Apoptotic effect of Kyprolis on multiple myeloma KMM-1 cellsthrough p73-mediated induction of G1 cell cycle arrest

Abstract

Background andAim:Sinceproteasome is strongly considered to be involved in thedevelopment and progression of a wide variety of hematological malignanciesin particular,multiple myeloma, blockage ofthis hemostasis system with different types of proteasomeinhibitorsseems to bea promising way of treatment for multiple myeloma.In this study, weinvestigatedthe effect of Kyprolis, a new irreversible proteasome inhibitor (PI), on thesurvival rate of multiplemyeloma-derived KMM-1 cell line.Material andMethods:To evaluate whether inhibition of proteasome using Kyprolis couldexert cytotoxic effect in multiple myeloma, KMM-1 cells werecultured withdifferentconcentrations (25-150 nM) of the inhibitorfor 24 and48 hours. Then trypan blue exclusionassay, MTT assay, flocytometric cell cycle analysiswere performedandwe evaluated geneexpression changes associated with apoptosis.Results:The resultsof this studydemonstrated that Kyprolisinducedboth cytotoxic and anti-proliferative effectsonKMM-1 cells. This inhibitor is able to reduce the cell survival andmetabolic activity inadose-andalsotime-dependent manner (p≤0.001). Moreover, wefound that Kyprolisincreasedcell populationinG1 phase of cell cycle to 52.33% probablythrough up-regulation of p73 gene expression (p≤0.05). Exposing multiple myeloma cells tothis proteasome inhibitor also ledto induction of apoptosis probably through alterationsin thegene expression of pro-and anti-apoptotic related genes (p≤0.05).Conclusions:The results of this study clearly indicated that Kyprolis had anti-tumor activityagainst KMM-1 cells.

Keywords

• kyprolis
• multiple myeloma
• apoptosis
• proteasome inhibitor
• kmm-1 cell line
• cell cycle