The efficacy of two-drug combination treatment may be schedule-dependent. We investigated a simulated in-vitro interaction between taxol and doxorubicin in a Cervical cancer cell line HeLa and the role of peroxiredoxin in cytotoxicity.

Two contradicting schedules of two drugs (taxol followed by doxorubicin or vice versa) were compared each other in terms of cytotoxicity in parental HeLa cell line and the peroxiredoxin (prx)-overexpressing variant. Cytotoxic activity was determined by MTT assay. Cell cycle pertubation was evaluated by flow cytometric analysis. Protein levels were determined by western blot.

The sequential treatment of taxol followed by doxorubicin (T--<D) yielded less cytotoxicity measured by MTT assay in prx-overexpressing HeLa cells than the reverse sequenced treatement did. In contrast, in parental HeLa cells, no cytotoxic difference was noted in accordance with sequences. In prx-overexpressing HeLa cells, apoptotic change was more prominent in the the sequence of doxorubucin followed by taxol (D--<T). This sequence dependency was further validated by the change in PARP activation which was prominent in D--<T sequence but barely observed in T--<D sequence. In parental cells, prominent PARP activations were evenly observed in both sequences. Protein level of cyclin D1, a proto-oncogen, was less decreased in the sequence of T--<D in prx-overexpressing cells compared with the reverese sequence of D--<T in which cyclin D1 was markedly decreased.

The cytotoxicity of taxol and doxorubicin combination is sequence-dependent in prx-overexpressing cells. These findings suggest that, in prx-overexpressing situation, it is worthy to concern about the treatment sequence when taxol and doxorubicin are supposed to employ to treat cancer of the uterine cervix.