RESUMO
Possible involvement of the system of protein poly(ADP-ribosyl)ation in the mechanisms of cardiotoxicity of doxorubicin, one of the most frequently used anticancer drug, was studied in cultures of cardiomyocytes H9c2. The treatment of H9c2 cells with doxorubicin (1 µM) led to a transient (after 6 h of incubation) increase in the nuclear level of poly(ADP-ribosyl)ated proteins. The observed data indirectly indicate the development of genotoxic stress in the doxorubicin-treated cells, probably caused by the stimulatory effects of doxorubicin and its metabolites on the production of reactive oxygen and nitrogen species.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Ativadores de Enzimas/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/enzimologia , Citoplasma/efeitos dos fármacos , Citoplasma/enzimologia , Doxorrubicina/farmacocinética , Ativadores de Enzimas/farmacocinética , Imunofluorescência , Dinâmica não Linear , Ratos , Fatores de TempoRESUMO
The impact of a number of synthetic nucleoside derivatives on the growth and survival of cultured human ovarian tumor cells (line SKOV-3) and normal human lung fibroblasts was investigated. It was shown that the dialdehyde derivatives of uridine, 1-ß-D-eritrofuranozyl uracil and 3'-O-ß-D-ribofuranosyl-2'-deoxythymidine, in contrast to their unoxidized counterparts, exert marked toxic effect on SKOV-3 cells. Cultured human fibroblasts were less susceptible to the damaging effect of the dialdehyde nucleosides. The dialdehyde derivative of 1-ß-D-eritrofuranozyl uracil demonstrated greatest differences in the cytotoxic effect on these cultures: inhibition of tumor SKOV-3 cells growth on 50% or more was achieved at the concentrations of this compound ten times lower than in the case of normal fibroblasts.
Assuntos
Aldeídos/farmacologia , Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Furanos/farmacologia , Uridina/farmacologia , Aldeídos/síntese química , Antineoplásicos/síntese química , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Furanos/síntese química , Humanos , Concentração Inibidora 50 , Especificidade de Órgãos , Ovário/efeitos dos fármacos , Ovário/patologia , Uridina/análogos & derivados , Uridina/síntese químicaAssuntos
Corantes Fluorescentes/síntese química , Oligopeptídeos/química , Prolina/análogos & derivados , Animais , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Fluorometria , Microscopia Confocal , Estrutura Molecular , Células PC12 , Feocromocitoma/metabolismo , Fotomicrografia , Porfobilinogênio/análogos & derivados , Porfobilinogênio/síntese química , Porfobilinogênio/química , Porfobilinogênio/farmacocinética , Prolina/química , Ratos , Análise EspectralRESUMO
The DNA polymerase iota (Pol iota), which has some peculiar features and is characterized by an extremely error-prone DNA synthesis, belongs to the group of enzymes preferentially activated by Mn2+ instead of Mg2+. In this work, the effect of Mn2+ on DNA synthesis in cell extracts from a) normal human and murine tissues, b) human tumor (uveal melanoma), and c) cultured human tumor cell lines SKOV-3 and HL-60 was tested. Each group displayed characteristic features of Mn-dependent DNA synthesis. The changes in the Mn-dependent DNA synthesis caused by malignant transformation of normal tissues are described. It was also shown that the error-prone DNA synthesis catalyzed by Pol iota in extracts of all cell types was efficiently suppressed by an RNA aptamer (IKL5) against Pol iota obtained in our work earlier. The obtained results suggest that IKL5 might be used to suppress the enhanced activity of Pol iota in tumor cells.
