The human U-1285 and
GLC(4) cell lines, both derived from
small cell carcinoma of the lung, are present in
doxorubicin-sensitive (U-1285 and
GLC(4)) and
doxorubicin-resistant MRP-expressing (U-1285dox and
GLC(4)/ADR) variants. These sublines were examined here with respect to their susceptibilities to the toxic effects of
selenite and compared to the toxic effects of
selenite on the promyelocytic
leukemia cell line HL-60 and its
doxorubicin-resistant
P-glycoprotein expressing variant. The
drug-resistant U-1285dox and
GLC(4)/ADR sublines proved to be 3- and 4-fold, respectively, more sensitive to the cytotoxicity of
selenite than the
drug-sensitive U-1285 and
GLC(4) sublines, whereas no difference was observed between the HL-60 sublines. The presence of
doxorubicin at a concentration equal to the IC(10) did not significantly potentiate the toxic effects of
selenite. The presence of
selenite did not significantly affect the expression of the multi-
drug resistant
proteins (
MRP1, LRP and topoisomerase IIalpha) in the
drug-resistant cells. The activities of
thioredoxin reductase (TrxR) were higher (50 and 25%, respectively) in the
drug resistant cell sublines U-1285dox and
GLC(4)/ADR compared to the
drug-sensitive parental lines. The activity of
glutathione reductase (GR) was essentially the same in the
drug-sensitive and -resistant cell lines. Exposure to
selenite resulted in a 4-fold increase in both TrxR and GR activities in U-1285 cells, an effect, which was less pronounced in the presence of
doxorubicin. Under similar conditions the increase in the TrxR activity in the resistant U-1285dox cell line, was only 30% and the activity of GR was unaltered. Different responses in the activity of the key
enzymes in
selenium metabolism are one possible mechanism explaining the differential cytotoxicity of
selenium in these cells.