Cross resistance between cisplatin and oxaliplatin in a low-level resistance lung cancer cell model

Oxaliplatin is thought to have activity against cisplatin resistant cancers and has fewer side effects than cisplatin. An understanding of the cellular and molecular reasons for this advantage would lead to further treatment improvements. A lack of cross resistance between cisplatin and oxaliplatin has been established in highly resistant cellular models. The aim of our study was therefore to compare how platinum resistance develops during clinically relevant drug treatment and whether cells develop similar resistance mechanisms to cisplatin and oxaliplatin. H69 human small cell lung cancer cells were exposed to IC20 doses of cisplatin or oxaliplatin for 4 days and were re-treated after a recovery period. The first exposure caused a reversible G2M cell cycle block, then a 3 week lag of cell growth with a drop in the proportion of cells in the G1 phase. This lag occurred for the first 5 exposures of both platinum drugs, while after the 6th exposure cells grew with a reduced lag. The oxaliplatin resistant cells recovered from drug treatment faster and could also survive higher doses than the cisplatin resistant cells. The resistant sublines produced by 8 exposures were equally resistant and cross resistant (1.5-2 fold) to cisplatin and oxaliplatin. This resistance was not mediated by a decrease in cellular accumulation of platinum. The resistant sublines were also not resistant to carboplatin, the anthracyclines or topoisomerase poisons but both were sensitive to taxanes. The oxaliplatin resistant cells were resistant to vinca alkaloids and sensitive to buthionine sulphoximine (BSO) whereas the cisplatin resistant cells showed the reverse. Treatment with BSO which depletes cellular glutathione, reversed the oxaliplatin resistance in both cell lines to a greater extent than the cisplatin resistance. However there was no change in the level of cellular glutathione between the cell lines. Based on these cross resistance profiles the resistance mechanisms are different between the cisplatin and oxaliplatin resistant cells. Alterations in tubulin, cell cycle proteins and other enzymes related to glutathione metabolism are probably involved in the cisplatin and oxaliplatin resistance mechanisms. This low-level resistance model shows cross resistance between cisplatin and oxaliplatin but unusually not carboplatin demonstrating that at clinically relevant doses the cross resistance profile of platinum drugs is different from highly resistant models.