2-DEOXY-D-GLUCOSE TOXICITY AND TRANSPORT IN HUMAN MULTIDRUG-RESISTANTKB CARCINOMA CELL-LINES

It is shown that a series of colchicine-selected multidrug-resistant ( MDR) human KB carcinoma cell lines displayed increasing 2-deoxy-D-gluc ose collateral sensitivity, which correlated with increasing multidrug resistance. The relative resistance of MDR cell lines to 2-deoxy-D-gl ucose was reduced to 0.73 (KB-8-5), 0.3 (KB-8-5-11) and 0.2 (KB-C1) wh en compared with parental KB-3-1 (1.0). 2-Deoxy-D-glucose accumulation was found to be reduced in the MDR cell lines in a manner that correl ated with 2-deoxy-D-glucose collateral sensitivity. At 30 min 2-deoxy- D-glucose accumulation was reduced to 0.61 (KB-8-5), 0.41 (KB-8-5-11) and 0.22 (KB-CI) relative to KB-3-1 uptake (1.0). The efflux of 2-deox y-D-glucose was not significantly different between resistant and sens itive cell lines. Analysis of 2-deoxy-D-glucose uptake kinetics, by in itial rate measurements, showed alterations in K-t and J(max) for MDR when compared with KB-3-1 cells. The levels of GLUT-1 facilitative tra nsporter were found to be reduced significantly in the MDR cell lines in total cell homogenate and plasma membrane fractions by using Wester n blot analysis. Changes in the plasma membrane level of GLUT-1 correl ated with 2-deoxy-D-glucose toxicity and uptake for MDR cell lines, wh ere relative GLUT-1 levels were reduced to 0.71 (KB-8-5), 0.43 (KB-8-5 -11) and 0.27 (KB-C1) relative to KB-3-1 (1.0). It is concluded that t he response of human KB MDR cells to 2-deoxy-D-glucose involved altera tions in the level and activity of the facilitative glucose transporte r GLUT-1, in a manner that is associated with the degree of multidrug resistance.