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

Since proteasome is strongly considered to be involved in the development and progression of a wide variety of hematological malignancies in particular, multiple myeloma, blockage of this hemostasis system with different types of proteasome inhibitors seems to be a promising way of treatment for multiple myeloma. In this study, we investigated the effect of Kyprolis, a new irreversible proteasome inhibitor (PI), on the survival rate of multiple myeloma -derived KMM-1 cell line.
Material and To evaluate whether inhibition of proteasome using Kyprolis could exert cytotoxic effect in multiple myeloma, KMM-1 cells were cultured with different concentrations (25-150 nM) of the inhibitor for 24 and 48 hours. Then trypan blue exclusion assay, MTT assay, flocytometric cell cycle analysis were performed and we evaluated gene expression changes associated with apoptosis.
The results of this study demonstrated that Kyprolis induced both cytotoxic and anti-proliferative effects on KMM-1 cells. This inhibitor is able to reduce the cell survival and metabolic activity in a dose- and also time-dependent manner (p ≤ 0.001). Moreover, we found that Kyprolis increased cell population in G1 phase of cell cycle to 52.33% probably through up-regulation of p73 gene expression (p ≤ 0.05). Exposing multiple myeloma cells to this proteasome inhibitor also led to induction of apoptosis probably through alterations in the gene expression of pro- and anti-apoptotic related genes (p ≤ 0.05).
The results of this study clearly indicated that Kyprolis had anti-tumor activity against KMM-1 cells.