Cross-resistance between cisplatin and antimony in a human ovarian carcinoma cell line

The metal compound cisplatin (DDP) is a widely used anticancer agent but naturally occurring and acquired resistance to DDP limits its effectiveness. Resistance is associated with a decreased accumulation of DDP and increased levels of glutathione and metallothioneins. Such changes also serve as protective and detoxification mechanisms for other metal salts in prokaryotes and lower eukaryotes. The aim of this study was to find metal salts for which the cross-resistance profile was the same as for DDP in sublines of the parental 2008 human ovarian carcinoma cells selected with either DDP (2008/C13*5.25) or CdCl2 and ZnCl2 (2008/MT). Among the metal salts tested the resistance profile of trivalent antimony most closely resembled that of DDP. DDP-selected cells were 15-fold resistant to DDP and 4.4-fold cross-resistant to antimony potassium tartrate, whereas of the cations tested (Cd2+, Zn2+, Ni2+ and Co2+) cross-resistance was observed only for Cd2+ (2.4-fold). When 2008 cells were selected for resistance to antimony (6.6-fold) they were found to be 16-fold cross-resistant to DDP. Accumulation of the DDP analogue cis-[3H]dichloro(ethylenediamine)platinum(II) was 59% lower in the DDP-selected subline and 48% lower in the antimony-selected variant than in the parental cell line. We conclude from the mutual cross-resistance to DDP and antimony potassium tartrate and from the impaired uptake of [3H]DEP in both the DDP and antimony-selected variants that DDP and antimony share a common mechanism of resistance. The significance of this observation lies in the fact that several evolutionarily conserved mechanisms for antimony detoxification are already known in lower organisms which may point the way to identification of additional DDP resistance mechanisms in mammalian cells.