The overcoming effects of buthionine sulfoximine(BSO), a specific inhibitor of glutathione synthesis. On the acquired resistance to cisplatin were investigated using MTT assay against human stomach adenocarcinoma cell line(MKN-45), human
pulmonary
adenocarcinoma cell line(PC-14), and their sublines resistant to cisplatin(MKN/CDDP and PC/CDDP). MKN/CDDP and PC/CDDP were established by stepwise exposure of MKN-45 and PC-14 to cisplatin. MKN/CDDP and PC/CDDP were 10.9 and 42.9 fold more
resistant to
cisplatin, respectively, compared to the respective parent cell line in terms of IC50 BSO at a concentration of 100μM did not inhibit the survivals of MKN-45, PC-14, MKN/CDDP and PC/CDDP. The survivals of MKN/CDDP and PC/CDDP were significantly
inhibited by the addition of BSO compared to cisplatin alone, The survivals of MKN-45 and PC-14 were also inhibited by the combined use of BSO and cisplatin, although the inhibition rates in MKN-45 and PC-14 were lower than those on MKN/CDDP and
PC/CDDP, respectively. The overcoming effects of BSO-mediated glutathione depletion were evaluated in terms of dose modification factor(DMF): DMFs in MKN-45, PC-14, MKN/CDDP and PC/CDDP were 2.59, 1.94, 3.51 and 5.98, respectively. These results
demonstrating that acquired resistance to cisplatin was significantly overcome by the addition of BSO suggest that BSO may be a potential clinical chemosensitizer to overcome the acquired resistance to cisplatin.
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