Bendamustine and melphalan kill myeloma cells similarly through reactive oxygen species production and activation of the p53 pathway and do not overcome resistance to each other

Abstract Because the old alkylating drug bendamustine (BDM) is currently under evaluation in patients with multiple myeloma, we compared its efficacy to that of melphalan in 29 human myeloma cell lines (HMCLs). The concentrations of BDM and melphalan that killed 50% of cells (LD50) in HMCLs were lin...

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Bibliographic Details
Published in:Leukemia & lymphoma 2014-09, Vol.55 (9), p.2165-2173
Main Authors: Surget, Sylvanie, Lemieux-Blanchard, Emilie, Maïga, Sophie, Descamps, Géraldine, Le Gouill, Steven, Moreau, Philippe, Amiot, Martine, Pellat-Deceunynck, Catherine
Format: Article
Language:English
Subjects:
bendamustine
Bendamustine Hydrochloride
cell cycle and apoptosis changes
Cell Death - drug effects
Cell Line, Tumor
drug resistance
Drug Resistance, Neoplasm - genetics
Drug Synergism
Humans
melphalan
Melphalan - pharmacology
Multiple Myeloma - genetics
Multiple Myeloma - metabolism
Myeloma
Nitrogen Mustard Compounds - pharmacology
Reactive Oxygen Species - metabolism
Signal Transduction - drug effects
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:Abstract Because the old alkylating drug bendamustine (BDM) is currently under evaluation in patients with multiple myeloma, we compared its efficacy to that of melphalan in 29 human myeloma cell lines (HMCLs). The concentrations of BDM and melphalan that killed 50% of cells (LD50) in HMCLs were linearly correlated (p < 0.001), and reactive oxygen (ROS) scavengers similarly inhibited cell death induced by both drugs. Sensitivity of HMCLs to both drugs was correlated to p53: the BDM and melphalan median LD50 values of TP53wild-type HMCLs were more than two-fold lower than those of TP53abnormal HMCLs (p < 0.001), and p53 silencing in TP53wt NCI-H929 cells inhibited BDM- and melphalan-induced cell death. Both drugs induced expression of p53 targets, p21, Puma and DR5, only in TP53wt HMCLs. In primary cells, both drugs induced an increase in DR5 expression in cells without del(17p). Finally, we demonstrated that the combined effect of BDM and melphalan was additive, and that BDM did not overcome melphalan resistance and vice versa.
ISSN:1042-8194
1029-2403
DOI:10.3109/10428194.2013.871277