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Molecular mechanisms contributing to cisplatin resistance in human cervix carcinoma cell lines

Acquired drug resistance of tumor cells is a major problem in chemotherapy. Two cisplatin (cDDP) resistant human cervix carcinoma cell lines were isolated from parental cell line (HeLa) using acute (HeLa CA) and chronic (HeLa CK) schedules of treatment with increasing concentrations of cDDP. Analysing the mechanism causing the cDDP resistant phenotype, we first checked DNA repair capacity of parental versus resistant cell lines. There was no difference in expression and DNA binding activity of mismatch repair proteins in both cell types. Also, the expression of nucleotid excision repair proteins, XPA and ERCC1, as well as overall repair capacity (UDS) of UV lesions were similar in all cell lines. Moreover, since cDDP resistant sublines were only slightly cross-resistant to UV light, NER seems not to play a major role in acquired cDDP resistance. Replication blockage, formation of single and double strand breaks, formation of interstrand cDDP adducts and expression of multidrug resistance-associated protein (MRP2) were also similar in all three cell lines. However, parental cells show a higher frequency of apoptosis after cDDP treatment as compared to resistant cell variants. Interestingly, we found a higher activation level of c-Jun-N-terminal kinase (JNK) and p38 kinase in the sensitive line upon cDDP treatment. Also DNA binding activity of AP-1 and c-Jun protein expression proved to be enhanced in sensitive cells upon cDDP treatment. Furthermore, cDDP treatment caused permanent G2 block in sensitive but not in resistant cell variants. Based on the data we suggest that increased activation of MAP kinase pathways contributes to the cisplatin sensitive phenotype by provoking programed cell death.

cisplatin; drug-resistance; tumor cells

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