Reactive oxygen species-specific mechanisms of drug resistance in paraquat-resistant acute myelogenous leukemia sublines

Reactive oxygen species (ROS)-specific mechanisms of drug resistance were e xplored in paraquat (PQ)resistant acute myelogenous leukemia cell (OCI/AML- 2) sublines. For this, PQ-resistant AML sublines, AML-2/PQ100 and AML-2/PQ4 00, were selected in the presence of PQ concentrations of 100 mu g/ml and 4 00 mu g/ml, respectively. They showed a moderate level of cross resistance to cisplatin and doxorubicin, They were also slightly more resistant than t he parental cell (AML-2/WT) to etoposide, camptothecin and daunorubicin. Th e resistance of PQ-resistant AML-2 sublines to cisplatin seemed to be due t o increased amounts of metallothionein, which was not only supported by rev ersal of resistance to cisplatin by propargylglycin (an inhibitor of metall othionein synthesis) but also confirmed by Western blot analysis and revers e transcription-PCR assay. In addition, both AML-PQ100 and /PQ400 sublines showed increased activities of Cu-, Zn-containing superoxide dismutase (Cu, Zn-SOD) and Mn-containing superoxide dismutase (Mn-SOD), whereas AML-2/PQ40 0, but not AML-2/PQ100, showed increased glutathione S-transferase activity as compared to that of AML-2/WT, However, there was no difference in other ROS-related cellular antioxidants between AML-2/WT and its PQ-resistant su blines, Taken together, these results strongly suggest that increases in le vels of metallothionein, glutathione S-transferase, Cu,Zn-SOD and Mn-SOD pl ay important roles in protective mechanisms against toxicity of PQ or ROS i n AML cells.