GLUTATHIONE DERIVATIVES ENHANCE ADRIAMYCIN CYTOTOXICITY IN A HUMAN LUNG ADENOCARCINOMA CELL-LINE

We evaluated the effects of a panel of glutathione derivative (S-butyl , S-decyl, S-ethyl, S-heptyl, S-hexyl, S-methyl, S-nonyl, S-octyl, S-p ropyl and S-pentyl glutathiones) on glutathione-S-transferase activity in the cell lysates of a human lung cancel; PC-9. Glutathione derivat ives inhibited glutathione-S-transferase activity in PC-9 cell lysates by up to 67%. When PC-9 cells were incubated with the IC50 concentrat ion of adriamycin (200 nM) and with nontoxic concentrations (1 mu M) o f the glutathione derivatives, cytotoxicity ranged from -20% to +55% o f the control levels. Enhancement of adriamycin toxicity by glutathion e derivatives was significantly correlated with the inhibition of glut athione-S-transferase activity. S-decylglutathione, which was one of t he most potent inhibitors of glutathione-S-transferase activity, signi ficantly enhanced rite adriamycin-induced antitumor effect in vivo. Fi ndings suggest that some glutathione derivatives, including the S-decy l, S-octyl, and S-hexyl glutathiones, enhance adriamycin-induced cytot oxicity, in part by inhibiting glutathione-S-transferase and that thes e agents may be useful as chemosensitizers for adriamycin therapy. In conclusion the present results showed that some glutathione derivative s enhanced sensitivity of tumor cells to ADR by inhibiting GST activit y. The use of BSO and EA as sensitizers to chemotherapy is currently b eing evaluated in clinical trials. The present data suggest that the w e of GSH derivatives to modulate GST activity may improve the response to ADR.