Changes in the free-radical state and the level of free iron during the development of drug resistance in tumor cells

Abstract

The free-radical state of K562 human erythroleukemia cells changes during the development of resistance to doxorubicin, an antitumor antibiotic with prooxidant action widely used in oncology. It was found that the level of superoxide anion in the resistant cells decreased. The addition of doxorubicin to the culture medium induced a much smaller increase in O 2 ∸ generation in the resistant cells than in the sensitive cells. Again, the semiquinone-type EPR signal with a g-factor of 2.006 considerably decreased in the resistant cells grown without doxorubicin as compared with the sensitive cells under the same conditions. The EPR study has shown that the level of paramagnetic nitrosyl complexes of nonheme iron in the resistant cells decreased, which indicates that the content of free nonheme iron declined in development of drug resistance. In addition, we have found with the use of RT-PCR that the level of mRNA of the transferrin receptor decreased in the resistant cells. The data suggest that the suppression of free-radical processes during the development of resistance of K562 cells to doxorubicin is a coordinated redox-dependent adaptive response.