No 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.

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There is a large discrepancy between the changes in drug coexisting difference in cellular sensitivity has repeatedly been accumulation and the changes in drug cytotoxicity that demonstrated. 4,5 In a number of studies, sensitive cells accompany development of anthracycline in multidrug-resistaccumulated two to 10 times more drug than multidrug-resist- and subsequent subcellular targeting of endosomes; (5) altered Keywords: anthracycline; microspectrofluorometry; cellular distribution; cell death; multidrug resistance; reversal rates and extent of exocytosis; (6) modified ionic environment, such as pH, calcium concentration of extra-, intra-, or subcellular compartments; and (7) alterations of the activity and expression of proteins necessary for drug detoxification and Introduction DNA replication and repair systems. 20 Concerning the plasma membrane composition and its implication in drug-resistance Anticancer drugs have been shown to target diverse intracelluphenomena, lipids components were shown to be important lar elements in conferring lethal effect in tumor cells.1-3 A disin determining the extent of daunomycin binding to the memparity between the defect in drug accumulation and the branes and in establishing the observed resistance-related differences in drug binding. 21Early studies of the cytotoxic mechanism of anthracyclines Correspondence: M Manfait