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* Corresponding author 1 MéDIAN - Médicaments : Dynamique Intracellulaire et Architecture Nucléaire 2 Laboratoire ORSOX

Abstract : The erythroid differentiation of K562 cells could be achieved by exposure to several pharmacologic agents, including hemin, butyric acid BA, and anthracycline antitumor drugs such as aclarubicin ACLA and doxorubicin DOX. When used at subtoxic concentrations, these drugs induce the overexpression of erythroid genes, leading to hemoglobinization of cells. Because anthracyclines are known to generate oxidative damage, we intended to demonstrate the involvement of an oxidative stress in the chemically induced differentiation process. The addition of antioxidants to anthracycline- and BA-induced cells decreased their growth and dramatically reduced the percentage of differentiated cells at day 3. Northern blot analysis showed that antioxidants also decrease the expression of erythroid genes and related transcription factors in induced cells. Moreover, analyses of oxidative stress markers showed that treatment with BA, ACLA, and DOX lead to a decrease in reduced glutathione and antioxidant enzymes glutathione peroxidase GPx, glutathione reductase GRase, CuZn superoxide dismutase SOD, and catalase CAT. In addition, DOX increased thiobarbituric acid reactants TBARs, and MnSOD activity was decreased by BA and DOX. Finally, the production of reactive oxygen species ROS by differentiating agents was demonstrated using the dihydroethidium probe in a microspectrofluorometric assay. Altogether, these results strongly suggest the involvement of an oxidative stress generated by BA or anthracyclines as the first step in the irreversible differentiation process. Additionally, these results underline the differences between BA, ACLA, and DOX molecular mechanisms.

Autor: B. Chénais - M. Andriollo - P. Guiraud - R. Belhoussine - P. Jeannesson -

Fuente: https://hal.archives-ouvertes.fr/


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