RESUMO
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.
Assuntos
Antioxidantes , Apoptose , Caspase 3 , Doxorrubicina , Fator 2 Relacionado a NF-E2 , Piridoxina , Espécies Reativas de Oxigênio , Doxorrubicina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Humanos , Piridoxina/farmacologia , Piridoxina/análogos & derivados , Caspase 3/metabolismo , Caspase 3/genética , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacosRESUMO
The cytotoxic activity of a series of dinitrosyl iron complexes (DNICs) with thioureas against cells of different origin has been studied in this work. The cytotoxicity of the studied DNICs proved to be substantially different depending on the structure of the complexes and cell line. Complexes with thiourea and 1,3-dimethylthiourea were found to induce notable cell death in different cell lines of both cancerous and non-cancerous origin, while the N-ethylthiourea-bearing complex induced cell death in cells derived from brain tumors. The studied DNICs effectively release NO while decomposing in solutions, as follows from the electrochemical analysis. It was found that the cytotoxic effects of the studied DNICs did not correlate with their NO-donating ability, hence suggesting that their cytotoxic activity is, in a big part, defined by the long-lived nitrosyl iron-sulfur intermediates formed during the decomposition of the complexes. The structures of the products formed upon hydrolytic decomposition of all studied DNICs have been studied by electrospray ionization mass spectrometry. Stable high-molecular cluster ions containing NO groups namely [Fe4S3(NO)7]- (Roussin's "black salt" anion), [Fe4S3(NO)5]-, [Fe4S4(NO)4]-, [Fe4S3(NO)4]- and [Fe4S3(NO)6]- have been detected in the solution of the N-ethylthiourea-bearing complex. The mechanism of Roussin's "black salt" anion formation in a solution of DNIC with N'-ethylthiourea was studied using density functional theory. This moved us near understanding the reasons for the formation of biologically active intermediates upon the decomposition of the complex with N'-ethylthiourea, which are apparently responsible for the unique antiglioma activity of the complex.
Assuntos
Neoplasias Encefálicas , Óxidos de Nitrogênio , Ânions , Cátions , Humanos , Ferro/química , Óxido Nítrico/química , Óxidos de Nitrogênio/química , Tioureia/farmacologiaRESUMO
The results of the study of the effect of a mononuclear dinitrosyl iron complex (DNIC7) with functional sulfur-containing ligands (NO donors) on the viability of multiple myeloma cells are presented. It was shown that DNIC7 decreased cell viability and inhibited the proliferation of multiple myeloma cells, i.e., exhibits cytotoxic properties. Fluorescent analysis showed that the DNIC7 compound decreases the level of intracellular glutathione and increases the level of reactive oxygen species in multiple myeloma cells. It is assumed that DNIC7 has a therapeutic potential for the treatment of cancer.
