The effect of ethyldeshydroxy-sparsomycin and cisplatin on the intracellular glutathione level and glutathione S-transferase activity

Abstract

Ethyldeshydroxy-sparsomycin (EdSm) is a rlbosomal pro tein synthesis Inhibitor which synerglstically enhances the antitumor activity of cisplatin against L.1210 leukemia In vivo. Because cellular glutathione (GSH) and glutathione Stransferases (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 de creased 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 of GST in L121Q-WT and L1210-Sm; however, In L1210-CDDP both the Vm QX and the Km 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 synergis tic combination of EdSm and cisplatin might be explained by EdSm switching off the cellular detoxification mechan ism for cisplatin, i.e. by Inhibition of de novo synthesis and subsequent depletion of GSH and GST.

Cisplatin Inhibition of Anthrax Lethal Toxin

“…Agents that sensitize tumors to cisplatin often do so by glutathione depletion or reduction of glutathione S-transferase activity (18,19,34). In a normal cell system or animal setting, cisplatin reacts primarily with the multitude of available thiols, leaving little drug to react with amino acid side chains of the cysteine-free anthrax toxin proteins.…”

Study of interrelations between resistance to cisplatin and composition of low molecular weight thiols in murine leukemia L1210 cell lines

“…It was about 30% higher in the resistant cells, both in treated and untreated in comparison to sensitive cells. But in controversy with these data no significant differences were detectable between sensitivity and resistance to cisplatin L1210 cell lines regarding glutathione level in other reports [17,23]. The other remarkable difference between two lines was the higher level of RI of glutathione in Rcells in comparison with S-cells.…”

Sparsomycin – a Review and Re-assessment

“…63,64 Further research established that 60 decreased the cellular protein levels and the overall glutathione S transferase activity in opposition to cisplatin which has detoxifying effects. 65 As a single agent, when administered i.p. 60 showed modest in vivo activity in mice against the B16 melanoma, good activity (T/C 197%) against the RC carcinoma, and weak or no activity against eight other cancers in vivo.…”