The combined effects of proteasome inhibitor bortezomib with topoisomerase I and II inhibitors on topoisomerase enzymes.

Abstract

DNA topoisomerases are ubiquitous enzymes that regulate conformational changes in DNA topology during essential cellular processes, and, for this reason, have been characterized as the cellular targets of a number of anticancer drugs. Bortezomib is a powerful proteasome inhibitor used in the treatment of hematological malignancies. In this study, we investigated the inhibitory effects of bortezomib on human topoisomerase I and II enzymes both alone and in combination modes with camptothecin and etoposide. The interactions of these drugs with topoisomerase enzymes were evaluated by relaxation assay in cell-free systems. IC50 values of the drugs on topoisomerase enzymes were calculated using the S probit analysis program. Bortezomib showed a very weak inhibition effect on topoisomerase I (IC50 = 87.11 mM). On the other hand, it had a strong inhibitory effect on topoisomerase II (IC50 = 1.41 mM). Our results indicated that bortezomib is effective not only on proteasome but also on topoisomerase II. In addition, bortezomib possesses an increased synergistic effect when used in combination with camptothecin and etoposide than when used alone. The results of this study point out that these data may build a framework for combination studies with bortezomib, camptothecin, and etoposide in the treatment of cancer.