Synergistic interaction of proteasome and topoisomerase II inhibition in multiple myeloma.
Multiple myeloma is a malignancy of terminally differentiated plasma cells and is incurable in the majority of the patients. Thus, novel effective treatment regimens are urgently needed. In this study, we examined the effects of co-treatment with proteasome-inhibitor bortezomib and topoisomerase II inhibitor etoposide in multiple myeloma cells lines OPM-2, RPMI-S and NCI-H929. Using the median effect method of Chou and Talalay, we evaluated the combination indices (CI) for simultaneous and sequential treatment schedules. In the sequential treatment schedule, we found strong synergistic effects in all three cell lines, even at low single-agent cytotoxicity levels. When cells were treated simultaneously with both drugs, the synergy was present but less pronounced than in the sequential treatment schedule. The synergistic effects observed in the co-treatment schedules were accompanied by an inhibition of anti-apoptotic effects that were induced by etoposide alone. Namely, bortezomib abrogated both etoposide-induced NF-kappaB activation and etoposide-induced bcl-2 up-regulation. Our data suggest that combining etoposide with bortezomib might be useful for cancer treatment, as bortezomib potentially inhibits counter-regulatory mechanisms of tumor cells, which are induced by topoisomerase II inhibition and which may contribute to acquired chemoresistance.
Department of Hematology and Oncology, Charité-Universitaetsmedizin Berlin, 10117 Berlin, Germany.
Ivana
I
von Metzler
Ulrike
U
Heider
Maren
M
Mieth
Britta
B
Lamottke
Martin
M
Kaiser
Christian
C
Jakob
Orhan
O
Sezer
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D059005:Topoisomerase II Inhibitors; D000069286:Bortezomib; D005047:Etoposide; D046988:Proteasome Endopeptidase Complex; D004250:DNA Topoisomerases, Type II