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Topoisomerases are essential nuclear enzymes that work to resolve topological problems that normally occur during DNA metabolism. Their involvement in crucial DNA associated-processes, such as replication, transcription and repair, mark them as a target of chemotherapeutic drugs such as camptothecins (CPTs). Therefore, finding other agents that may alter their activity is of great importance. Previous data showed that certain tyrosine kinase antagonists, tyrphostins, inhibit the catalytic activity of the cellular topoisomerase I (topo I). We examined the effect of clinically used tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, on topo I in breast and prostate cancer cells. While erlotinib and gefitinib inhibit cellular topo I in treated cells without affecting the levels of the enzyme protein, in vitro assays show that erlotinib, but not gefitinib, inhibits the DNA relaxation activity of purified topo I. Erlotinib was found to reduce the DNA-binding ability of topo I, however, the reduction in topo I activity in gefitinib-treated cells is probably due to post-translational modifications of the enzyme protein. A combined treatment of either erlotinib or gefitinib with CPT increased the effect of CPT on the activity of cellular topo I, which supports the increased anticancer effect observed in MCF7 cells. These results suggest that topo I is a novel target of erlotinib and a combination of TKIs with topo I inhibitors may be an effective treatment for breast cancer.

Topoisomerase I as a target of erlotinib and gefitinib: Efficacy of combined treatments with camptothecin