shown that the enzyme MPO is the molecular target of DNICs. It was found that six DNICs inhibited the activity of MPO and one compound potentiated it. The evaluation of their efficiency showed that two DNICs effectively inhibited the activity of MPO by 50% at IC50 = 2 × 10-4 M and IC50 = 5 × 10-7 M.