Preclinical evaluation of combined topoisomerase and proteasome inhibition against pediatric malignancies

Abstract

Background/Aim: The toxicity of the proteasome inhibitor MG132 was tested alone and combined either with the topoisomerase I inhibitor topotecan or the topoisomerase II inhibitor etoposide against a panel of 18 cell lines representing six pediatric tumor types. Materials and Methods: MG132, topotecan, etoposide and their combination were evaluated. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Combination indices for simultaneous treatment schedules were determined by the method of Chou and Talalay. Results: Concentrations inducing growth inhibition of 50% (GI50s) ranged between 0.140-1.30 μmol/l (median=0.55 μmol/I) for MG132. GI50s of 0.004-3.48 μmol/l (median=30 nmol/I) were calculated for topotecan and 0.117-45.0 μmol/l (median=2.74 μmol/l) for etoposide. Additive/synergistic effects were observed in eight cell lines (including all Ewing sarcoma cell lines) for the combination of MG132 with etoposide, but only in three cell lines for its combination with topotecan. Conclusion: The combination of proteasome and topoisomerase II inhibitor deserves further evaluation, especially for Ewing sarcoma.