Ethyldeshydroxy-sparsomycin (
EdSm) is a ribosomal protein synthesis inhibitor which synergistically enhances the antitumor activity of
cisplatin against
L1210 leukemia in vivo. Because cellular
glutathione (GSH) and
glutathione S-
transferases (GST) are reported to interfere with the antitumor activity of
cisplatin, we analyzed the effect of
EdSm and
cisplatin on GSH and GST activity in selected
tumor cells. For this purpose we used three murine
leukemia tumors with different sensitivities towards
EdSm and
cisplatin: L1210-WT, sensitive to both drugs, L1210-Sm, resistant to
EdSm, and L1210-CDDP, resistant to
cisplatin. No significant differences were detectable between these three cell lines regarding the population doubling time, the cell size, and the cellular level of
protein and
glutathione. Neither of the resistant L1210 subclones showed
P-glycoprotein expression.
Drug exposure, however, changed the intracellular dynamics. Exposure to
EdSm strongly decreased the amount of cellular
protein, decreased the overall GST activity and led to GSH depletion, whereas exposure to
cisplatin induced a rise in the amount of
protein, in GSH, and in the total GST activity. These effects are dose-dependent and correlate well with the sensitivity of the
tumor cells for
EdSm or
cisplatin. In addition, exposure to
EdSm lowered the V(max) of GST in L1210-WT and L1210-Sm; however, in L1210-CDDP both the V(max) and the K(m) were increased. That this was not a direct effect of
EdSm on GST was shown in a cell-free system, where
EdSm did not influence the GST activity nor could it act as a substrate for GST. Our results suggest that the synergistic combination of
EdSm and
cisplatin might be explained by
EdSm switching off the cellular detoxification mechanism for
cisplatin, i.e. by inhibition of de novo synthesis and subsequent depletion of GSH and GST.